ILAPRN22O • Illinois APRNs Limited Time Offer - 30 Hours/27 Pharm Hours

Table of Contents

ILAPRN22O • Illinois APRNs Limited Time Offer - 30 Hours/27 Pharm Hours

How to Receive Credit

NetCE 10 Hour Course #90844 • Hyperlipidemias and Atherosclerotic Cardiovascular Disease

90844 • Hyperlipidemias and Atherosclerotic Cardiovascular Disease

1. INTRODUCTION AND EPIDEMIOLOGY OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASES

2. ETIOLOGY OF ATHEROSCLEROSIS

3. RISK FACTORS FOR HYPERLIPIDEMIA

4. AN OVERVIEW OF LIPIDS

5. AN OVERVIEW OF LIPOPROTEINS

6. CLASSIFICATION OF HYPERLIPIDEMIAS

7. APPROACHES TO CLINICAL MANAGEMENT OF HYPERLIPIDEMIAS

8. LIFESTYLE MODIFICATION

9. LIPID-LOWERING MEDICATIONS

10. CLINICAL ASSESSMENT OF RISK ASSOCIATED WITH HYPERLIPIDEMIAS

11. CLINICAL GUIDELINES FOR THE TREATMENT OF HYPERLIPIDEMIAS

12. CONCLUSION

13. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #95142 • Optimizing Opioid Safety and Efficacy

95142 • Optimizing Opioid Safety and Efficacy

1. INTRODUCTION

2. DEFINITIONS

3. OPIOID ANALGESIC SAFETY, RISKS, AND BENEFITS: FACTS VERSUS FALLACIES

4. EPIDEMIOLOGY OF PAIN

5. CONSEQUENCES OF UNTREATED OR UNDERTREATED CHRONIC PAIN

6. RISK FACTORS FOR CHRONIC PAIN

7. BARRIERS TO ADEQUATE PAIN CARE

8. THE ENDOGENOUS OPIOID SYSTEM AND OPIOID ANALGESIC MECHANISMS

9. OPIOID ANALGESIC PHARMACOLOGY

10. PHARMACOKINETIC FACTORS IN OPIOID ANALGESIC RESPONSE

11. CDC GUIDELINES FOR OPIOID PRESCRIBING IN CHRONIC PAIN

12. GENERAL RECOMMENDATIONS FOR ANALGESIC PRESCRIBING

13. PATIENT FACTORS AND OPIOID ANALGESIC RESPONSE

14. OPIOID SELECTION, INITIATION, AND MANAGEMENT

15. OPIOID ANALGESIC SIDE EFFECTS AND MANAGEMENT

16. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 5 Hour Course #95074 • Antibiotics Review

95074 • Antibiotics Review

1. INTRODUCTION

2. GENERAL CHARACTERISTICS OF ANTIBIOTICS

3. ANTIBIOTIC RESISTANCE

4. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

5. PENICILLINS

6. CEPHALOSPORINS

7. CARBAPENEMS

8. MONOBACTAMS

9. AMINOGLYCOSIDES

10. MACROLIDES

11. QUINOLONES

12. SULFONAMIDES

13. TETRACYCLINES

14. VANCOMYCIN

15. ANTIMICROBIAL PEPTIDES

16. PLEUROMUTILINS

17. INVESTIGATIONAL ANTIBIOTICS FOR DRUG-RESISTANT MICRO-ORGANISMS

18. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

ILAPRN22O • Illinois APRNs Limited Time Offer - 30 Hours/27 Pharm Hours

A. José Lança, MD, PhD

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

ILAPRN22O • Illinois APRNs Limited Time Offer - 30 Hours/27 Pharm Hours

Expiration Date: 07/31/2025

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

90844 • Hyperlipidemias and Atherosclerotic Cardiovascular Disease

A. José Lança, MD, PhD

www.netce.com

Copyright © 2022 NetCE, All rights reserved.

In the United States, more than 11% of the population 20 years of age and older have abnormally high concentrations of lipids in the plasma. It is well established that hyperlipidemia is associated with increased cardiovascular (CV) morbidity and mortality. Furthermore, it is equally well established that reduction of plasma lipids has a beneficial effect on CV health in individuals potentially at risk and reduces occurrence of new events in patients that have experienced prior CV disease. This course will review pathophysiologic and epidemiologic studies that establish the role of dyslipidemias in the development of vascular pathology. In addition, an updated approach to the pharmacologic mechanism of action of lipid-lowering drugs will be discussed, including the therapeutic benefits of pharmacologic and nonpharmacologic approaches to lipid control. A review of guidelines for the evaluation of risk factors associated with hyperlipidemias will be provided, and current evidence-based guidelines for the therapy of hyperlipidemias will be thoroughly discussed. Finally, the importance of patient education, compliance to therapy, and lifestyle changes will be emphasized.

Table of Contents

90844 • Hyperlipidemias and Atherosclerotic Cardiovascular Disease

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION AND EPIDEMIOLOGY OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASES

2. ETIOLOGY OF ATHEROSCLEROSIS

FATTY STREAK FORMATION

PLAQUE FORMATION

PLAQUE DISRUPTION

3. RISK FACTORS FOR HYPERLIPIDEMIA

4. AN OVERVIEW OF LIPIDS

PHYSIOLOGIC ROLES

ABSORPTION, SYNTHESIS, AND METABOLISM

5. AN OVERVIEW OF LIPOPROTEINS

STRUCTURE AND MOLECULAR COMPONENTS

CLASSES OF LIPOPROTEINS AND LIPOPROTEIN PHYSIOLOGY

6. CLASSIFICATION OF HYPERLIPIDEMIAS

PRIMARY HYPERLIPIDEMIAS

SECONDARY HYPERLIPIDEMIAS

7. APPROACHES TO CLINICAL MANAGEMENT OF HYPERLIPIDEMIAS

8. LIFESTYLE MODIFICATION

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

9. LIPID-LOWERING MEDICATIONS

DRUGS THAT INHIBIT CHOLESTEROL ABSORPTION IN THE INTESTINE

FIBRATES

STATINS

NICOTINIC ACID DERIVATIVES

FISH OIL DERIVATIVES

STEROLS AND STANOLS

ADENOSINE TRIPHOSPHATE-CITRATE LYASE (ACL) INHIBITOR

NOVEL PHARMACOTHERAPIES FOR HYPERLIPIDEMIAS

ROLE OF LIPID-LOWERING DRUGS IN THE PREVENTION OF ASCVD MORBIDITY AND MORTALITY

10. CLINICAL ASSESSMENT OF RISK ASSOCIATED WITH HYPERLIPIDEMIAS

11. CLINICAL GUIDELINES FOR THE TREATMENT OF HYPERLIPIDEMIAS

12. CONCLUSION

13. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

90844 • Hyperlipidemias and Atherosclerotic Cardiovascular Disease

Education Category. Medical / Surgical

Release Date. 08/01/2022

Expiration Date. 07/31/2025

Course Overview

In the United States, more than 11% of the population 20 years of age and older have abnormally high concentrations of lipids in the plasma. It is well established that hyperlipidemia is associated with increased cardiovascular (CV) morbidity and mortality. Furthermore, it is equally well established that reduction of plasma lipids has a beneficial effect on CV health in individuals potentially at risk and reduces occurrence of new events in patients that have experienced prior CV disease. This course will review pathophysiologic and epidemiologic studies that establish the role of dyslipidemias in the development of vascular pathology. In addition, an updated approach to the pharmacologic mechanism of action of lipid-lowering drugs will be discussed, including the therapeutic benefits of pharmacologic and nonpharmacologic approaches to lipid control. A review of guidelines for the evaluation of risk factors associated with hyperlipidemias will be provided, and current evidence-based guidelines for the therapy of hyperlipidemias will be thoroughly discussed. Finally, the importance of patient education, compliance to therapy, and lifestyle changes will be emphasized.

Audience

This course is designed for physicians, physician assistants, nurses, and pharmacy professionals who may intervene to limit the effects of hyperlipidemias in their patients, promoting better long-term health and preventing cardiovascular disease.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 10 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 10 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 10 ANCC contact hour(s). NetCE designates this continuing education activity for 7 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 12 hours for Alabama nurses. NetCE designates this activity for 10 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-22-011-H01-P. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 10 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. This activity has been designated for 10 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 1 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through July 29,2025); Alabama, Provider #ABNP0353, (valid through July 29, 2025); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; South Carolina, Provider #50-2405. West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to provide a review of hyperlipidemia in the pathogenesis of cardiovascular disease, as well as the therapeutic benefits of pharmacologic and nonpharmacologic approaches to treatment. The objectives are to promote team-based care, foster patient awareness and shared provider-patient decision-making, and promote implementation of lifestyle changes and compliance with guideline-directed therapy for prevention of cardiovascular disease.

Learning Objectives

Upon completion of this course, you should be able to:

1. Discuss the incidence of cardiovascular disorders, expected epidemiologic trends, and relevance to society and healthcare systems.

2. Discuss the relevance of hyperlipidemias in the etiology of atherosclerosis and cardiovascular diseases.

3. Identify risk factors for hyperlipidemias.

4. Describe the exogenous and endogenous pathways of lipid synthesis and metabolism.

5. Describe the various types of lipoproteins.

6. Evaluate lipid profiles and identify the most clinically relevant types of hyperlipidemias.

7. Analyze the importance of lifestyle modification in managing hyperlipidemias.

8. Discuss the targeting of specific steps in lipid synthesis and metabolism related to the mechanism of action of drugs that inhibit cholesterol absorption in the intestine.

9. Describe the therapeutic efficacy and indications of fibrates, statins, and nicotinic acid derivatives.

10. Determine the role of fish oil derivatives and sterols and stanols in the management of hyperlipidemias.

11. Identify patients at risk for coronary heart disease and outline the evidence-based guidelines for the treatment of these patients.

Faculty

A. José Lança, MD, PhD, received his Medical Degree at the University of Coimbra in Coimbra, Portugal, and completed his internship at the University Hospital, Coimbra. He received his PhD in Neurosciences from a joint program between the Faculties of Medicine of the University of Coimbra, Portugal, and the University of Toronto, Toronto, Canada. He was a Gulbenkian Foundation Scholar and received a Young Investigator Award by the American Brain & Behavior Research Foundation.
Dr. Lança participated in international courses and conferences on neurosciences. He has contributed to a better understanding of the mechanisms underlying the ontogenetic development of the brain opiatergic system. As a research scientist at the Addiction Research Foundation (ARF) in Toronto, he initiated research on the functional role played by dopaminergic cell transplants on alcohol consumption, leading to the publication of the first research reports on cell transplantation and modulation of an addictive behavior. Subsequently, he also investigated the role played by other neurotransmitter systems in the limbic system and mechanisms of reward, co-expression of classical neurotransmitters and neuropeptides and potential role in neuropsychiatric disorders.
He is an Assistant Professor in the Department of Pharmacology and Toxicology at the Faculty of Medicine and at the Faculty of Dentistry at the University of Toronto, where he lectures and directs several undergraduate and postgraduate pharmacology and clinical pharmacology courses. He was the Program Director for Undergraduate Studies in the Department of Pharmacology and Toxicology of the University of Toronto. He has developed clinical pharmacology courses for the Medical Radiation Sciences and Chiropody Programs of The Michener Institute for Health Sciences at the University of Toronto.
Dr. Lança’s commitment to medical education started while a medical student, teaching in the Department of Histology and Embryology, where he became cross-appointed after graduation. In Toronto, he has contributed extensively to curriculum development and teaching of pharmacology to undergraduate, graduate, and medical students.
He has authored research and continuing education in peer-reviewed publications and is the author of six chapters in pharmacology textbooks. Dr. Lança has conducted research in various areas including neuropharmacology, pharmacology of alcoholism and drug addiction, and herbal medications.
He has developed and taught courses and seminars in continuing medical education and continuing dental education. His commitment to continuing education emphasizes an interdisciplinary approach to clinical pharmacology.

Faculty Disclosure

Contributing faculty, A. José Lança, MD, PhD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John V. Jurica, MD, MPH

Jane C. Norman, RN, MSN, CNE, PhD

Randall L. Allen, PharmD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION AND EPIDEMIOLOGY OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASES

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in developing countries and accounts for 25.7% of all deaths in the United States and 45% of deaths in Europe [1,2]. According to the World Health Organization (WHO), 17.9 million people die each year from cardiovascular disease, an estimated 32% of all deaths worldwide [3]. It has been estimated that by 2030, ASCVD will account for approximately 23 million annual deaths worldwide, an increase of more than 5 million from current estimates [3].

In developed countries, both the prevalence of ASCVD and the rate of mortality have declined. In the United States, from 2006 to 2016, the number of heart-related deaths declined by 18.6%. The prevalence and mortality rates have decreased as the result of risk factor reduction and advances in diagnosis and medical and surgical treatments [1,4,5,6]. Developing countries, however, are continuing to face an increase in ASCVD, which has been partially attributed to an increased prevalence of hypertension, hyperlipidemia, and diabetes, as well as a 75% increase in tobacco consumption between 1991 and 2001 [7]. Tobacco smoking is among the top three risk factors that account for the most disease burden in China and India [8].

In the United States in 2014–2015, the estimated direct and indirect cost of ASCVD was $351.2 billion [1]. This figure is projected to increase to $1.1 trillion by 2035 [1]. As a comparison, the estimated 2011 annual direct cost of all cancer and benign neoplasms combined is $84 billion, versus $213.8 billion for direct costs of ASCVD [1].

The elevated costs of cardiovascular pathology for individuals, society, and healthcare systems require a novel approach based not only on improved diagnosis and management of disease but primarily on more effective prevention and early intervention. This not only requires a change in general perceptions but also a different approach toward prevention by physicians and other healthcare professionals [9,10].

The etiology of ASCVD is complex and multifactorial and influenced by a variety of modifiable (e.g., hyperlipidemia, obesity, hypertension, diabetes, smoking, physical inactivity, diet) and non-modifiable (e.g., family history, age, gender) risk factors. Modifiable risk factors play a fundamental role in primary and secondary prevention of ASCVD and account for up to 90% of population-attributable cardiac risk [11,12].

A high concentration of plasma lipids (i.e., hyperlipidemia), and high concentrations of low-density lipoprotein (LDL) cholesterol in particular, are implicated in the etiology of atherosclerosis and increased incidence of ASCVD such as coronary artery disease, peripheral vascular disease, and ischemic cerebrovascular disease. Hyperlipidemias are also associated with primary hypertension and metabolic syndrome [13,14].

American Heart Association data from 2015 to 2018 show unfavorable lipid measures of LDL cholesterol >130 mg/dL were present in 27.8% of adults 20 years of age and older, and total blood cholesterol concentrations >240 mg/dL (6.2 mmol/L) were present in 11.5% of adults [234]. Both lipid parameters are associated with excess risk of cardiovascular morbidity and mortality [15].

Hyperlipidemia, and specifically hypertriglyceridemia (150–400 mg/dL or 1.7–4.5 mmol/L), is often present in patients with metabolic syndrome, a disorder characterized by abdominal obesity, hypertension, insulin resistance, low levels of high-density lipoprotein (HDL), and increased risk of ASCVD [13]. Hypertriglyceridemia is also associated with pancreatitis, and severe hypertriglyceridemia has been established as the etiology of up to 7% of pancreatitis. Hypertriglyceridemia-induced pancreatitis rarely occurs unless levels exceed 1,700 mg/dL (20 mmol/L) [16].

Effective lipid management has been shown to slow the progression of atherosclerosis and lower morbidity and mortality of ASCVD [17,18,19,20,21,22,23]. As a result, early diagnosis and appropriate clinical management of hyperlipidemias has become a public health priority in the primary and secondary prevention of ASCVD [24]. Guidelines for the management of hyperlipidemias focus not only on the administration of lipid-lowering drugs but also the implementation of lifestyle changes [24]. Together, these interventions assist with patient adherence and improve clinical outcomes [22,23]. This approach requires collaboration among all members of the multidisciplinary team of healthcare providers, including physicians, nurses, pharmacists, dietitians, counselors, and physiotherapists [9,25].

2. ETIOLOGY OF ATHEROSCLEROSIS

Atherosclerosis results from a chronic inflammatory process that targets medium- and large-sized arteries. This process begins in childhood and progresses slowly with age. However, the condition is rapidly accelerated by a variety of genetic and environmental factors, and hyperlipidemia is a major risk factor in the pathogenesis and progression of atherosclerosis [12,14,26,27].

An elevated concentration of LDL is a major cause of atherosclerosis and increased ASCVD [14,17,18,19,20,21,22]. The causative role of hyperlipidemia has been supported by the finding that decreasing the plasma levels of LDL and triglycerides has a beneficial effect on primary and secondary prevention of ASCVD by reversing, to some extent, the underlying pathology of atherosclerosis [23].

Atherosclerotic vascular disease develops in three progressive stages: fatty streak formation, plaque formation, and plaque disruption [12,27,28,29,30,31].

FATTY STREAK FORMATION

Fatty streaks are flat yellow discolorations on the arterial inner (i.e., luminal) surface that neither protrude into the lumen nor disrupt blood flow. The precise mechanisms responsible for the formation of fatty streaks are unclear but endothelial dysfunction is accepted as the primary event in atherogenesis. Physical stressors (e.g., turbulent blood flow at branching points) as well as chemical stressors (e.g., hyperlipidemia, cigarette smoking) alter endothelial cell functions in a complex and interdependent process. This results in:

- Impairment of the role of endothelial cells as a barrier, allowing for the abnormal accumulation of lipids in the sub-endothelial layer and their subsequent transformation (oxidation)

- Release of pro-inflammatory cytokines (e.g., interleukin 1 [IL-1] and tissue necrosis factor-α [TNF-α])

- Release of cell surface adhesion molecules that attract leukocytes (e.g., leukocyte adhesion molecules [LAM], monocyte chemotactic protein 1 [MCP-1], intercellular adhesion molecule 1 [ICAM-1])

- Decreased availability of vasodilator compounds such as nitric oxide and prostacyclin

- Stimulation of prothrombotic effect and platelet aggregation

Together, physical and chemical stressors promote endothelial dysfunction and trigger the initial sub-endothelial accumulation and transformation of oxidized LDL. Initially, oxidized LDL acts as a proinflammatory mediator to attract circulating leukocytes (e.g., monocytes and T-lymphocytes) to the sub-endothelium. Second, dysfunctional endothelial cells and modified smooth muscle cells secrete macrophage-stimulating factors that lead to the expression of scavenger receptors or acetyl-LDL receptors on the surface of macrophages and smooth muscle cells [28]. These scavenger receptors selectively bind to oxidized LDL and promote phagocytosis by macrophages and transformed smooth muscle cells, which become lipid-laden and are known as foam cells. Increased numbers of foam cells and extracellular lipids account for the appearance of fatty streaks [12,27,28,29,31].

PLAQUE FORMATION

As atherogenesis progresses, arterial fatty streaks increase in size as the result of continuing infiltration by smooth muscle cells, which migrate from the underlying muscular layer and accumulate oxidized LDL, and infiltration by T-lymphocytes, which synthesize and release inflammatory cytokines. These changes increase the number of foam cells and exacerbate local inflammation. In time, extracellular accumulation of LDL, collagen, elastic fibers, and calcium deposits contribute to the formation of larger and thicker atherosclerotic vascular plaques. Histology shows that atherosclerotic plaques consist of a large lipid core surrounded by a fibrous cap. After decades of development, the plaque grows in size and exhibits features of a chronic inflammatory process within the vessel wall [28]. The arterial wall undergoes a restructuring process that initially grows outward and preserves the lumen diameter. At this stage, the condition is asymptomatic and goes undetected in angiographic studies. As time progresses, larger plaques start to protrude into the lumen and partially disrupt blood flow. Disruption of laminar blood flow also inhibits the expression of superoxide dismutase, a powerful antioxidant, further contributing to oxidation of LDL. This more advanced stage is associated with symptoms of ischemia and may be detected by angiography [12,27,28,29,31,32].

PLAQUE DISRUPTION

As noted, the lipid core of atherosclerotic plaque is initially surrounded by a thicker fibrous cap that provides some degree of stability. As plaques grow in size, their lipid cores become increasingly larger with high concentrations of foam cells, extracellular calcification, and accumulation of oxidized LDL. Interestingly, it has been shown that oxidized LDL promotes apoptosis (i.e., programmed cell death) and causes foam cell death, which leads to plaque necrosis, instability, and increased potential for thrombogenesis [33,34]. At this stage, plaques further protrude into the lumen and disrupt blood flow. Turbulent blood flow increases shear stress in the periphery of the plaque, known as the shoulder region, further increasing risk of instability, plaque disruption, clot formation, and thrombogenesis. These events are often accompanied by symptoms associated with acute ischemia (e.g., angina, myocardial infarction [MI], intermittent claudication, stroke). Lesions at this stage are able to be detected in angiographic studies and ultrasonography [12,27,28,29,31,32].

3. RISK FACTORS FOR HYPERLIPIDEMIA

As discussed, hyperlipidemia has been established as a main risk factor in the development of atherosclerosis and ASCVD. Together with obesity, hypertension, diabetes, smoking, and physical inactivity, hyperlipidemia is a known modifiable risk factor of ASCVD. Additionally, several biomarkers, including C-reactive protein (CRP), hyperhomocysteinemia, and lipoprotein(a), are also considered modifiable risk factors of ASCVD. Modifiable risk factors play a major role in the pathogenesis of ASCVD because they activate the endothelium and stimulate the release of proinflammatory mediators and cell surface adhesion molecules. Because modifiable risk factors account for up to 90% of population-attributable cardiac risk, regulation of these factors has a beneficial effect on the primary and secondary prevention of ASCVD [11,12].

In addition to modifiable risk factors, the American Heart Association (AHA) and the American College of Cardiology (ACC) have included "risk-enhancing factors" in their 2018 guideline on the management of blood cholesterol (Table 1). Projections of future risk derived from primary risk factors and risk-enhancing factors can be used to adjust the intensity of LDL-lowering therapy and enhance clinician-patient risk discussion [24]. When risk is uncertain, a coronary artery calcium score can help facilitate decision-making in adults 40 years of age and older. The identification of familial hypercholesterolemia is a priority in children, adolescents, and young adults. Across all age groups, the emphasis is on reducing lifetime ASCVD risk through a heart-healthy lifestyle [24].

Table 1: AHA/ACC RISK-ENHANCING FACTORS

- Family history of premature ASCVD (men: age younger than 55 years; women: age younger than 65 years)

- Primary hypercholesterolemia (LDL 160–189 mg/dL; non-HDL 190–219 mg/dLa)

- Metabolic syndrome

- Chronic kidney disease (i.e., eGFR 15–59 mL/min/1.73 m^2 with or without albuminuria, not treated with dialysis or kidney transplantation)

- Chronic inflammatory conditions (e.g., psoriasis, rheumatoid arthritis, HIV/AIDS)

- History of premature menopause (before 40 years of age) and history of pregnancy-associated conditions that increase later ASCVD risk (e.g., pre-eclampsia)

- High-risk race/ethnicity (e.g., South Asian ancestry)

- Persistentlya elevated, primary hypertriglyceridemia (≥175 mg/dL) and/or other lipid/biomarkers associated with increased ASCVD risk, including (if measured):

- Elevated hsCRP (≥2.0 mg/L)

- Elevated Lp(a): a relative indication for its measurement is family history of premature ASCVD. Lp(a) ≥50 mg/dL or ≥125 nmol/L constitutes a risk-enhancing factor, especially at higher levels of Lp(a).

- Elevated Apo B ≥130 mg/dL: a relative indication for its measurement is triglyceride ≥200 mg/dL. A level ≥130 mg/dL corresponds to an LDL >160 mg/dL and constitutes a risk-enhancing factor

- ABI <0.9

aOptimally, three determinations.

ABI = ankle-brachial index; Apo B = Apolipoprotein B; eGFR = estimated glomerular filtration rate; HIV/AIDS = human immunodeficiency virus/acquired immunodeficiency syndrome; hsCRP = high-sensitivity C-reactive protein; Lp(a) = lipoprotein(a).

Source: [24]

Experimental studies in animals with genetic abnormalities identical to human familial hypercholesterolemia (absence or 50% reduction in LDL receptors in homozygous or heterozygous individuals, respectively) as well as epidemiologic studies of human populations have established that high levels of LDL cholesterol are atherogenic [35,36,37]. A number of clinical studies, including the Framingham Heart Study, the Multiple Risk Factor Intervention Trial, and the Lipid Research Clinics, have also reported a direct relationship between elevated concentrations of LDL cholesterol (or total cholesterol) and an increase in cardiovascular morbidity and mortality [1,17,18,19,20,21,23,25,38,39]. Lipid management with a combination of pharmacotherapy and lifestyle changes aimed at the reduction of cholesterol levels effectively slows the progression of atherosclerosis and plays a pivotal role in the primary and secondary prevention of ASCVD [1,17,18,19,20,21,22,23,25,37,39,40,41].

Chronically high levels of CRP, and high sensitivity CRP (hsCRP) in particular, are biomarkers of ASCVD, regardless of whether they play a causal role in atherogenesis or if they are the result of underlying atherosclerosis [12,27,42]. The AHA and the Centers for Disease Control and Prevention have issued a joint statement regarding hsCRP values [43]. Concentrations of hsCRP less than 1 mg/L are associated with low risk, and 1–3 mg/L is correlated with moderate risk for ASCVD. Patients with levels greater than 3 mg/L are at high risk for ASCVD [43]. An hsCRP level >10 mg/L has been observed in acute plaque rupture, which may lead to thrombosis [44]. Ongoing clinical studies suggest that lowering the plasma levels of both hsCRP and LDL may be a main goal in the secondary prevention of ASCVD [42].

High homocysteine blood levels (greater than 15 mcmol/L) are associated with increased oxidative stress and secretion of proinflammatory factors. Both mechanisms stimulate smooth cell proliferation and accelerate atherosclerosis [27,45].

Numerous clinical studies have also revealed that high levels of lipoprotein(a) are associated with significant increases in ASCVD [12,27,31,46,47,48]. Lipoprotein(a) is a subtype of LDL that includes apoprotein A (Apo A) in its structure. The role of lipoprotein(a) in atherogenesis relates to a variety of mechanisms including inhibition of fibrinolysis by preventing the transformation of plasminogen to plasmin, enhanced capacity to traverse the arterial endothelium, and low affinity for the LDL-receptor mediated clearance from circulation [47]. High lipoprotein(a) concentrations (greater than 30 mg/dL) in patients with an elevated total cholesterol:HDL ratio (greater than 5.5) or other major risk factors indicates the need for a more aggressive therapy to further lower LDL [23,49].

4. AN OVERVIEW OF LIPIDS

PHYSIOLOGIC ROLES

Lipids play a crucial role in living organisms as a source of energy and as structural constituents of cell membranes and complex molecules such as steroids and eicosanoids (e.g., prostaglandins, thromboxane A2, leukotrienes) and lipid-soluble vitamins [30,50,51]. In brief, the most important lipids are phospholipids, cholesterol, fatty acids, and triglycerides.

Phospholipids are structural components of cell membranes, myelin, lipoproteins, and blood clotting factors. Cholesterol is a structural component of cell membranes and a precursor of other steroids, namely steroid hormones, bile acids, and signaling molecules. Cholesterol is mainly synthesized in the liver but is also absorbed in the intestine from dietary sources and enterohepatic circulation.

Fatty acids are a source of energy. Their general structure is represented as R-COOH, where R represents a hydrocarbon chain. More than 100 fatty acids have been identified, and they differ on length of the hydrocarbon chain and number of carbon-carbon double bonds. Fatty acids without carbon-carbon double bonds are classified as saturated; those with carbon-carbon double bonds are classified unsaturated. Unsaturated fatty acids are further differentiated into monounsaturated or polyunsaturated based on the number of carbon-carbon double-bonds. Saturated fatty acids are waxy solids at room temperature, while unsaturated fatty acids are liquids.

Intracellular free fatty acids are present in trace amounts and esterified with glycerol to form more complex lipids, including triglycerides. Most double bonds in unsaturated fatty acids are in the cis form. Some edible fats, including hydrogenated vegetable products such as oils, margarines, and shortenings, are rich in trans fatty acids. Trans fatty acids (also known as partially hydrogenated fats) have physical properties similar to saturated fats and are solid at room temperature. They are inexpensive to produce, give foods a desirable texture and taste, have a long shelf-life, and can be reused to deep-fry foods. These properties make trans fats particularly attractive to commercial enterprises and fast-food restaurants. However, their increased dietary intake is associated with increased ASCVD. Awareness of this link has led to the concerted effort to decrease or eliminate their availability and dietary intake. Clear information on trans fats, particularly useful for patients and the general population, is readily available from the American Heart Association (Resources).

Triglycerides are a combination of three fatty acids attached to a single glycerol molecule. They are the main source of dietary fat and can also be synthesized in the liver from intermediary metabolites of excess carbohydrates. Triglycerides accumulate in adipose tissue and muscle cells and can later be mobilized as non-esterified free fatty acids as a source of energy when dietary sources are not readily available.

Cholesterol and triglycerides have significant roles in the process of atherogenesis. They are virtually insoluble in water, and to facilitate their transport in plasma and lymph, they are packaged in larger spherical macromolecules known as lipoproteins.

ABSORPTION, SYNTHESIS, AND METABOLISM

Circulating lipids have two distinct but interrelated origins and metabolic pathways: the exogenous (i.e., dietary source) and the endogenous pathways (i.e., hepatic synthesis) [52].

Exogenous Pathway

Dietary lipids provide 30% to 40% of calories in Western diets. With the exception of the essential fatty acids (e.g., linoleic, linolenic), most lipids can also be synthesized by humans. Triglycerides, specifically, account for more than 95% of dietary lipid intake. Cholesterol from animal sources and small amounts of plant sterols comprise the majority of dietary lipid intake. Free fatty acids, phospholipids, and fat-soluble vitamins account for the remaining lipids from dietary sources [46,50,53].

Dietary fat is digested by enzymes produced in the mouth, stomach, and pancreas. The small intestine is the main site of lipid transformation and absorption. In the small intestine, triglycerides are hydrolyzed by gastric and pancreatic lipases, phospholipids are transformed by phospholipase A2 into lysophospholipids and fatty acids, and cholesterol is hydrolyzed by bile salts and pancreatic hydrolase (also known as cholesterol esterase).

Studies have established that cholesterol absorption in the small intestine is regulated by selective transporters, such as the Niemann-Pick C1 like 1 (NPC1L1). Selective inhibition of NPC1L1 prevents intestinal absorption of dietary cholesterol, a mechanism targeted by ezetimibe, a lipid-lowering drug. In the enterocyte, free cholesterol is esterified to cholesteryl esters by the enzyme acyl-CoA cholesterol acyltransferase isoform 2 (ACAT2) and incorporated into chylomicrons [54].

In a separate pathway, after enzymatic hydrolysis, free fatty acids and monoacylglycerides are transported to the intestinal cells in bile-salt micelles. Micelles deliver the lipid molecules to the enterocyte, and bile salts remain in the lumen, where they are subsequently re-used to form new micelles.

Intracellularly, lipid molecules are re-assembled and packaged in chylomicrons. These are large lipoproteins (75–1,200 nm in diameter) rich in triglycerides and cholesterol but poor in protein content. Chylomicrons are released by exocytosis into the extracellular space, enter the lymphatics, and ultimately reach the bloodstream. Circulating chylomicrons are transformed by lipoprotein lipase, an enzyme expressed in endothelial cells of the capillaries in muscle and adipose tissue, and deliver triglycerides to the muscle (for energy) and adipose tissue (for storage). Chylomicron remnants deliver the cholesterol and the remaining triglycerides to the liver, where cholesterol is used in the synthesis of bile salts and triglycerides and free fatty acids are used in the production of energy by β-oxidation and synthesis of new molecules of cholesterol. The synthesis of cholesterol in hepatocytes is known as the endogenous pathway.

It is relevant to mention that unesterified cholesterol can also be transported back into the intestinal tract by selective transporters, such as the ATP-binding cassette transporters ABCG5 and ABCG8 [55]. A new generation of lipid-lowering drugs that stimulate the ATP-binding cassette transporter is being investigated [56].

Endogenous Pathway

The hepatic pathway is the major source of cholesterol in the body. It is well-established that daily cholesterol synthesis in the liver has a circadian pattern, with lowest levels in the day (30% to 35%) and highest levels at night (65% to 70%). This diurnal rhythm in cholesterol synthesis is regulated by HMG-CoA activity [240]. Selective inhibitors of HMG-CoA reductase, such as statins, effectively prevent the synthesis of cholesterol and are powerful hypolipidemic drugs [31,57].

Newly formed cholesterol molecules can either be transiently stored in the hepatocytes or further transformed either into bile salts, steroids, or "packaged" in lipoproteins. These lipoproteins, which carry cholesterol and triglycerides from the liver into the circulation, are known as very-low density lipoproteins (VLDL) and have a very high content in triglycerides and cholesterol. VLDLs comprise 15% to 20% of the total blood cholesterol and most of the circulating triglycerides [31,52].

In the liver, cholesterol is also eliminated by biliary secretion in the form of bile acids. Bile acids, which are highly soluble in water, are released by the hepatocytes into the biliary canaliculi and then transported to the gallbladder, where they are stored in bile and later released into the lumen of the small intestine. Most bile acid molecules (>95%) are not excreted in the feces, but rather are reabsorbed in the ileum, enter the portal circulation, and are then extracted with high first-pass efficiency by hepatocytes. This process of recycling bile acids between liver and intestine is known as enterohepatic circulation. In fact, recycled cholesterol from bile acids is a major source of cholesterol and represents 75% of the total cholesterol that goes through the intestine; dietary cholesterol, even in patients with rich diets, accounts only for up to 25%.

5. AN OVERVIEW OF LIPOPROTEINS

STRUCTURE AND MOLECULAR COMPONENTS

Triglycerides and cholesterol are non-polar lipids that are virtually insoluble in water. To facilitate their transport in plasma and lymph, they are packaged as lipoproteins. These large spherical macromolecules that transport cholesterol and triglycerides in the plasma vary in size (ranging from 5–1,200 nm in diameter) and density (determined by the ratio of lipid to protein content).

Lipoproteins have a hydrophobic core of non-polar triglycerides and cholesteryl ester (a form of cholesterol linked by an ester bond to a fatty acid) surrounded by a monolayered shell of more water-soluble phospholipids, non-esterified cholesterol, and amphipathic surface proteins known as apoproteins.

Apoproteins (also known as apolipoproteins) are a family of surface proteins that perform three important functions in lipid physiology: stabilize the structure of the lipoprotein shell, activate enzymes in the plasma and endothelial cells, and bind to selective cell receptors [27,30,31,58]. Specific apoproteins regulate the metabolic fate of lipoproteins; their role can be compared to "molecular zip codes" that determine the destination of specific lipoproteins in the body. Each type of lipoprotein contains one or more specific types of apoproteins.

There are four major classes of apoproteins: Apo A, Apo B, Apo C, and Apo E. In terms of clinical relevance, the following lipoproteins are the most important: Apo A-I, Apo A-II, Apo B-100, Apo C, and Apo E [27,31].

CLASSES OF LIPOPROTEINS AND LIPOPROTEIN PHYSIOLOGY

Lipoproteins are classified by size and density. Because proteins are denser than lipids, the greater the protein content, the greater the density of the lipoprotein. There are five types of lipoproteins: chylomicrons, VLDLs, intermediate-density lipoproteins (IDLs), LDLs, and HDLs (Table 2).

Table 2: PLASMA LIPOPROTEINS

Characteristic

Chylomicrons

Very-Low-Density Lipoprotein (VLDL)

Intermediate-Density Lipoprotein (IDL)

Low-Density Lipoprotein (LDL)

High-Density Lipoprotein (HDL)

Density

<0.95 g/mL

0.95–1.006 g/mL

1.006–1.019 g/mL

1.019–1.063 g/mL

1.063–1.210 g/mL

Diameter

75–1,200 nm

30–80 nm

25–35 nm

18–25 nm

5–12 nm

Protein

2%

10%

18%

25%

33%

Total lipid

98%

90%

82%

75%

67%

Triglycerides

83%

50%

31%

10%

8%

Cholesterol

8%

22%

29%

45%

30%

Phospholipid

7%

18%

22%

20%

29%

Major apoproteins

Apo B-48 Apo C-II Apo E

Apo B-100 Apo C-II Apo E

Apo B-100 Apo C-II

Apo B-100

APO A-I APO A-II Apo C-II Apo E

Source: Compiled by Author

Plasma Lipid Profiles

Prior to discussing the properties of the various lipoproteins, it is important to review the most pertinent information related to plasma lipid profiles. In fasting individuals, total cholesterol in plasma is carried primarily in VLDL, LDL, and HDL. Accordingly, total cholesterol is equal to the sum of VLDL, HDL, and LDL.

Clinical laboratories measure total cholesterol, HDL, and triglycerides. Most triglycerides are found in VLDL, which has five times as much triglyceride by weight as cholesterol. Therefore, the amount of cholesterol in VLDL can be calculated as triglycerides (mg/dL) divided by 5 or triglycerides (mmol/dL) divided by 2.2.

For more than 50 years, most clinical laboratories have calculated the value of LDL cholesterol indirectly, according to the Friedewald equation [59,60]:

LDL (mg/dL) = total cholesterol (mg/dL) – HDL (mg/dL) – [triglycerides (mg/dL) / 5]

Or, if the International System of Units is used, total LDL may be calculated as:

LDL (mmol/dL) = total cholesterol (mmol/dL) – HDL (mmol/dL) – [triglycerides (mmol/dL) / 2.2]

A modified Friedewald equation is also used and has been suggested to have a higher level of accuracy in calculating LDL values [61,62]. This equation is:

LDL (mg/dL) = [non-HDL cholesterol (mg/dL) x 0.9] – [triglycerides (mg/dL) x 0.1]

It is known that in hypertriglyceridemia, LDL calculated using the Friedewald equation can be unreliable, particularly at levels <70 mg/dL. The increased prevalence of high triglyceride states (e.g., diabetes, obesity) and the use of novel lipid lowering medications (e.g., proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) have provided an impetus for finding improved methods for estimating LDL.

Direct LDL assays are not standardized and can be even less accurate than the Friedewald equation. In one study of seven direct methods for measuring LDL, total assessment errors ranged from 13.3% to 13.5% across assays in healthy individuals and from -26.6% to 31.9% in individuals with known ASCVD or dyslipidemias. The National Cholesterol Education Program has a target total error goal of ≤13%, meaning that all seven direct assays failed standard accuracy goals [63,64].

Several prior equations have attempted to improve upon the Friedewald equation, but most used the same fixed ratio between triglycerides and VLDL. In a study of more than 1.3 million fasting and nonfasting patients, Martin and colleagues derived and validated a novel equation that replaced the fixed ratio with one of 180 adaptable ratios based on the patient's individual non-HDL and triglyceride values. The overall accuracy of the Martin/Hopkins approach compared with direct measurement was 92% for HDL and 85% for triglycerides. LDL estimation accuracy with the Martin/Hopkins equation was 94%, compared with 77% with the Friedewald method [65]. The 2018 AHA/ACC guideline acknowledges the importance of accurate LDL estimation and recommends measuring LDL either directly or with an alternative method (e.g., the Martin/Hopkins equation) [24,63].

Evidence Based Practice Recommendation

In adults who are 20 years of age or older and not on lipid-lowering therapy, the ACC/AHA assert measurement of either a fasting or a nonfasting plasma lipid profile is effective in estimating ASCVD risk and documenting baseline LDL. If an individual has ingested an extremely high-fat meal in the preceding eight hours, it may be prudent to assess lipids on another day after counseling the patient to avoid such meals.

http://www.onlinejacc.org/content/73/24/e285?_ga=2.118995977.141815126.1563751668-1264536891.1558548868

Last Accessed: July 25, 2022

Level of Evidence: Expert Opinion/Consensus Statement

The ratio of total cholesterol (TC) to HDL (TC:HDL) and the ratio of LDL to HDL (LDL:HDL) are clinically relevant predictors of coronary heart disease (CHD) risk. The lower the ratio value, the better the predicted outcome [66,67,68,69]. The Apo B:Apo A-I lipoprotein ratio has also been used as a predictor for CHD. However, comparative studies have concluded that Apo B:Apo A-I ratio for prediction of CHD "does not provide incremental value for CHD risk prediction over established traditional lipid ratios" [66]. However, the ratio may be useful for evaluating the severity of CHD [70]. A cross-sectional study enrolled 792 patients with angiographically defined CHD following hospital admission. The patients were placed into three groups based on the degree of angiographic atherosclerosis or the number of stenotic coronary branches. Demographic and biochemical data were collected, and lipoprotein ratios were calculated. According to the results, the ratios of LDL:HDL and Apo B:Apo A-I increased with increasing degree of angiographic atherosclerosis, and the ratios of triglyceride:HDL, TC:HDL, LDL:HDL and Apo B:Apo A-I increased with the number of stenotic coronary branches. The ratios of TC:HDL, LDL:HDL, and Apo B:Apo A-I were positively associated with both the degree of atherosclerosis and the number of stenotic vessels, and the ratio of triglyceride:HDL was positively associated with the number of stenotic vessels. The Apo B:Apo A-I ratio was also shown to be a direct mediator between the risk factors of age, BMI, HDL, LDL, and severity of CHD [70].

Chylomicrons

Chylomicrons are large lipoproteins 75–1,200 nm in diameter that are very rich in lipids (98% content), mainly triglycerides (83%) and cholesterol (8%), and have the lowest protein content (2%) of all lipoproteins. Chylomicrons are only synthesized in the intestine and are produced in large amounts during fat ingestion [53]. In normolipidemic individuals they are present in the plasma for 3 to 6 hours after fat ingestion and are absent after 10 to 12 hours fasting [14].

Chylomicrons secreted by intestinal cells are known as "incomplete" chylomicrons because they only express Apo B-48. After entering the lymph and later reaching the bloodstream, chylomicrons interact with circulating HDL, from which they receive Apo C-II and Apo E and then referred to as "complete" chylomicrons. In the capillaries of muscle and adipose tissue, chylomicrons are transformed by the enzyme lipoprotein lipase, a process that requires Apo C-II as a cofactor. As a result of this process, 90% of the triglycerides are hydrolyzed to free fatty acids and glycerol that will be used either as a source of energy in the muscle or stored in the adipose tissue. Individual chylomicrons have a short half-life of 15 to 20 minutes [71]. After interaction with lipoprotein lipase, these cholesterol-rich chylomicron remnants deliver cholesterol and triglycerides to the liver. This process of endocytosis is mediated by a protein, the LDL receptor, expressed on the surface of hepatocytes and requires Apo E and Apo B as cofactors [72].

The concentration of chylomicrons can only be lowered by reducing dietary fat consumption or by drugs that inhibit the intestinal absorption of cholesterol. However, drugs specifically targeting the step of chylomicron secretion have not yet been developed [14]. Although rare, individuals with a genetic deficiency that results in low lipoprotein lipase activity may present with abnormally high concentrations of circulating triglycerides (1,000–5,000 mg/dL) [31].

Very-Low-Density Lipoproteins

VLDLs are smaller than chylomicrons (80 nm in diameter) and have a very high triglyceride and cholesterol content—five times as much triglycerides by weight as cholesterol. As noted, VLDL makes up 15% to 20% of the total blood cholesterol and most of the circulating triglycerides [73].

In the muscle and adipose tissue capillaries, lipoprotein lipase interacts with circulating VLDL, from which it removes triglycerides in a process that requires Apo C-II as a cofactor, as described for chylomicrons. VLDL also expresses Apo E and Apo B-100. Apo B-100 plays a fundamental role in the regulation of circulating cholesterol.

From a metabolic viewpoint, both chylomicrons and VLDL deliver triglycerides to muscle and adipose tissue [30]. However, whereas chylomicrons are an integral part of the exogenous pathway and carry dietary lipids, VLDL transport triglycerides and cholesterol synthesized in the liver as a part of the endogenous pathway. From a clinical perspective, it is particularly relevant to point out that the hepatic synthesis of VLDL is increased when the concentration of free fatty acids in the liver is increased (e.g., in high-fat diets) as well as when adipose tissue releases high amounts of free fatty acids in the circulation (e.g., as a result of obesity or diabetes) [46]. Genetic deficiencies that result in either total (abetalipoproteinemia) or partial liver failure to produce Apo B-100 (familial hypobetalipoproteinemia) inhibit the release of VLDL by hepatocytes and result in fatty liver [74].

Intermediate-Density Lipoproteins

IDLs, also known as VLDL remnants, are created when VLDL is depleted in triglycerides as a result of the hydrolysis by the enzyme lipoprotein lipase. IDLs have a short half-life (less than 30 minutes) and undergo liver absorption by selective uptake mainly by binding to the LDL receptor, with Apo B-100 and Apo E as required cofactors. Genetic variants of Apo E are responsible for low binding to the LDL receptor, which results in high concentrations of circulating VLDL and IDL, a condition clinically known as type III hyperlipoproteinemia [14,75].

Low-Density Lipoproteins

LDLs play a central role in atherogenesis and are often called "bad cholesterol." The discovery of the LDL receptor by Goldstein and Brown and their work elucidating its role in cholesterol homeostasis is one of the most important advances in cardiovascular research. Their studies have been a major contribution to the understanding of the mechanisms underlying hyperlipidemias [72]. The proatherogenic role of LDL on the release of pro-inflammatory cytokines (e.g., IL-1, TNF-α) and adhesion molecules (e.g., LAM, ICAM-1) is well established.

LDLs are the product of VLDL and IDL metabolism by lipoprotein lipase. LDL is the most cholesterol-rich of all lipoproteins, and even in healthy individuals, LDLs carry two-thirds of the circulating cholesterol [14]. LDL has a half-life of 1.5 to 2 days, which accounts for a plasma concentration higher than VLDL and IDL [14,46,53,57].

There are several subtypes, also known as subfractions, of LDL, and it has been proposed that smaller, denser LDL particles are more atherogenic than larger and less dense LDL. However, research suggests that the use of clinically available LDL subfractions to estimate the risk of ASCVD is premature [76,77,78].

Plasma clearance of LDL is primarily mediated by the LDL receptor expressed on the cell surface. Although LDL receptors are expressed in various cell types, approximately 75% of all LDL receptors are expressed in hepatocytes [79]. The uptake of LDL in hepatocytes is mediated by the interaction between the LDL receptor and Apo B-100 (the only apoprotein expressed in LDL), which acts as a ligand at the LDL receptor. This selective and highly effective mechanism accounts for the extraction of approximately 75% of all LDL from plasma [80]. Hepatic LDL receptors are downregulated by the high delivery of cholesterol by chylomicrons or dietary saturated fat and upregulated by decreased cholesterol and saturated fat intake [46,81].

The crucial role of LDL in atherogenesis results from it being oxidized in the arterial subendothelium. Oxidized LDL has a high affinity for the scavenger receptor expressed in macrophages undergoing endocytosis, which leads to intracellular accumulation and the transformation of lipid-rich macrophages into foam cells.

Genetic mutations of either the LDL receptor or Apo B-100 alter the effectiveness of the binding and increase the plasma concentration of LDL. Familial hypercholesterolemia and familial defective Apo B-100 are examples of clinical conditions that result from these genetic mutations [82,83]. Homozygotes for familial hypercholesterolemia inherit two mutant LDL receptor genes and present with a 6- to 10-fold elevation in plasma LDL from birth. These patients suffer from advanced CHD starting in early childhood [72,84].

The expression of LDL receptors in the liver is also regulated by the intracellular enzyme HMG-CoA reductase. Inhibition of HMG-CoA reductase, for example by the administration of statins, not only results in direct inhibition of the intracellular synthesis of cholesterol but indirectly increases the expression of LDL receptors and therefore promotes the LDL-receptor-mediated removal of circulating cholesterol.

The LDL receptor is also relevant from a clinical perspective because both thyroid hormones and estrogens stimulate its expression in the liver [80,85]. Consequently, deficiencies of these hormones decrease the availability of LDL receptors and result in increased concentrations of circulating LDL and increased risk of ASCVD [14,80].

The subtype of lipoprotein(a) is associated with increased risk for ASCVD [12,27,31,46,47]. Lipoprotein(a) has a similar lipid composition to more typical LDL but has a higher protein content [86]. The atherogenic role of lipoprotein(a) relates to its unique molecular properties and results in the inhibition of fibrinolysis, enhanced capacity to traverse the arterial endothelium, and low affinity for the LDL-receptor-mediated clearance from circulation [47]. Lipoprotein(a) also exhibits platelet activating and pro-inflammatory properties that further contribute to atherogenesis [87]. Patients with high levels of lipoprotein(a) (greater than 30 mg/dL) and an elevated total cholesterol:HDL ratio (>5.5) or other major risk factors require a more aggressive therapy to lower LDL [23,49]. Lowering circulating LDL remains the primary goal in the treatment and prevention of atherosclerosis and ASCVD [15,22,24].

High-Density Lipoproteins

HDLs are the smallest (5–12 nm in diameter) but the densest lipoproteins (33% protein content). HDL removes cholesterol from the periphery and transports it to the liver [53]. HDLs are a heterogeneous population classified based on size, density, and apoprotein content. The two most important subclasses of HDL express either Apo A-I alone or both Apo A-I and A-II, but the clinical relevance of the various subtypes is unknown [88].

HDL concentration in the plasma is inversely related to the risk of ASCVD, and for this reason HDL is also known as "good cholesterol." The role played by HDL in the transport of cholesterol from the periphery to the liver, known as reverse cholesterol transport, and subsequent excretion in bile is a very well-understood mechanism through which HDL protects against atherosclerosis [88,89].

Two main factors are involved in cholesterol removal from the periphery. First, a cell membrane protein (ABCA1) promotes the efflux of cholesterol from cell membranes; second, ABCA1 interacts with Apo A-I from HDL and captures cholesterol. Cholesterol, in the form of cholesteryl esters, is subsequently transferred to LDL, which will carry it to the liver. In the liver, hepatic extraction requires binding to the LDL receptor. Genetic mutations that cause loss of function of ABCA1 result in extremely low levels of HDL and cholesterol accumulation in the liver, spleen, tonsils, and central and peripheral nervous systems. This results in early-life coronary and peripheral artery disease, a condition known as Tangier disease or familial alpha-lipoprotein deficiency [90,91].

In vitro and in vivo studies have revealed that HDL has anti-inflammatory and antioxidant properties and inhibits atherogenesis. It has been suggested that high levels of HDL have a protective effect on the development of atherosclerosis and ASCVD [88,92].

However, authors of a systematic review of clinical studies concluded that "simply increasing the amount of circulating HDL does not necessarily confer cardiovascular benefits" and that reduction of LDL should remain "the primary goal for lipid-modifying interventions" [93]. Other researchers concluded that raising endogenous HDL levels in humans to reduce the development of atherosclerosis "has yet to be established conclusively" [88]. Together, these studies further support the recommendation that lowering LDL should remain the target goal for patients with hyperlipidemia and/or at risk for ASCVD-related conditions [22,24].

6. CLASSIFICATION OF HYPERLIPIDEMIAS

Hyperlipidemias, also known as dyslipidemias, are elevations of LDL cholesterol either alone or in conjunction with triglycerides. As noted, they may also be associated with low HDL.

In 2013, the National Heart, Lung, and Blood Institute (NHLBI) discontinued its publication of clinical practice guidelines, instead choosing to provide its systemic evidence reviews to professional organizations, who then publish guidelines based on these and other findings [94]. This change affected five cardiovascular disease-related documents that were in the process of being crafted, including those addressing cholesterol, blood pressure, risk assessment, lifestyle interventions, and obesity. The AHA and the ACC published guidelines intended to update the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) recommendations in 2013, but these guidelines focused primarily on optimal statin use and did not address specific risk factors or lifestyle changes [95].

In the 2013 ACC/AHA update to the NCEP-ATP III, one major change in the treatment recommendations was the removal of specific LDL and non-HDL-cholesterol target values. The NCEP-ATP III guidelines indicated that the target goal for LDL should be <100 mg/dL; however, the Expert Panel determined that there was not sufficient evidence to support treatment to a specific target goal [96,97]. The 2018 AHA/ACC update to the 2013 guideline includes a limited restoration of LDL treatment targets, particularly in higher-risk groups, based on the results of U.S. population studies and randomized controlled trials confirming the general principle that for LDL, "lower is better" [24]. For the purposes of this course, the 2018 AHA/ACC guideline recommendations will be discussed.

Hyperlipidemias are classified by etiology as primary or secondary, or by phenotype according to identification of lipoprotein patterns, as with Fredrickson phenotypic classification (Table 3). In practice, a combination of both classifications is used, as the patient's condition is first identified based on clinical evidence and lipid profile, providing the data required for classification based on etiology [31,46,67,79,98].

Table 3: LIPOPROTEIN PATTERNS OF HYPERLIPIDEMIAS (FREDRICKSON PHENOTYPES)

Phenotype

Elevated Lipoproteins

Elevated Lipids

I

Chylomicrons

Triglycerides

IIa

LDL

Cholesterol

IIb

LDL and VLDL

Triglycerides and cholesterol

III

VLDL and chylomicron remnants

Triglycerides and cholesterol

IV

VLDL

Triglycerides

V

Chylomicrons and VLDL

Triglycerides and cholesterol

Source: [46,98]

Advances in genetics, genomics, and proteomics have contributed to a better understanding of the pathophysiology of numerous diseases and to the development of new and selective therapies. However, their contribution to the study of primary hyperlipidemias is still limited [99]. While gene therapy is being developed to treat some patients with known genetic abnormalities, the genetic profile and molecular basis of primary hypertriglyceridemia has been determined in only 5% to 10% of cases, and the percentage is even lower for secondary hyperlipidemia [100,101,102].

PRIMARY HYPERLIPIDEMIAS

Primary hyperlipidemias result from single or multiple genetic mutations that target any of the molecules that participate in the endogenous and exogenous lipid pathways. These mutations result in increased plasma concentrations of cholesterol (pure or isolated hypercholesterolemia), triglycerides (pure or isolated hypertriglyceridemia), or both (mixed or combined hyperlipidemia) and are the result of either increased synthesis or decreased clearance. HDL concentrations may be lower than normal, either from decreased synthesis or increased clearance.

At the early stages, primary hyperlipidemias are asymptomatic. However, as the disease progresses, a constellation of signs and symptoms develop, such as eruptive xanthomas (located on the trunk, back, buttocks, elbows, knees, hands, and feet), severe hypertriglyceridemia (greater than 2,000 mg/dL), lipemic plasma (i.e., plasma develops a creamy supernatant when incubated overnight), and lipemia retinalis (i.e., creamy white-colored blood vessels in the fundus) often associated with premature CHD or peripheral vascular disease [46,100,103].

Familial hypercholesterolemia and familial defective Apo B-100 are examples of clinical conditions that result from LDL receptor and Apo B-100 deficiencies, respectively [82,83,104]. Other genetic mutations cause familial hypertriglyceridemia, familial combined hyperlipidemia, familial chylomicronemia, and familial dysbetalipoproteinemia [31,46,100,105,106].

Polygenic hypercholesterolemia, also known as nonfamilial hypercholesterolemia, is the most common form of hyperlipidemia, with a prevalence of more than 25% in the American population [106]. Polygenic hypercholesterolemia is a typical example of the combination of multiple genetic deficiencies that result in decreased activity of the LDL receptor and reduction of LDL clearance. This underlying genetic susceptibility, not yet completely understood, becomes apparent with dietary intake of saturated fats, obesity, and sedentary lifestyle. Twenty percent of polygenic hypercholesterolemia patients have a family history of CHD. Patients present with mild-to-high increases in total cholesterol (250–350 mg/dL or 6.5–9.0 mmol/L) and LDL (130–250 mg/dL or 3.33–6.45 mmol/L). A combination of lifestyle changes (e.g., reduction in saturated fat) and lipid-lowering drugs (e.g., statins, bile acid sequestrants, ezetimibe, niacin) effectively control the condition [31,107].

Familial hypercholesterolemia is an autosomal dominant disease responsible for defective LDL receptors that results in either reduction in receptor synthesis or inability of the receptor to bind and/or efficiently remove LDL. The heterozygous form (caused by a single abnormal copy of the gene) has a prevalence of 1 per every 500 in the United States, and the homozygous form (from two abnormal copies) occurs in 1 of every 1 million Americans [107,108]. Patients typically present with tendon xanthomas, premature MI (5% by 30 years of age and 50% by 50 years of age in untreated heterozygotes), elevated total cholesterol (275–500 mg/dL in heterozygotes and 700–1,200 mg/dL in homozygotes), and elevated triglycerides (250–500 mg/dL in heterozygotes and >500 mg/dL in homozygotes) [107,108]. Familial hypercholesterolemia heterozygotes respond to lifestyle changes and drug therapy that combines statins with other drugs that upregulate the LDL receptors, such as bile acid sequestrants, ezetimibe, or niacin. Due to the high risk of CHD and MI in homozygous patients, the clinical management requires early treatment in medical centers specialized in lipid treatment and often requires LDL apheresis (i.e., extracorporeal removal of LDL) and liver transplantation [30,31,46,107,108]. Three drugs have been approved by the U.S. Food and Drug Administration (FDA) for homozygous familial hypercholesterolemia since 2012, a microsomal triglyceride transfer protein inhibitor (lomitapide), an antisense oligonucleotide inhibitor (mipomersen), and an adenosine triphosphate-citrate lyase inhibitor (bempedoic acid). A box warning for risk of hepatotoxicity was added to mipomersen in 2016. Lomitapide and mipomersen inhibit the synthesis of Apo B–100, while bempedoic acid inhibits renal tubular organic anion transporter 2 [109,110,233]. Familial hypertriglyceridemia is a common autosomal dominant disease characterized by high triglycerides (200–500 mg/dL or 2.3–5.7 mmol/L) and normal LDL. Lipid-lowering drugs (e.g., fibrates, niacin, statins) combined with diet and weight loss are the most appropriate therapy [30].

SECONDARY HYPERLIPIDEMIAS

Secondary hyperlipidemias are associated with primary underlying conditions such as obesity (increased triglycerides and decreased HDL), diabetes (increased triglycerides and increased total cholesterol), alcohol abuse (increased triglycerides and increased HDL), chronic renal insufficiency (increased total cholesterol and increased triglycerides), and hypothyroidism (increased total cholesterol). It has been postulated that these events expose an underlying genetic or metabolic deficiency that increases the individual's susceptibility to develop hyperlipidemia [31,100].

Along with polygenic hypercholesterolemia, atherogenic dyslipidemia is one of the most common forms of hyperlipidemias. Atherogenic dyslipidemia is found in approximately 25% of patients with dyslipidemias and is usually diagnosed in patients with metabolic syndrome. In atherogenic dyslipidemia patients there is increased mobilization of triglycerides and cholesterol from adipose tissue to the circulation. This results in increased concentrations of triglycerides and VLDL rich in Apo C-III. Apo C-III inhibits lipoprotein lipase and prevents extraction of triglycerides from VLDL. Moderate-to-high increases in triglycerides (150–500 mg/L or 1.69–5.65 mmol/dL) result from high fat intake and mobilization from adipose tissue and VLDL secretion by the liver. These patients are treated with lifestyle changes aimed at weight reduction and increasing physical activity (which stimulates lipoprotein lipase activity). Statins (to lower VLDL) and fibrates (to lower triglycerides) are the most appropriate drugs to complement lifestyle changes [31,111]. Studies support the use of antioxidants as well as newer fibrates in the treatment of atherogenic dyslipidemia based on their agonism at the peroxisome proliferator-activated receptor α (PPAR-α) [112,113].

Secondary hyperlipidemias can also be associated with a number of drug-induced conditions such as estrogen therapy (increased triglycerides and increased total cholesterol), atypical antipsychotics (increased triglycerides), corticosteroids (increased total cholesterol), selective α-blockers without intrinsic sympathetic activity or α-antagonism (increased total cholesterol and decreased HDL), and thiazides (modest increase in total cholesterol and LDL) [67,114].

In summary, secondary hyperlipidemias with elevated triglycerides are the primary lipid abnormality in patients with obesity, diabetes, alcohol abuse, hormone replacement therapy, and atypical antipsychotic therapy. Secondary hyperlipidemias with elevated cholesterol are the main dyslipidemia in patients with chronic renal failure, hypothyroidism, and typical β-blocker use (e.g., propranolol, atenolol).

From a clinical perspective, identifying the lipid profile, classifying the hyperlipidemia, and managing comorbidity are each necessary in order for patients to achieve lower cholesterol and triglyceride levels required to reduce ASCVD risk [22,25,46,100,105].

7. APPROACHES TO CLINICAL MANAGEMENT OF HYPERLIPIDEMIAS

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force (USPSTF) recommends that adults without a history of cardiovascular disease (CVD) use a low- to moderate-dose statin for the prevention of cardiovascular events and mortality when all of the following criteria are met:

- They are 40 to 75 years of age.

- They have one or more CVD risk factors.

- They have a calculated 10-year risk of a cardiovascular event of 10% or greater.

https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/statin-use-in-adults-preventive-medication

Last Accessed: July 25, 2022

Strength of Recommendation/Level of Evidence: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

Management of existing hyperlipidemia is a cornerstone in the prevention and management of ASCVD. In large randomized controlled trials, LDL lowering has been consistently shown to reduce the risk of ASCVD. However, in clinical practice, absolute responses in LDL levels to statin therapy depend on baseline LDL levels and the intensity of lipid-lowering therapy. Furthermore, it is important to bear in mind that as cardiovascular risk increases, so does the absolute benefit of therapeutic interventions proven to lower LDL cholesterol levels; both the absolute risk and the magnitude of LDL cholesterol level reduction achieved are important [235]. A given dose of statins produces a similar percentage reduction in LDL levels across a broad range of baseline levels; therefore, percentage reduction is a more reliable indicator of statin efficacy. The 2018 AHA/ACC guideline uses percentage reduction to estimate the efficacy of statin therapy, with the primary goal being a ≥50% reduction in LDL levels [24].

Hypertriglyceridemia is associated with an increased risk of ASCVD events and acute pancreatitis, and lowering triglyceride levels in high-risk patients (e.g., those with ASCVD or diabetes) is associated with decreased cardiovascular morbidity and mortality. The management of mixed dyslipidemia remains controversial, so treatment should focus primarily on lowering LDL levels [105].

Baseline levels are used to estimate risk of ASCVD, guide treatment decisions, and accurately evaluate response to therapy. It is important to note that baseline cholesterol levels may vary by geography and among ethnic minority populations. For example, cholesterol values are about 20% higher in the Western population than in the Asian population [67]. The 2018 AHA/ACC guideline provides recommendations for the accurate measurement of baseline LDL levels (Table 4) [24,63].

Table 4: AHA/ACC RECOMMENDATIONS FOR ASSESSMENT OF BASELINE LEVELS OF LDL AND NON-HDL

In adults 20 years of age or older not on lipid-lowering therapy, measurement of either a fasting or a nonfasting plasmaa lipid profile is effective in estimating ASCVD risk and documenting baseline LDL (Class I, based on moderate-quality evidence).

In adults 20 years of age or older in whom an initial nonfasting lipid profile reveals a triglyceride level of ≥400 mg dL (≥4.5 mmol/L), perform a repeat lipid profile in the fasting state for assessment of fasting triglyceride levels and baseline LDL (Class I, based on moderate-quality evidence).

For patients with an LDL level <70 mg/dL (<1.8 mmol/L), measurement of direct LDL or modified LDL estimate is reasonable to improve accuracy over the Friedewald formula (Class IIa, based on limited data).

In adults 20 years of age or older without a personal history of ASCVD but with a family history of premature ASCVD or genetic hyperlipidemia, measurement of a fasting plasma lipid profile is reasonable as part of an initial evaluation to aid in the understanding and identification of familial lipid disorders (Class IIa, based on limited data).

aBoth fasting and nonfasting total cholesterol and HDL levels appear to have similar prognostic value and associations with ASCVD outcomes. Therefore, nonfasting samples can be used for risk assessment in primary prevention and for assessment of baseline LDL levels prior to initiation of a statin. If more precision is necessary, fasting lipids can be measured, but a nonfasting sample is reasonable for most situations.

Source: [24]

8. LIFESTYLE MODIFICATION

Evidence Based Practice Recommendation

The ACC/AHA recommend a diet emphasizing intake of vegetables, fruits, legumes, nuts, whole grains, and fish decrease ASCVD risk factors.

http://www.onlinejacc.org/content/73/24/e285?_ga=2.118995977.141815126.1563751668-1264536891.1558548868

Last Accessed: July 25, 2022

Level of Evidence: I (Strong)

Management of hyperlipidemia is but one component of a general strategy for reducing the risk of ASCVD. It is important that healthcare professionals have a good understanding of other measures required for effective risk reduction, including lifestyle changes that may facilitate lipid management before there is need of pharmacotherapy. The 2019 AHA/ACC Guideline on the Primary Prevention of Cardiovascular Disease presents recommendations related to lifestyle modification (e.g., diet and physical activity), patient comorbidities (e.g., obesity, diabetes, hypertension), and patient-centered approaches (e.g., team-based care, shared decision-making, assessment of social determinants of health) to management [236]. The recommendations for management of hyperlipidemia in the AHA/ACC 2018 Cholesterol Clinical Practice Guidelines have been included in the 2019 AHA/ACC guideline.

Modifiable lifestyle factors for cardiovascular disease risk reduction include diet, weight reduction, physical activity (exercise), and smoking cessation [24,236]. The 2018 AHA/ACC guideline on management of blood cholesterol and 2019 guideline on primary prevention of cardiovascular disease concur on the recommendations for good nutrition, diet, and exercise [24,236]. All adults should consume a healthy diet that [236]:

- Emphasizes the intake of fruits, vegetables, nuts, and whole grains

- Includes low-fat dairy products, poultry, fish, legumes, and nontropical vegetable oils

- Limits the intake of sweets, sugar-sweetened beverages, refined carbohydrates, red meat, and processed meats

- Replaces saturated fat (no more than 5% to 6% of calories from saturated fat) with dietary monounsaturated and polyunsaturated fats

- Avoids the intake of trans fat

It is important to adapt the dietary pattern to the patient's calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions, including diabetes. For adults with obesity, counseling and caloric restriction are recommended for achieving and maintaining weight reduction [236]. A successful dietary approach to lipid lowering requires instruction by a dietitian or other knowledgeable healthcare professional.

Instructions to patients should not be presented as a list of "foods to avoid" but rather should provide dietary alternatives and teach the patients how to make appropriate dietary choices and control portions. A balanced diet, particularly in the modality known as the Mediterranean diet, is associated with a significant reduction in cardiovascular events and mortality [116,117,118]. The Mediterranean diet is characterized by meals predominately consisting of vegetables/fruits, lean protein, and healthy fats (e.g., olive oil) and the moderate consumption of wine. Plans such as those offered by the USDA's Dietary Guidelines for Americans, the AHA Diet and Lifestyle Recommendations, and the DASH Eating Plan can also help the patient achieve recommended lifestyle changes [119,120,121].

Physical activity stimulates the activity of lipoprotein lipase in adults as well as in children, lowers triglycerides and VLDL, and promotes cardiovascular fitness and weight loss [31,122]. Adults should engage in 150 minutes per week of accumulated moderate-intensity or 75 minutes per week of vigorous-intensity aerobic physical activity to reduce ASCVD risk [236]. An example of moderate exercise is brisk walking; examples of vigorous exercise are swimming, biking, and playing tennis. Combining moderate and vigorous physical activity allows for a proportionate reduction in time allotted to exercise each week.

Although dietary changes should always be included in the treatment of hyperlipidemias, the length of time given to lifestyle changes prior to initiation of pharmacotherapy remains controversial. In patients with low cardiovascular risk, it has been proposed that the efficacy of dietary and other lifestyle changes can be assessed in two to three visits over a two- to three-month period. Drug therapy is recommended only in select patients with moderately-high LDL (≥160 mg/dL) or patients with very-high LDL (190 mg/dL). High-intensity or maximal statin therapy plus ezetimibe and/or a PCKS9 inhibitor is recommended for the patient at very-high risk (i.e., history of multiple major ASCVD events) [24].

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

Because patient education is such a vital aspect of encouraging lifestyle changes in patients with elevated lipid levels, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between clients/patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter.

9. LIPID-LOWERING MEDICATIONS

Prior to discussing specific therapeutic indications of lipid-lowering drugs in the treatment of hyperlipidemias, it is timely to summarize their relevant mechanisms of action and therapeutic properties. The subsequent sections provide updated information regarding the pharmacologic properties and clinical profile of lipid-lowering drugs and uses the pharmacologic resources and therapeutic guidelines recommended in North America, as well as current drug information [25,30,31,46,57,105,100,123,124,125,126,127,128].

DRUGS THAT INHIBIT CHOLESTEROL ABSORPTION IN THE INTESTINE

Bile Acid-Binding Resins

Mechanism of Action and Clinical Pharmacology

Evidence Based Practice Recommendation

Under certain circumstances, the ACC/AHA assert that nonstatin medications (i.e., ezetimibe, bile acid sequestrants, and PCSK9 inhibitors) may be useful in combination with statin therapy.

http://www.onlinejacc.org/content/73/24/e285?_ga=2.118995977.141815126.1563751668-1264536891.1558548868

Last Accessed: July 25, 2022

Level of Evidence: Expert Opinion/Consensus Statement

Bile acid-binding resins, also known as bile acid sequestrants, are cationic polymers that bind to the negatively charged bile acids in the lumen of the intestine. The bile-acid complex cannot be absorbed by the intestinal mucosa and is subsequently eliminated in the feces [129]. Bile acids are the source of 75% of cholesterol in the intestine, and inhibition of their reabsorption effectively disrupts chylomicron formation and decreases the availability of cholesterol and triglycerides in the liver.

These events upregulate 7α-hydroxylase, also known as cytochrome P450 7A1 (CYP7A1), the enzyme responsible for the synthesis of bile acid in the liver. This increases the conversion of cholesterol to bile acid synthesis in hepatocytes. Consequently, the intracellular recruitment of cholesterol to bile acid synthesis both depletes its intracellular storage and upregulates the expression of LDL receptors to remove circulating cholesterol. Ultimately, the therapeutic benefit of these drugs is to lower circulating LDL by 10% to 24% [30].

The LDL-lowering benefit of bile acid-binding resins is offset in the long term by the upregulation of cholesterol and triglyceride synthesis and a possible increase in VLDL synthesis. Accordingly, these drugs should be used cautiously in patients with hypertriglyceridemia.

Bile acid-binding resins lower the incidence of coronary events in middle-aged men by about 20%, with no significant effect on total mortality [67]. Overall, bile acid-binding resins have a solid safety record, have been shown to lower LDL by 10% to 24%, and help reduce the risk of CHD [30,31,130,131]. Colesevelam, the newest drug in this class, lowers glycated hemoglobin and fasting plasma glucose and is approved as add-on therapy for glycemic control in select patients with type 2 diabetes [109,132].

Adverse Effects

Bile acid-binding resins have very low potential to cause systemic adverse effects because they are not absorbed systemically. However, some patients may report gastrointestinal symptoms, including constipation (10%), dyspepsia, and bloating (1% to 8%) [109,133].

Drug Interactions

The bile acid-binding resins cholestyramine, colestipol, and to a lesser extent colesevelam inhibit intestinal absorption of a variety of lipophilic drugs. This includes fat-soluble vitamins (A, D, E, and K), corticosteroids, estrogens, progestins, thyroid and thyroxine preparations, and negatively charged (i.e., acidic) compounds such as warfarin, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, valproic acid, folic acid, furosemide and thiazide diuretics, digitalis glycosides, tetracyclines, propranolol, and the oral antidiabetic drugs glipizide, troglitazone, and glyburide. These drug interactions increase intestinal elimination of the drug-resin complexes, resulting in decreased absorption, drug bioavailability, and therapeutic efficacy.

Cholesterol Absorption Inhibitors

Mechanism of Action and Clinical Pharmacology

Cholesterol absorption inhibitors block the intestinal absorption of cholesterol of dietary and biliary origin as well as plant sterols. Plant sterols (also known as phytosterols) and ezetimibe block the absorption of cholesterol in the intestine through two different mechanisms of action. Phytosterols are more hydrophobic than cholesterol and displace the latter from micelles, promoting its intestinal elimination. The absorption of sterols and cholesterol across cells of the intestinal lumen requires the participation of the molecular transporter NPC1L1. Sterol binding to the NPC1L1 transporter further inhibits cholesterol absorption. Sterols are available from plant sources, dietary fiber supplements, and plant sterol-enriched margarines. If absorbed in the intestine, sterols' action against cholesterol is compromised.

Ezetimibe selectively targets and inhibits the transporter NPC1L1, preventing the uptake of cholesterol and phytosterol across the intestinal lumen. Inhibition of cholesterol absorption increases the expression of hepatic LDL receptors and enhances clearance of LDL from the circulation. Ezetimibe is indicated as adjunctive therapy to diet for the reduction of total cholesterol, LDL, and Apo B in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia [109,133]. It lowers LDL by 15% to 20% and causes minimal increases in HDL, but its beneficial effect on prevention of CHD remains unclear. This agent is synergistic with statins and, if taken in conjunction, can lower LDL by up to 25% in addition to the results obtained by statins alone [109,134]. Ezetimibe is available in a combination formulation with the statin simvastatin under the brand name Vytorin. A second combination formulation combining ezetimibe with the statin atorvastatin, brand name Liptruzet, received FDA approval in 2013. However, Liptruzet was recalled in 2014 for packaging issues and discontinued in 2016 [109,133,135,136].

Ezetimibe reduces cholesterol absorption by approximately 50%. However, quite unlike the bile acid-binding resins, it does not prevent the absorption of triglycerides or fat-soluble vitamins, and the effects of ezetimibe in the prevention of CHD have not yet been clearly established [30,46,67,137,138].

Adverse Effects

Upper respiratory tract infection (4%), sinusitis (3%), diarrhea (4%), arthralgia (3%), and pain in an extremity (4%) are the most commonly reported adverse events associated with these medications [109].

Drug Interactions

Ezetimibe interacts with cyclosporine, cholestyramine, and fibrates. The combination of ezetimibe with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases, as well as in pregnant and nursing women [109,133].

FIBRATES

Mechanism of Action and Clinical Pharmacology

Fibrates, also known as fibric acid derivatives, are agonists at the PPAR-α. These nuclear receptors are expressed primarily in hepatocytes and muscle cells, and their stimulation by fibrates results in activation of specific genes and subsequent changes in lipid metabolism. The lipid-lowering properties of fibrates result from multiple mechanisms of action, namely activation of lipoprotein lipase, which lowers triglycerides and VLDL; inhibition of Apo C-III synthesis in the liver, preventing the inhibitory action of Apo C-III on lipoprotein lipase activity; and stimulation of Apo A-I and Apo A-II expression, which increases HDL levels [139].

The removal of triglycerides from chylomicrons alters the size and composition of LDL from small, dense particles (which are thought to be more atherogenic due to their susceptibility to oxidation) to large, buoyant, and less atherogenic particles that have a greater affinity for LDL receptors and are rapidly cleared from the plasma. The fibrates fenofibrate, gemfibrozil, and bezafibrate decrease triglyceride levels by 20% to 50%, increase HDL 10% to 20%, and lower LDL by about 5% to 15%, although the latter result is quite variable [109].

Fibrates are indicated in the treatment of hypertriglyceridemias and dysbetalipoproteinemia and in individuals with moderately elevated triglyceride levels (150–400 mg/dL or 1.7–4.5 mmol/L), a sign often associated with metabolic syndrome. Fibrates are also indicated in the prevention of pancreatitis in patients with severely high triglyceride levels (greater than 1,000 mg/dL or 11.3 mmol/L) [109].

Fibrates are one of the most prescribed lipid-lowering drugs, second only to statins, and it is clinically relevant that they have been shown to reduce fatal and non-fatal ASCVD by about 20%, although their effect on LDL, as mentioned previously, is limited and variable.

Adverse Effects

Fibrates are usually well tolerated. Gastrointestinal side effects such as diarrhea, nausea, dyspepsia, and abdominal pain, are reported by 5% of patients. Even less common adverse effects include skin rash, myalgias, headache, and impotence [109].

Drug Interactions

Myositis occurs in up to 5% of patients taking a fibrate who are also being treated with statins. When combined with statins, fenofibrate is the preferred drug because it has less risk of rhabdomyolysis compared with gemfibrozil [140].

Fibrates potentiate the effects of oral anticoagulants (e.g., warfarin), as they compete for their binding sites to albumin. Fibrates also increase cholesterol excretion into the bile, leading to a risk of cholelithiasis. In patients with suspected cholelithiasis, diagnostic studies should be conducted; if gallstones are found, fibrate therapy should be discontinued [109].

STATINS

Mechanism of Action and Clinical Pharmacology

HMG-CoA reductase inhibitors, usually known as statins, are the most effective and the most prescribed class of lipid-lowering drugs. Statins selectively inhibit HMG-CoA reductase, the enzyme responsible for the conversion of HMG-CoA to mevalonate, the rate-limiting step in cholesterol synthesis in the liver [109]. Inhibition of HMG-CoA reductase leads to increased expression of the hepatic LDL receptor and increased clearance of LDL from the circulation [235]. Statins are the primary pharmacotherapeutic agents used to lower LDL cholesterol levels.

The first statin to be tested and approved for clinical use, lovastatin, was isolated from the mold Aspergillus terreus, and pravastatin and simvastatin are chemically modified derivatives of the original molecule. Atorvastatin, fluvastatin, and rosuvastatin are synthetic compounds with distinct molecular structures. Lovastatin, pravastatin, and simvastatin are inactive prodrugs that require hydroxylation in the liver into their active forms. Although all statins are clinically very effective, rosuvastatin, atorvastatin, and simvastatin have the highest drug efficacy in this class (Table 5).

Table 5: STATIN DOSES REQUIRED TO REDUCE LDL TO BASELINE GOAL

Agent

Percent Reduction in LDL Necessary to Reach Goal

20% to 25%

26% to 30%

31% to 35%

36% to 40%

41% to 50%

51% to 55%

Rosuvastatin

—

—

—

5 mg

10 mg

20–40 mg

Atorvastatin

—

—

10 mg

20 mg

40 mg

80 mg

Simvastatin

—

10 mg

20 mg

40 mg

80 mga

—

Lovastatin

—

20 mg

40 mg

80 mg

—

—

Pravastatin

10 mg

20 mg

40 mg

80 mg

—

—

Fluvastatin

20 mg

40 mg

80 mg

—

—

—

Pitavastatin

—

1–4 mg

—

—

—

—

aIncreasing to 80 mg is not routinely recommended. Reserve for patients who have been taking this dose for more than 12 consecutive months without evidence of myopathy.

Source: [14,24,109,141]

The selective inhibition of hepatic HMG-CoA reductase initiates a cascade of events that results in decreased synthesis of cholesterol; decreased liver release of VLDL; and activation of the transcription factor SREBP2, which upregulates the LDL receptor and consequently increases the clearance of plasma LDL. As 60% to 70% of serum cholesterol is synthesized in the liver by HMG-CoA reductase, inhibition of this enzyme drastically lowers circulating LDL [142].

In addition to the lipid-lowering actions of statins, studies suggest that the drugs are also implicated in a number of additional actions known as pleiotropic effects. This includes modulation of endothelial function, decrease in vascular inflammation, neuroprotection, and immunomodulation by inhibition of major histocompatibility complex II expression, which is upregulated in patients with myocarditis, multiple sclerosis, and rheumatoid arthritis [143,144,145]. Statins have been linked to a reduction in the risk of developing Alzheimer disease independent of the drugs' lipophilicity [145,146].

As stated, the percentage reduction in LDL levels is used to estimate the efficacy of statin therapy, with the primary goal being a ≥50% reduction [24]. In clinical practice, absolute responses in LDL levels to statin therapy depend on baseline levels and the intensity (i.e., low, moderate, or high) of lipid-lowering therapy [24].

In addition to efficacy, therapeutic goals, and patient preferences, the clinical choice of a statin also considers cost and drug safety. Lovastatin, simvastatin, and pravastatin have all been shown to be safe in clinical trials involving thousands of subjects for five or more years. This should be particularly taken into account when treating younger patients.

The combination of statins with other lipid-lowering drugs further improves the lipid-lowering outcome. The combination of simvastatin with ezetimibe lowers LDL by an additional 18% to 20% compared with simvastatin alone [147]. Administration of a statin with a bile acid-binding resin (e.g., cholestyramine, colestipol) produces 20% to 30% greater reductions in LDL than statins alone [148,149].

Statins are well absorbed through the gastrointestinal system and are metabolized in the liver by cytochrome P450. Metabolites are eliminated through the bile and excreted in the feces and, to a much lesser extent, by the kidneys. These drugs should not be used in patients with active liver disease and should be used cautiously at lower doses in patients with kidney disease [109].

Statins are effective in the prevention of ASCVD [67,150,151]. In a 2009 review and meta-analysis, these drugs are referred to as "the most important advance in stroke prevention since the introduction of aspirin and antihypertensive treatments" [152]. Analysis of the risk-benefit ratio of statins after one year of treatment reveals that an estimated 1,587 cases of fatal and non-fatal cases of ASCVD were prevented against 3.4 cases of rhabdomyolysis [140,153,154]. Randomized controlled trials across differing risk categories of patients have shown that statins confer significant relative risk reductions in cardiovascular events and all-cause mortality [235].

Adverse Effects

Dizziness (7%), diarrhea (4.5%), nausea/vomiting (3%), and abdominal cramps (3%) are among the most frequently reported adverse effects. Statins are contraindicated during pregnancy and lactation [128].

Statins are associated with hepatotoxicity and elevated transaminases in 1% to 2% of patients [128]. However, in 2014, the FDA concluded that the rate of liver injury associated with statin use is rare enough that routine liver enzyme screening while using statins is not needed. It is recommended that liver enzyme tests be performed before statin use begins and then only if there are symptoms of liver damage, including extreme fatigue, loss of appetite, right upper abdominal discomfort, dark urine, or jaundice [155,156].

The FDA has also noted a small increase in the risk for type 2 diabetes while taking statins. It is noted that there may be a need to assess blood sugar levels after beginning statin use, especially in those with other risk factors [156].

The incidence of myopathy, characterized by muscle pain, weakness, and grossly elevated creatine kinase levels (>10 times the upper limit of normal), with the use of a statin alone is reported in 0.1% to 0.2% of patients [128]. Yet, studies have indicated that the occurrence of statin-induced myopathy may be much higher than originally reported, as high as 10% to 15% of patients treated with statins [140,157].

A deficiency in coenzyme Q10 (CoQ10), a product of the HMG-CoA reductase pathway selectively inhibited by statins, has been proposed as a possible mechanism of statin-related myotoxicity. Although CoQ10 serum levels are below normal in patients taking statins, there is no direct correlation between myotoxicity and CoQ10 levels in muscle cells. Furthermore, studies of supplementation with CoQ10 to prevent myopathy in patients taking statins have not found conclusive evidence of effectiveness [140,158,159,160]. Alternatively, other studies have shown that the inhibition of HMG-CoA reductase by statins inhibits mitochondrial function, increases intracellular calcium, and activates apoptosis (i.e., programmed cell death) [161]. This latter mechanism is being further investigated and may play a crucial role in the development of lipid-lowering drugs with an even higher safety profile [140].

The occurrence of rhabdomyolysis, defined as skeletal muscle necrosis with release of potentially toxic muscle cell components into the general circulation, has been rarely reported. Possible complications of rhabdomyolysis include myoglobinuric acute renal failure, disseminated intravascular coagulation, hyperkalemia, and cardiac arrest.

The risk of myopathy or rhabdomyolysis increases with higher statin plasma levels, which can be the result of higher doses, decreased hepatic clearance, or drug interactions [109,156,162].

The AHA/ACC recommend that a clinician-patient risk discussion be conducted prior to the initiation of statin therapy to review and weigh the risk reduction benefit against the potential for adverse effects, drug-drug interactions, and safety. Patients with statin-associated muscle symptoms should be evaluated for nonstatin causes and predisposing factors. When a statin is indicated, identify predisposing factors for statin-associated side effects (e.g., new-onset diabetes mellitus, muscle symptoms) prior to initiating statin therapy (Table 6) [24].

Table 6: AHA/ACC RECOMMENDATIONS FOR STATIN SAFETY AND MANAGEMENT OF STATIN-ASSOCIATED SIDE EFFECTS

In patients with nonsevere statin-associated side effects, reassess and rechallenge to achieve maximal LDL lowering by modified dosing regimen, alternate statin, or in combination with nonstatin therapy (Class I, based on moderate-quality evidence).

In patients with increased diabetes risk or new-onset diabetes, continue statin therapy with added emphasis on adherence, net clinical benefit, and core principles of healthy lifestyle (Class I, based on moderate-quality evidence).

In patients treated with statins, measure creatine kinase levels in individuals with severe SAMS and objective muscle weakness. Measure liver transaminases as well as total bilirubin and alkaline phosphatase (hepatic panel) if symptoms suggest hepatotoxicity (Class I, based on limited data).

In patients at increased ASCVD risk with chronic, stable liver disease (including non-alcoholic fatty liver disease), when appropriately indicated, it is reasonable to use statins after obtaining baseline measurements and determining a schedule of monitoring and safety checks (Class I, based on moderate-quality evidence).

In patients at increased ASCVD risk with severe SAMS or recurrent SAMS despite appropriate statin rechallenge, it is reasonable to use randomized controlled trial-proven nonstatin therapy that is likely to provide net clinical benefit (Class IIa, based on moderate-quality evidence).

SAMS = statin-associated muscle symptoms.

Source: [24]

Drug Interactions

Statins have pharmacokinetic interactions with drugs that inhibit their metabolism and increase their bioavailability, such as CYP3A4 inhibitors (e.g., azole antifungals, erythromycin, protease inhibitors, amiodarone, grapefruit) and CYP2C9 inhibitors (e.g., NSAIDs, phenytoin, warfarin), as well as drugs that potentiate statins' therapeutic and adverse effects (e.g., fibrates, niacin). These interactions increase statin toxicity [67,128,163]. Interaction between statins and fibrates, particularly with gemfibrozil, increases the risk of rhabdomyolysis. For this reason, fenofibrate is preferred when the two classes are combined [140].

Clinical Outcome

Evidence Based Practice Recommendation

The more LDL is reduced on statin therapy, the greater will be subsequent risk reduction. Therefore, the ACC/AHA recommend patients with clinical ASCVD be treated with a maximally tolerated statin to lower LDL levels by ≥50%.

https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000677

Last Accessed: July 25, 2022

Level of Evidence: I (Strong)

Statins, the most potent lipid-lowering drugs, are indicated in a variety of clinical conditions and are effective in the prevention of ASCVD and stroke. They lower LDL in a dose-dependent manner by 20% to 55% and are accepted as the drug of choice in the treatment of elevated LDL. They are also effective in the treatment of hypertriglyceridemias when levels are greater than 250 mg/dL, although fibrates remain the drug of choice for hypertriglyceridemias. When elevation of HDL is required, niacin remains the drug of choice, although co-administration of statins and niacin may be considered in patients who also have an elevated LDL. Co-administration of statins and niacin, fibrates, or ezetimibe increases the lipid-lowering benefit but also increases the risk for adverse effects. Furthermore, randomized controlled trials do not support the use of fibrates and niacin as add-on drugs to statin therapy. However, if a fibrate is necessary in a patient being treated with a statin, it is safer to use fenofibrate than gemfibrozil due to lower risk of severe myopathy [24]. These patients should be carefully monitored.

In patients taking statins who develop myopathy and creatine kinase levels 10 or more times higher than normal, immediate discontinuation of the drug is recommended. Dietary therapy and lifestyle changes should be implemented and other lipid-lowering drugs, such as niacin, fibrates, and bile-acid sequestrants, should be considered. The National Lipid Association Muscle Expert Panel guidelines recommend considering the re-introduction of low doses of statins in conjunction with ezetimibe in cases in which the lipid-lowering benefit of statins outweighs the risk of myopathy [140,164].

NICOTINIC ACID DERIVATIVES

Mechanism of Action and Clinical Pharmacology

Niacin, also known as nicotinic acid or vitamin B3, is a water-soluble vitamin that at physiologic levels is a substrate for nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), important cofactors in intermediary metabolism. Niacin is available in normal- or extended-release formulation as well as in conjunction with lovastatin (as Advicor).

The lipid-lowering and vasodilatory effects of niacin are not related to its vitamin properties. The discovery that the vasodilatory properties of niacin result from its binding to a G protein-coupled receptor (GPR109A) expressed in blood vessels has allowed for better understanding of the mechanisms underlying its metabolic and vascular effects [165]. In addition, further evidence suggests that the lipid-lowering effects result from niacin binding to another G protein-coupled receptor on adipocytes that inhibits lipoprotein lipase and prevents triglyceride release from chylomicrons. The vasodilatory effect of niacin, on the other hand, involves the release of vasodilatory prostaglandins D2 and E2 [30].

It is relevant to emphasize that niacinamide, a nicotinic acid derivative usually preferred as a vitamin supplement, has neither lipid-lowering nor vasodilatory properties [30,166]. The lipid-lowering effects of niacin require a dose of 1,500–3,000 mg/day, whereas the recommended vitamin dose is 50 mg/day.

Niacin has low cost, a long history of clinical trials, and extensive use as a safe lipid-lowering drug, supported by evidence that it is effective in the prevention of ASCVD [31]. However, it is no longer recommended, except in specific clinical situations, such as a patient with triglyceride levels >500 mg/dL, a patient who is not able to achieve desired response, or a patient with intolerance to other therapies [109]. Although niacin has a mild LDL-lowering action, randomized controlled trials do not support its use as an add-on to statin therapy, and it is not listed as an LDL-lowering drug option in the 2018 AHA/ACC guideline [24]. Niacin has not been shown to reduce ASCVD outcomes beyond that achieved with statin use, and it may be associated with harm [167,168,169].

FISH OIL DERIVATIVES

Mechanism of Action and Clinical Pharmacology

A 1975 study conducted by Danish scientists showed that the composition of plasma lipids (e.g., cholesterol esters, triglycerides, phospholipids) varied considerably in the Inuit population of Greenland when compared both to the European Danish and to Inuit living in Denmark [170]. Interestingly, epidemiologic studies showed that Inuit living in Greenland following a traditional diet rich in fat had a lower mortality from ASCVD than Inuit living in Denmark who followed a Western diet. This puzzling observation is known as the "Eskimo paradox" [171]. It is now well established that, although individual genetic background plays an important role in the development of ASCVD, the answer is the type of dietary fat consumed. Greenland Inuit consume a traditional diet rich in omega-3 fatty acids from fish and fish-eating mammals (seal and whale) rather than a diet poor in omega-3 sources such as the traditional Western diet [172].

Omega-3 polyunsaturated fatty acids are considered essential fatty acids because humans, as well as other mammals, are unable to synthesize these compounds efficiently. Eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) are omega-3 polyunsaturated fatty acids derived from alpha-linolenic acid (ALA). Although humans are able to transform negligible amounts of ALA into EPA and DHA (<1%), dietary supplementation is the only physiologically relevant source [173]. Omega-3 fatty acids EPA and DHA are abundant in fatty fish, such as salmon, mackerel, sardines, trout, and herring, and other seafood sources, as well as in walnuts and canola, flaxseed, and linseed oils. Vegetable oils such as soybean, corn, sunflower, safflower, and cotton seed oils are good dietary sources of omega-6 fatty acids, which will be discussed in detail later in this course [57,174,175,176].

Although the mechanism of action of omega-3 fatty acids is not yet completely understood, both preclinical and clinical studies provide solid evidence that EPA and DHA both reduce the synthesis and secretion of VLDL and increase triglyceride removal from VLDL and chylomicrons through the upregulation of lipoprotein lipase [177]. The distinct mechanisms of action of omega-3 fatty acids differ from other lipid-lowering drugs, which helps to explain why they have complementary lipid benefits when administered with statins [173]. Omega-3 fatty acids also have well established antiarrhythmic, antihypertensive, anti-atherogenic, and antithrombotic properties [173,178,179,180,181,182,183].

Omega-3 fatty acids are effective in primary and secondary prevention of CHD, reduce the risk of sudden cardiovascular mortality by 45%, and provide a 20% relative risk reduction in overall mortality [175,180,184,185,186,187,188]. EPA and DHA omega-3 fatty acids lower triglycerides by 20% to 50% and were approved by the FDA in 2004 as adjunct to the diet for the treatment of very high triglyceride levels (≥500 mg/dL or 5.65 mmol/L) [189]. The effects on LDL seem to vary among studies from moderate dose-dependent increases to decreases in LDL. A moderate increase in HDL (5% to 10%) is more consistently reported [173,190,191]. As a result, omega-3 fatty acids are used in the treatment of hypertriglyceridemias, either alone or in conjunction with other lipid-lowering drugs.

Omega-3 fatty acids are readily available as dietary supplements in the United States. It is important to note that dietary supplements are not FDA-required to demonstrate safety and efficacy prior to marketing, whereas prescription products are. Dietary supplements generally contain lower levels of EPA and DHA than prescription products, are not approved or intended to treat disease, and may have levels of EPA and DHA that vary widely within and between brands. Supplements should not be substituted for prescription products, as they may also contain unwanted cholesterol or fats or potentially harmful components, including toxins and oxidized fatty acids [192].

Omega-3 fatty acids also are readily available in the United States as prescription medications. One prescription medication is comprised of 900 mg of ethyl esters of omega-3 fatty acids, a combination of EPA (approximately 500 mg) and DHA (approximately 400 mg) [189]. A second available medication consists of 1,000 mg omega-3 in free fatty acid form, which is intended to improve the bioavailability [193]. This drug contains approximately 500–600 mg EPA, 150–250 mg DHA, and 150–350 mg other omega-3 fatty acids. Drug labeling dosage information indicates a dose of 4 g/day, taken as a single 4-g dose (four capsules) or as two 2-g doses (two capsules twice daily) [189]. In one study, a minimum dose of 500 mg per day of combined EPA/DHA was recommended for individuals without underlying overt ASCVD, and 800-1,000 mg/day was recommended for individuals with CHD and heart failure [194]. A 2009 review validated the beneficial effects of EPA/DHA alone or in conjunction with fibrates in the reduction of triglycerides. It also further corroborated the safety profile of omega-3 polyunsaturated fatty acids [195]. In 2019, the FDA approved icosapent ethyl, a prescription omega-3 fatty acid, as an adjunctive therapy (to maximally tolerated statin therapy) to reduce the risk of cardiovascular events in adults with elevated triglyceride levels (≥150 mg/dL), cardiovascular disease and/or diabetes, and at least two additional risk factors [232].

The omega-3 fatty acids EPA and DHA are safe and cost effective and are indicated as an adjunct to diet in patients with hypertriglyceridemias [109,189]. They may be considered for triglyceride levels >1,000 mg/dL and may be used alone or in conjunction with HMG-CoA reductase inhibitors [109]. Omega-3 fatty acids are effective in the prevention of ASCVD. Their effect on cardiovascular morbidity and mortality has not been determined [189].

Adverse Effects

Omega-3 fatty acids are remarkably well tolerated. Minor gastrointestinal symptoms (e.g., fishy aftertaste, eructation, diarrhea) may be observed in a dose-related manner [189]. Clinical trials have concluded that omega-3 fatty acids do not have adverse effects on plasma glucose levels, bleeding, levels of muscle or liver enzymes, or kidney or nerve function.

Contaminants such as methylmercury, polychlorinated biphenyls, and dioxins may be concentrated in certain species of fish, such as shark, swordfish, king mackerel, and golden snapper. The FDA and the Environmental Protection Agency have issued a statement advising women who are or may become pregnant, breastfeeding mothers, and young children to avoid eating some types of fish and to eat fish and shellfish that are lower in mercury [196]. However, the levels of contaminants in omega-3 fatty acids, either as generic supplements or in the ethyl ester formulation, are well below acceptable levels of toxicity due to extensive purification processes. In April 2009, the FDA posted a warning regarding the ethyl ester formulations of omega-3 fatty acids reporting anaphylactic or severe allergic reactions (i.e., rash, hives, itching, difficulty breathing, tightness in the chest, swelling of the mouth, face, lips, or tongue) and hemorrhagic diathesis [197].

Drug Interactions

Due to their antiplatelet effect, omega-3 fatty acids may increase bleeding time in a dose-dependent manner [109,189]. However, no cases have been reported, even when administered at high doses alone or in combination with anticoagulant medications. In patients receiving anticoagulant medication, it has been recommended that bleeding times be monitored during the first three to six months, the time normally required for omega-3 fatty acids to reach their maximum clinical effect.

STEROLS AND STANOLS

Mechanism of Action and Clinical Pharmacology

Plant sterols and stanols, also known as phytosterols, are bioactive compounds structurally and physiologically similar to cholesterol. Sterols are present naturally in small quantities in many fruits, vegetables, nuts, seeds, cereals, legumes, vegetable oils, and other plant sources, and stanols occur in even smaller quantities in many of the same sources [57,173,174,175,176,198,199].

Omega-6 polyunsaturated fatty acids such as gamma-linoleic acid (GLA) are derived from linoleic acid. Omega-9 polyunsaturated fatty acids, unlike omega-3 and omega-6, are non-essential because they can be synthesized in humans. The most relevant omega-9 fatty acid is oleic acid, which is present in olive oil, and supplementation is not required.

The lipid-lowering properties of omega-6 polyunsaturated fatty acids, and linoleic acid in particular, are related to their ability to alter various steps of the intestinal absorption of cholesterol. Specifically, they downregulate the intestinal expression of the cholesterol transporter NPC1L1, compete with cholesterol for binding to NPC1L1, lower the cholesterol esterification rate by ACAT2, decrease the amount of cholesterol secreted via the chylomicrons, and upregulate the expression of ATP-binding cassette-transporters ABCG5 and ABCG8 in intestinal cells, which may result in an increased excretion of cholesterol by the enterocyte back into the lumen [199].

The beneficial role played by omega-6 polyunsaturated fatty acids in the prevention of CHD results from their transformation into anti-inflammatory and vasodilatory eicosanoids, such as prostacyclin and lipoxin A4. Some studies, however, have recommended dietary reductions in omega-6 intake, based on the potential risk of increased transformation of omega-6 into pro-inflammatory, vasoconstrictive, pro-platelet aggregation eicosanoids, such as prostaglandin E2, thromboxane A2, and leukotriene B4. An advisory of the AHA has concluded that [200]:

Aggregate data from randomized trials, case-control and cohort studies, and long-term animal feeding experiments indicate that the consumption of at least 5% to 10% of energy from omega-6 polyunsaturated fatty acids reduces the risk of CHD relative to lower intakes. The data also suggest that higher intakes appear to be safe and may be even more beneficial (as part of a low-saturated-fat, low-cholesterol diet). In summary, the AHA supports an omega-6 polyunsaturated fatty acid intake of at least 5% to 10% of energy in the context of other AHA lifestyle and dietary recommendations. To reduce omega-6 polyunsaturated fatty acid intakes from their current levels would be more likely to increase than to decrease risk for CHD.

Adverse Effects

No serious side effects have been reported with omega-6 fatty acids. Some minor gastrointestinal effects may resemble those described for the omega-3 polyunsaturated fatty acids. Plant sterols and stanols lower plasma levels of beta-carotene by 25% and vitamin E by 8% [201].

Drug Interactions

Bile acid sequestrants and additives and drugs that impair the absorption of fat and soluble nutrients, such as olestra and orlistat, have the potential to significantly impair absorption of omega-3, 6, and 9 polyunsaturated fatty acids.

ADENOSINE TRIPHOSPHATE-CITRATE LYASE (ACL) INHIBITOR

Mechanism of Action and Clinical Pharmacology

As noted, in 2020, the FDA approved bempedoic acid for the treatment of Heterozygous familial hypercholesterolemia or established ASCVD [233]. Bempedoic acid is the first in the class of adenosine triphosphate-citrate lyase (ACL) inhibitors. By inhibiting ACL, a hepatic enzyme involved in the synthesis of cholesterol, bempedoic acid decreases the conversion of mitochondrial-derived citrate to cytosolic ACL, creating less substrate for cholesterol and fatty acid synthesis. This ultimately decreases liver cholesterol synthesis and decreases serum LDL-C levels by upregulating LDL receptors [239].

Bempedoic acid is available as monotherapy and in a tablet with ezetimibe as combination therapy. It is an option to modify statin therapy or for patients who cannot tolerate statins. This combination has been demonstrated in clinical trials to lower LDL-C levels by 36% and, when given as monotherapy, bempedoic acid and ezetimibe have been respectively shown to lower LDL-C levels by 15% to 23% and by 13% to 20%, respectively [239]. The usual dose is 180 mg bempedoic acid and, if used, 10 mg ezetimibe once daily.

Adverse Effects

Potential adverse effects associated with bempedoic acid include leukopenia, thrombocythemia, upper respiratory tract infection, and, most commonly, hyperuricemia and gout. Gout and hyperuricemia are more common at higher doses and related to inhibition of tubular OAT2, which may increase blood uric acid levels [109]. It usually develops within the first four weeks of treatment initiation and persists until cessation of administration.

Rupture or injury of tendon has rarely (<1%) occurred, typically involving the rotator cuff, biceps tendon, or Achilles tendon [109]. Risk factors include age older than 60 years, concomitant use of corticosteroids or fluoroquinolones, kidney failure, and prior tendon disorders.

Drug Interactions

Bempedoic acid can increase the serum concentration of certain drugs metabolized by the liver, including elagolix, voxilaprevir, and asunaprevir and should be avoided in patients taking these medications [109]. It may also increase the serum levels of the statins simvastatin and lovastatin. If bempedoic acid is coadministered with these agents, the dose should be limited to no more than 20 mg daily for simvastatin or 40 mg daily for lovastatin [109,239].

NOVEL PHARMACOTHERAPIES FOR HYPERLIPIDEMIAS

The discovery of lipid-lowering drugs has been a major contribution to the clinical management of hyperlipidemias and the prevention of ASCVD. However, the incidence of lipid disorders and resultant cardiovascular pathology continues to increase worldwide.

Existing available therapies are generally effective. Statins are the most prescribed lipid-lowering drugs because of their therapeutic efficacy and beneficial effects on the prevention of ASCVD, although the potential for the occurrence of serious adverse effects in a small number of patients requires monitoring. Other therapies, including bile acid-binding resins, ezetimibe, fibrates, niacin, and omega-3 polyunsaturated fatty acids, either alone or co-administered with other lipid-lowering drugs, including statins, can further lower LDL and triglycerides or raise HDL. However, patients with severe hypercholesterolemia or those intolerant to statins may not attain the recommended targets with available regimens. In fact, it is estimated that 10% of patients are not able or cannot tolerate available therapies to achieve recommended LDL goals [140]. So, continued research for globally effective pharmacotherapy is underway.

Advances in pharmacologic research have provided new molecular insights on lipid metabolism, and translational knowledge is being applied to the development of novel therapies including squalene synthase inhibitors (e.g., lapaquistat), new generation cholesterol absorption inhibitors, ATP-binding cassette transporter activators/cholesterol excretion stimulators, a new generation of nicotinic acid analogs, microsomal triglyceride transfer protein inhibitors, antisense oligonucleotides against Apo B-100 (e.g., mipomersen), and PCSK9, a serine protease synthesized in the liver, being investigated for its regulatory effect on LDL receptors [56,202,203,204,205,206].

Squalene synthase modulates the first committed step of hepatic cholesterol biosynthesis. Its inhibition results in a reduction in cholesterol synthesis in the liver and upregulation of the LDL receptor. Inhibition of squalene synthase activity occurs downstream from HMG-CoA reductase inhibited by statins. Theoretically, squalene synthase inhibitors reduce LDL cholesterol without causing the myopathy side effect seen with upstream inhibition of HMG-CoA. As of 2013, only one synthase inhibitor, lapaquistat (TAK-475), has undergone extensive development in clinical trials as a monotherapy; however, two cases of severe liver enzyme elevations among more than 5100 study participants exposed to the drug resulted in termination of the development program [207,208].

New-generation cholesterol absorption inhibitors (e.g., AVE5530) share some mechanistic properties with ezetimibe, a NPC1L1 transporter inhibitor. However, rather than being partially absorbed in the intestine, they remain in the lumen where they can exert their pharmacologic actions more effectively than ezetimibe. As a result, these agents can inhibit cholesterol absorption for up to 24 hours [209]. These drugs have been subjected to clinical trials. To date, four trials have been terminated and one completed, with results not yet available [210].

The process of cholesterol being transported back into the intestinal tract by selective transporters, such as the ATP-binding cassette transporters, has also been a target for potential treatments [55]. A new generation of drugs that is able to stimulate the ATP-binding cassette transporter and promote cholesterol elimination by enterocytes is being investigated [56].

The discovery of a G protein-coupled receptor for nicotinic acid has provided new insights on its lipid-lowering properties. This has raised the possibility of developing selective agonists that will not share its flush-inducing side effects [165,203].

Microsomal triglyceride transfer protein catalyzes the assembly of cholesterol, triglycerides, and Apo B-100. Microsomal triglyceride transfer protein inhibitors (e.g., AEGR-733, lomitapide) inhibit intestinal assembly of chylomicrons and hepatic synthesis of VLDL, consequently lowering LDL. Initial clinical results showed a dose-dependent reduction of LDL by 19% to 30% when administered alone, or by 46% when administered in combination with ezetimibe [211]. Research is ongoing [212,213].

Antisense oligonucleotides (e.g., mipomersen) are single-stranded DNA that bind to matching mRNA and induce its selective degradation. Pre-clinical studies and small clinical trials have shown a 30% to 50% reduction in LDL with the use of these agents. Increases in transaminases and injection site reactions have been observed, and larger clinical trials are being conducted [210,214].

Downregulation of the LDL receptor by PCSK9 is one regulatory mechanism that controls plasma LDL cholesterol concentrations. Studies have demonstrated that the PCSK9 enzyme binds to the hepatic LDL receptor and promotes its degradation, which in turn decreases LDL uptake and increases plasma LDL cholesterol levels. However, PCSK9 may have much broader roles than initially thought. For example, when human PCSK9 is injected into LDL receptor-deficient mice, it is still rapidly cleared by the liver, suggesting that it is physiologically also cleared by receptors other than the LDL receptor [215,216,217,218].

PCSK9 inhibitors are monoclonal antibodies that inactivate the PCSK9 enzyme and promote clearance of LDL from the circulation. Administration of PCSK9 inhibitors can reduce serum LDL cholesterol by 60% [235]. In 2015, the FDA approved two PCSK9 inhibitors, alirocumab and evolocumab, to be used in conjunction with diet and statin therapy to reduce LDL cholesterol. To date, clinical trials of PCSK9 inhibitor therapy as an adjunct to statins have been conducted for secondary prevention of ASCVD in high-risk patients [235]. The demonstrated benefit is modest, the cost relatively high, and the long-term safety not yet well-established.

ROLE OF LIPID-LOWERING DRUGS IN THE PREVENTION OF ASCVD MORBIDITY AND MORTALITY

As discussed, the clinical approach to hyperlipidemias is aimed at the primary and secondary prevention of ASCVD. As the evidence has shown, it is clear that lipid-lowering strategies play a fundamental role in the primary prevention of ASCVD. Primary prevention is defined as the long-term management of individuals at increased risk for but without clinical evidence of ASCVD and who have not undergone revascularization procedures [220]. Secondary prevention is defined as the clinical management of individuals with a history of ASCVD.

Primary prevention of hyperlipidemias aims to avert new onset CHD and is considered an important aspect of the societal approach to the promotion of cardiovascular health [25]. The goal of primary prevention is to assess and reduce risk factors for CHD in each age group and to emphasize adherence to a healthy lifestyle. This is achieved through two complementary approaches: population strategies and clinical "individual" strategies [24]. Population (public health) strategies shift the distribution of risk factors of the target population to more desirable levels. For example, the 2018 AHA/ACC guideline emphasizes promotion of a heart-healthy lifestyle that improves cardiovascular health and prevents dyslipidemia and other ASCVD risk factors for all age groups. Successful implementation of these recommendations on a population level requires the multidisciplinary team of healthcare providers to help bridge the gap between public health and patient management by supporting and advocating for continued public health initiatives and by encouraging a collaborative effort among healthcare professionals, government agencies, schools, the food industry, and the media [25].

Healthcare delivery is complex, and barriers to guideline implementation can occur at both the public and individual level (Table 7) [24].

Table 7: AHA/ACC RECOMMENDATIONS TO IMPROVE ADHERENCE TO GUIDELINE IMPLEMENTATION

Provide interventions focused on improving adherence to therapy (e.g., telephone reminders, calendar reminders, integrated multidisciplinary educational activities, pharmacist-led interventions) (Class I, based on high-quality evidence).

Identify patients not receiving guideline-directed medical therapy, and facilitate initiation of appropriate guideline-directed medical therapy using multifaceted strategies to improve guideline implementation (Class I, based on moderate-quality evidence).

Conduct patient-clinician discussion prior to therapy to promote shared decision-making (Class I, based on moderate-quality evidence).

Source: [24]

The effectiveness of primary prevention on the cholesterol levels of aging patients has been validated by the slower rate of increase in cholesterol levels associated with aging in patients for whom primary prevention strategies have been implemented [23,25,221]. Attaining lower LDL and triglyceride plasma concentrations can be achieved by a combination of lifestyle changes and drug therapy. As stated, the 2018 AHA/ACC guideline continues to emphasize the adoption of a heart-healthy lifestyle from adolescence onward, as this reduces ASCVD risk at all ages. In all age groups, lifestyle therapy is the primary intervention for metabolic syndrome [24].

Secondary prevention should be initiated in patients with clinical ASCVD. A meta-analysis of randomized controlled trials conducted by the Cholesterol Treatment Trialists demonstrated that lowering LDL with statins reduces major ASCVD events and also benefits patients with stroke or peripheral artery disease [222,223]. Compared with moderate-intensity statin therapy, high-intensity statin therapy significantly reduced major vascular events by 15% with no significant reduction in coronary deaths. High-intensity statin therapy generally reduces LDL levels by ≥50%. However, as stated, absolute benefit depends on baseline levels [24]. Lifestyle changes provide only moderate improvement of the lipid profile in patients with previous ASCVD, so although they should be implemented, pharmacotherapy is required to attain therapeutic goals [23,24].

The complexity of health status in patients with a history of ASCVD requires an approach of multifactorial risk reduction. Multifactorial risk reduction has a synergistic effect on disease progression and clinical outcomes and should be associated with a case management approach [23,224,225]. Case management allows for collaborative and effective expert evaluation, systematic intervention, and regular follow-up. Management should focus not only on the appropriate drug choices but also on patient education and counseling [23,24,225,226].

10. CLINICAL ASSESSMENT OF RISK ASSOCIATED WITH HYPERLIPIDEMIAS

The Framingham Heart Study took the lead in creating risk-prediction equations, and previous guidelines made use of the Framingham risk score algorithm. However, the 2013 Work Group for the guideline on assessment of cardiovascular risk decided against using the Framingham algorithm due to its use of an exclusively white sample population and the limited scope of the outcome (i.e., to determine CHD alone) [227]. Instead, the Group compiled data from five community-based cohorts that were broadly representative of the U.S. population. The final pooled cohorts included participants from several large, racially and geographically diverse, NHLBI-sponsored studies. The Group validated pooled cohort equations that provided sex- and race-specific estimates of 10-year risk of first, hard ASCVD event (i.e., MI and stroke, fatal and nonfatal) for African-American and white men and women 40 to 79 years of age (Table 8). Variables included in the risk equation were age, total cholesterol, HDL, systolic blood pressure, diabetes, and current smoking status [227].

Table 8: DISTRIBUTION OF ESTIMATED 10-YEAR RISK OF FIRST HARD ASCVD EVENT IN ASCVD-FREE NONPREGNANT U.S. POPULATION, 40 TO 79 YEARS OF AGE, BY SEX AND RACE/ETHNICITYa

Population

Predicted 10-Year Risk of ASCVD Event

<2.5%

2.5% to 4.9%

5.0% to 7.4%

7.5% to 9.9%

10.0% to 14.9%

15.0% to 19.9%

≥20.0%

Total

33.4%

21.0%

12.7%

7.4%

8.9%

6.3%

10.2%

All Races/Ethnicities

Men

17.4%

22.7%

15.6%

10.1%

12.1%

8.8%

13.3%

Women

48.0%

19.5%

10.0%

5.0%

5.9%

4.1%

7.5%

White Race/Ethnicity

Men

18.0%

22.4%

15.7%

10.0%

11.7%

8.7%

13.6%

Women

47.1%

20.4%

10.7%

5.1%

5.5%

4.1%

7.1%

African American Race/Ethnicity

Men

1.4%

23.9%

20.6%

11.8%

17.4%

11.1%

13.8%

Women

36.5%

18.7%

10.9%

6.5%

9.4%

5.7%

12.3%

Hispanic Race/Ethnicity

Men

24.0%

22.1%

13.2%

10.6%

11.4%

6.2%

12.6%

Women

59.4%

14.5%

7.5%

4.5%

4.9%

3.0%

6.3%

Other Race/Ethnicities

Men

20.8%

27.1%

11.6%

7.2%

11.5%

12.3%

9.4%

Women

59.8%

18.6%

4.4%

1.7%

6.4%

2.4%

6.7%

aData derived by applying pooled cohort equations to National Health and Nutrition Examination Surveys, 2007–2010.

Source: [227]

Data from the Women's Health Initiative initially appeared to indicate that the pooled cohort equations overestimated the risk of ASCVD, but when event surveillance was improved by data from Centers for Medicare and Medicaid Services, it was found that the equations discriminated risk well [228]. However, because the algorithms may over- or underestimate risk for individual patients, the 2013 AHA/ACC guideline on assessment of cardiovascular risk additionally introduced the clinician-patient risk discussion to facilitate decisions about appropriate therapy. This risk discussion is an integral part of the decision-making process in the 2018 AHA/ACC guideline on the management of blood cholesterol [24,227].

As stated, the pooled cohort equations estimate risk of hard ASCVD events among patients 40 to 79 years of age who are without pre-existing disease. Because pooled cohort equations are population equations, the estimates and recommendations for therapy should be considered in the context of the patient's individual circumstances. Patients are considered to be at elevated risk if the pooled cohort equations estimate is ≥7.5% [24].

The 2018 and 2019 AHA/ACC guidelines concur with the recommendation that clinical management should be based on calculation of the patient's 10-year estimated risk of ASCVD, as this will influence the intensity of management, whether it be lifestyle modification, drug therapy, or both [24,236]. In children, adolescents, and young adults, priority should be estimation of lifetime risk and promotion of lifestyle risk reduction [24]. The ACC ASCVD risk assessment tool is available (http://tools.acc.org/ASCVD-Risk-Estimator-Plus) to estimate the risk of ASCVD within 10 years. The risk calculator is intended for use in patients 40 to 75 years of age who do not have diabetes and whose LDL cholesterol is 70–189 mg/dL [235].

The AHA/ACC recommends that for adults 40 to 70 years of age, clinicians routinely assess traditional risk factors and calculate the estimated 10-year risk of ASCVD [24,236]. For adults 20 to 39 years of age, clinicians should assess (monitor) ASCVD risk factor status every three to six years. For adults at borderline risk (5% to <7.5% 10-year ASCVD risk) or intermediate risk (7.5% to <20% 10-year ASCVD risk), additional risk-enhancing factors can be used to guide decisions about therapeutic interventions; such factors may include family history of premature ASCVD, chronic inflammatory disease (e.g., rheumatoid arthritis, lupus), chronic kidney disease, early menopause, or metabolic syndrome. In adults at intermediate risk or borderline 10-year ASCVD risk, if risk-based decisions for preventive therapy such as statin treatment remain uncertain, it is reasonable to measure a coronary artery calcium score to guide clinician-patient risk discussion [236].

For purposes of shared clinical decision making, the AHA/ACC categorizes patients according to level of cardiovascular disease risk at 10 years and recommends routine clinician-patient ASCVD risk discussion in relation to the level of risk [24,236]:

- Low (<5%): Risk discussion should emphasize healthy lifestyle to reduce risk.

- Borderline (5% to <7.5%): If there are risk enhancers present, then risk discussion regarding benefit of moderate-intensity statin therapy.

- Intermediate (7.5% to <20%): If risk estimate plus added risk enhancers favor statin therapy, discussion on benefit of initiating moderate-intensity statin to reduce LDL-C by 30% to 49%.

- High (≥20%): Discussion on benefit of statin therapy to reduce LDL-C by 50% or more combined with adoption of a healthy lifestyle.

A 10-year "intermediate" risk score (10% to 15%) does not automatically mandate a statin, but rather should lead to discussion and shared decision-making between the clinician and the patient [229]. Drug therapy is recommended only in select patients with moderately-high LDL (≥160 mg/dL) or patients with very-high LDL (190 mg/dL).

Two higher-risk patient categories are those with severe hypercholesterolemia (LDL ≥190 mg/dL) and older adults with diabetes. Patients with severe hypercholesterolemia and adults 40 to 75 years of age with diabetes are candidates for immediate statin therapy without further risk assessment. Adults with diabetes should start with a moderate-intensity statin (i.e., one that lowers LDL by 30% to 49%). A high-intensity statin (i.e., one that lowers LDL by ≥50%) may be indicated as the patient accrues multiple risk factors. In all other adults 40 to 75 years of age, the 10-year risk of ASCVD should guide therapeutic decision making. The higher the 10-year risk, the more likely the patient will benefit from evidence-based statin treatment [24].

11. CLINICAL GUIDELINES FOR THE TREATMENT OF HYPERLIPIDEMIAS

Treatment guidelines for hyperlipidemias were developed by the NCEP-ATP III [230]. These guidelines were partially updated by the 2013 ACC/AHA guideline; however, as discussed, the recommendations provided by the 2018 AHA/ACC guideline and adapted by the 2019 AHA/ACC guideline on primary prevention of CVD will be presented [24,236]. In 2020, the Department of Veterans Affairs and the Department of Defense (VA/DoD) also published a clinical practice guideline for the management of dyslipidemia [237]. The VA/DoD guideline is designed for the adult population older than 40 years of age and eligible for healthcare in the VA and DoD health systems. Healthcare professionals working within the VA and DoD systems, and others participating in care of patients within the systems, may wish to review the VA/DoD document, as there are differences between these guidelines and the AHA/ACC guidelines, such as the intensity of statin recommended, the risk level thresholds for statin treatment, and the use of adjunctive therapies for primary prevention in patients on statins [238].

Guidelines on management of hyperlipidemia specify four major categories of patients for whom statins may be considered (Table 9) [24]:

- Those with clinical ASCVD

- Those with severe hypercholesterolemia (LDL ≥190 mg/dL)

- Those 40 to 75 years of age with diabetes and LDL ≥70 mg/dL

- Those 40 to 75 years of age with no diabetes but with LDL ≥70 mg/dL and ≥7.5% 10-year ASCVD risk

Table 9: AHA/ACC RECOMMENDATIONS FOR STATIN THERAPY

Age

Patient Factors

Recommendation

Target % LDL

Patients with ASCVD

≤75 years

Clinical ASCVD

High-intensity statin (initiate or continue)

≥50%

Clinical ASCVD and contraindication to high-intensity statin

Moderate-intensity statin (initiate or continue)

30% to 49%

Clinical ASCVD, at very high risk, being considered for PCKS9 inhibitor therapy

Maximally-tolerated LDL-lowering therapy (with maximally tolerated statin and ezetimibe)

Clinical ASCVD, at very high risk, on maximally tolerated LDL-lowering therapy, with LDL ≥70 mg/dL or non-HDL ≥100 mg/dL

It is reasonable to add PCSKP-I following clinician-patient discussion

Clinical ASCVD, on maximally tolerated statin therapy, at very high risk, with LDL ≥70 mg/dL

It is reasonable to add ezetimibe

≥75 years

Clinical ASCVD and evaluated for ASCVD risk reduction, statin adverse effects, drug-drug interactions, patient frailty and preferences

It is reasonable to initiate moderate- or high-intensity statin

30% to 49%

Currently tolerating high-intensity statin therapy and evaluated for ASCVD risk reduction, statin adverse effects, drug-drug interactions, patient frailty and preferences

It is reasonable to continue high-intensity statin

Clinical ASCVD, currently receiving maximally tolerated statin therapy but LDL level remains ≥70 mg/dL

It may be reasonable to add ezetimibe

Heart failure and reduced ejection fraction attributable to ischemic heart disease and reasonable life expectancy (3 to 5 years), not on statin therapy due to ASCVD

May consider initiation or moderate-intensity statin therapy

Clinical ASCVD, on maximally tolerated statin therapy, at very high risk, with LDL ≥70 mg/dL

It is reasonable to add ezetimibe

Patients with Severe Hypercholesterolemia

20 to 75 years

LDL ≥190 mg/dL

Maximally-tolerated statin therapy

≥50%

LDL ≥190 mg/dL, achieves <50% reduction in LDL while receiving maximally tolerated statin and/or have LDL ≥100 mg/dL

Ezetimibe therapy is reasonable

Baseline LDL ≥190 mg/dL, achieves <50% reduction in LDL levels and has fasting triglycerides ≤300 mg/dL while taking maximally tolerated statin and ezetimibe therapy

Consider adding a bile acid sequestrant

30 to 75 years

Heterozygous FH with LDL ≥100 mg/dL while taking maximally tolerated statin and ezetimibe therapy

Consider adding a PCSK9 inhibitor

≥50%

40 to 75 years

Baseline LDL ≥220 mg/dL, achieves on-treatment LDL ≥130 mg/dL while receiving maximally tolerated statin and ezetimibe therapy

Consider adding a PCSK9 inhibitor

≥50%

Patients with Diabetes

40 to 75 years

Diabetes

Moderate-intensity statin, regardless of estimated 10-year ASCVD risk

—

Diabetes and LDL 70–189 mg/dL

Reasonable to assess 10-year risk of first ASCVD event using race-, sex-specific pooled cohort equations

—

Diabetes with multiple ASCVD risk factors

Reasonable to prescribe high-intensity statin

≥50%

≥75 years

Diabetes and on statin therapy

Reasonable to continue statin therapy

Diabetes and 10-year ASCVD risk ≥20%

May be reasonable to add ezetimibe to maximally tolerated statin

≥50%

>75 years

Diabetes

May be reasonable to initiate statin therapy after clinician-patient risk discussion

—

20 to 39 years

Diabetes with specific risk enhancersa

May be reasonable to initiate statin therapy

—

Patients with No Diabetes But Other Risk Factors

40 to 75 years

LDL ≥70 mg/dL and 10-year ASCVD risk ≥7.5%

Moderate-intensity statin, if favored by clinician-patient risk discussion

—

aDiabetes of long duration (≥10 years type 2, ≥20 years type 1), albuminuria, eGFR <60 mL/min/1.73 m^2, retinopathy, neuropathy, ankle-brachial index <0.9

Source: [24]

In addition to the patient factors discussed, race and ethnicity inform and influence the estimates of ASCVD risk, treatment intensity, use of lipids, and other issues. For example, when evaluating ASCVD risk, it is useful for the clinician to know that risk in people of South and East Asian origin varies by country of origin. When evaluating lipid issues, it is useful to know that Hispanic/Latina women have a higher prevalence of low HDL compared with Hispanic/Latino men. When evaluating metabolic issues, it is useful to know that there is an increased prevalence of diabetes and hypertension among Black Americans. Country-specific race/ethnicity, along with the patient's socioeconomic status, may affect the estimation of risk by pooled cohort equations [24].

Other at-risk patient groups include those with moderate or severe hypertriglyceridemia, women with gender-specific history (e.g., premature menopause, history of pregnancy-associated disorders), adults with chronic kidney disease, adults with chronic inflammatory disorders and HIV, older adults (≥75 years of age), young adults (20 to 39 years of age), and children and adolescents. The 2018 AHA/ACC guideline provides recommendations and considerations for clinical decision-making for these unique patient populations [24]. Additionally, the guideline continues to emphasize adherence to a heart-healthy lifestyle from adolescence onward; promote assessment of lifetime ASCVD risk for young adults 20 to 40 years of age; and emphasize comprehensive lifestyle improvements to prevent development of metabolic syndrome [231].

Adherence to changes in lifestyle and effects of LDL-lowering medication should be assessed by measuring fasting lipids 4 to 12 weeks after initiation of statin therapy or dose adjustment, and every 3 to 12 months thereafter to assess adherence and safety indicators. Good adherence to an LDL-lowering diet will reduce LDL levels by 10% to 15%. Moderate-intensity statins may reduce LDL levels by another 30% to 40%, and high-intensity statins by ≥50%. The intensity of statin therapy will vary according to the patient's age and risk category [24].

The 2022 AHA/ACC/HFSA Guidelines for the management of Heart Failure recommend the use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in the treatment of heart failure with reduced ejection fraction [241]. Numerous randomized controlled trials have found that patients with diabetes and ASCVD without heart failure have improved survival and reduced hospitalizations when treated with SGLT2is. SGLT2i therapy prevents heart failure hospitalizations in patients with type 2 diabetes and improves outcomes in patients with heart failure with reduced ejection fraction whether or not they also have diabetes [242]. The mechanism of action of SGLT2i on the improvement in heart failure events is still not clearly elucidated, but it seems to be independent of glucose lowering effects. Proposed mechanisms include [242]:

- Promotion of osmotic diuresis and reductions in plasma volume in patients with and without diabetes, therefore reducing cardiac preload

- Improvements in endothelial function and promotion of peripheral vasodilation, therefore reducing cardiac afterload

- Improvements in myocardial metabolism, reduction of arterial stiffness, and interaction with the Na+/H+ exchanger, improving cardiac efficiency

The recommendations in the 2022 AHA/ACC/HFSA guidelines are also in agreement with the Heart Failure Guidelines Update of the Canadian Cardiovascular Society, published in 2021 [243].

12. CONCLUSION

Cardiovascular diseases are a leading cause of death in developed countries. Although the prevalence of ASCVD in developed countries has increased in the past 40 years, the mortality rate has declined as the result of advances in diagnosis and medical and surgical treatments.

The complex interaction between modifiable, non-modifiable, and risk-enhancing risk factors underlies the etiology of ASCVD. It is now well established that hyperlipidemias, and high concentrations of LDL in particular, are implicated in the etiology of atherosclerosis and increased incidence of ASCVD such as coronary artery disease, peripheral vascular disease, and ischemic cerebrovascular disease. Hyperlipidemias are also associated with primary hypertension and metabolic syndrome. As a result, prevention, early diagnosis, and appropriate clinical management of hyperlipidemias have become a public health priority.

Effective lipid management slows the progression of atherosclerosis and lowers morbidity and mortality associated with ASCVD. This requires not only a change in general perceptions but also a multidisciplinary approach to prevention that involves all members of the healthcare team, including physicians, nurses, pharmacists, dietitians, counselors, and physiotherapists.

The evidence-based guidelines for the assessment of cardiovascular risk, treatment goals, lifestyle changes, and pharmacotherapy developed by the AHA/ACC should be followed as the gold standard in clinical practice [24,95,115,120,227]. The primary target in the treatment of hyperlipidemias is to lower LDL; the secondary targets are treating high triglycerides, low HDL, and metabolic syndrome. A variety of lipid-lowering drugs with a favorable risk-benefit profile, in conjunction with implementation of lifestyle changes, is available to meet these goals.

A better understanding of the molecular elements and physiology of the exogenous and endogenous lipid pathways has played a fundamental role in the development of the most potent lipid-lowering drugs. Scientific advances have led to the development of a newer generation of drugs, now undergoing several stages of clinical evaluation, with the potential to improve on existing drugs' risk-benefit profiles. The important role played by the implementation of lifestyle changes, including a balanced diet, in achieving a healthy lipid profile and decreasing the incidence of ASCVD cannot be overstated and should be an integral part of disease management.

13. RESOURCES

The following resources are provided for those clinicians in need of additional information or as patient education sources.

American Heart Association (AHA)

https://www.heart.org

Professional Heart Daily (A service provided by the AHA)

https://professional.heart.org

My Life Check: Life's Essential 8

https://www.heart.org/en/healthy-living/healthy-lifestyle/lifes-essential-8

Heart and Stroke Foundation of Canada

https://www.heartandstroke.ca

Centers for Disease Control and Prevention Cholesterol Homepage

https://www.cdc.gov/cholesterol

National Center for Health Statistics

https://www.cdc.gov/nchs

National Heart, Lung, and Blood Institute

https://www.nhlbi.nih.gov

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95142 • Optimizing Opioid Safety and Efficacy

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2023 NetCE, All rights reserved.

This course will offer an extensive overview of opioids and their use in pain medicine. Opioid analgesic medications can bring substantial relief to patients suffering from pain. The patient population receiving opioid therapy for pain is diverse and exhibits a broad range of behavioral responses to opioids. To provide appropriate treatment of pain, clinicians must understand, identify, and manage these potential responses. This course will cover the various available opioid options for the treatment of pain of varying severity, with an emphasis on appropriate matching of opioid agents to patients.

Table of Contents

95142 • Optimizing Opioid Safety and Efficacy

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. DEFINITIONS

3. OPIOID ANALGESIC SAFETY, RISKS, AND BENEFITS: FACTS VERSUS FALLACIES

PRESCRIPTION OPIOID ANALGESIC FATAL OVERDOSE RATES

PRESCRIPTION OPIOID ANALGESIC PRESCRIBING RATES

PRESCRIPTION OPIOID ANALGESICS AND HEROIN

EVIDENCE OF LONG-TERM OPIOID BENEFIT FOR CHRONIC PAIN

PRIMARY CONTRIBUTORS TO OPIOID ANALGESIC-RELATED FATALITIES

4. EPIDEMIOLOGY OF PAIN

5. CONSEQUENCES OF UNTREATED OR UNDERTREATED CHRONIC PAIN

6. RISK FACTORS FOR CHRONIC PAIN

PSYCHOSOCIAL RISK FACTORS

MEDICAL RISK FACTORS

COMMON COMORBID CONDITIONS

7. BARRIERS TO ADEQUATE PAIN CARE

8. THE ENDOGENOUS OPIOID SYSTEM AND OPIOID ANALGESIC MECHANISMS

ENDOGENOUS OPIOID PEPTIDES

OPIOID RECEPTORS

OPIOID ANALGESIC MECHANISM

9. OPIOID ANALGESIC PHARMACOLOGY

MU OPIOID RECEPTOR FULL AGONISTS

PARTIAL AGONIST OPIOIDS

MIXED AGONIST/ANTAGONIST OPIOIDS

OPIOID ANTAGONISTS

OTHER OPIOIDS IN CLINICAL USE

10. PHARMACOKINETIC FACTORS IN OPIOID ANALGESIC RESPONSE

ABSORPTION AND DISTRIBUTION

METABOLISM AND ELIMINATION

ADVERSE DRUG INTERACTIONS

PHARMACODYNAMIC DRUG-DRUG INTERACTIONS

11. CDC GUIDELINES FOR OPIOID PRESCRIBING IN CHRONIC PAIN

DETERMINING WHETHER OR NOT TO INITIATE OPIOIDS FOR PAIN (RECOMMENDATIONS 1 AND 2)

OPIOID SELECTION AND DOSAGE DETERMINATION (RECOMMENDATIONS 3, 4, AND 5)

DECIDING DURATION OF INITIAL OPIOID PRESCRIPTION AND CONDUCTING FOLLOW-UP (RECOMMENDATIONS 6 AND 7)

ASSESSING RISK AND ADDRESSING HARMS OF OPIOID USE (RECOMMENDATIONS 8, 9, 10, 11, AND 12)

CRITICAL RESPONSE TO CDC GUIDELINES

12. GENERAL RECOMMENDATIONS FOR ANALGESIC PRESCRIBING

13. PATIENT FACTORS AND OPIOID ANALGESIC RESPONSE

AGE

MEDICAL COMORBIDITIES

GENETIC FACTORS

ANTICIPATING FACTORS THAT ALTER PATIENT RESPONSE TO OPIOIDS

14. OPIOID SELECTION, INITIATION, AND MANAGEMENT

OPIOID RESPONSIVENESS

RECENT OPIOID EXPOSURE

ROUTES OF ADMINISTRATION AND FORMULATIONS

DOSING

DOSE TITRATION

OPIOID ROTATION OR SWITCHING

15. OPIOID ANALGESIC SIDE EFFECTS AND MANAGEMENT

SEDATION

PRURITUS

OPIOID-INDUCED CONSTIPATION AND BOWEL DYSFUNCTION

NAUSEA AND VOMITING

RESPIRATORY DEPRESSION

SEROTONIN SYNDROME

NEONATAL ABSTINENCE SYNDROME

MORPHINE AND CARDIAC RISK

NEUROPSYCHIATRIC EFFECTS

IMMUNOLOGIC CHANGES

ENDOCRINE EFFECTS

ACETAMINOPHEN TOXICITY

OPIOID USE DISORDERS

16. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95142 • Optimizing Opioid Safety and Efficacy

Education Category. Pharmacology

Release Date. 06/01/2023

Expiration Date. 05/31/2026

Course Overview

This course will offer an extensive overview of opioids and their use in pain medicine. Opioid analgesic medications can bring substantial relief to patients suffering from pain. The patient population receiving opioid therapy for pain is diverse and exhibits a broad range of behavioral responses to opioids. To provide appropriate treatment of pain, clinicians must understand, identify, and manage these potential responses. This course will cover the various available opioid options for the treatment of pain of varying severity, with an emphasis on appropriate matching of opioid agents to patients.

Audience

This course is designed for physicians, physician assistants, nurses, pharmacists, and other healthcare professionals involved in the care of patients who may benefit from the use of opioids to address pain.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 15 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 15 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 15 ANCC contact hour(s). NetCE designates this continuing education activity for 15 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 18 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 15 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. NetCE designates this activity for 15 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-23-012-H08-P. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. Successful completion of this CME activity, which includes participation in the activity with individual assessments of the participant and feedback to the participant, enables the participant to earn 15 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 1.5 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through July 29,2025); Alabama, Provider #ABNP0353, (valid through July 29, 2025); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; South Carolina, Provider #50-2405. West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This course meets the Michigan requirement for 2 hours of continuing education in pain and pain symptom management. This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to provide clinicians with the information necessary to choose the appropriate opioid agents for their patients, with a resultant improvement in patients' quality of life and compliance with prescribed treatments.

Learning Objectives

Upon completion of this course, you should be able to:

1. Define terms often used in discussion of opioid prescribing.

2. Analyze common myths related to opioid analgesic safety.

3. Recall the epidemiology of pain.

4. Outline the individual and societal impact of undertreated pain.

5. Describe risk factors for and comorbidities of chronic pain.

6. Evaluate barriers to adequate pain care.

7. Describe the endogenous opioid system and effects of opioid analgesia.

8. Discuss the classification and properties of the various mu opioid receptor full agonist agents.

9. Compare and contrast other types of opioid analgesics and antagonists.

10. Identify pharmacokinetic factors in opioid analgesic response.

11. Outline the Centers for Disease Control and Prevention's (CDC's) guidelines for opioid prescribing for chronic pain.

12. Recall other general recommendations for safe and effective long-term opioid use for chronic pain.

13. Identify patient factors that affect opioid analgesic response.

14. Describe issues that affect choices regarding opioid selection, rotation, and titration.

15. Discuss the identification and appropriate treatment of opioid analgesic side effects.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Sharon Cannon, RN, EdD, ANEF

Randall L. Allen, PharmD

Mary Franks, MSN, APRN, FNP-C

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Opioid analgesics are approved by the U.S. Food and Drug Administration (FDA) for the treatment of moderate or severe pain. However, individual patients differ greatly in clinical response (e.g., efficacy, side effects, safety) to different opioid analgesics, and patient populations show widely variable response to the same opioid and dose [1]. These response variations make opioid prescribing challenging. Scientific advances have improved the understanding of how opioid response is conditioned by genetic factors, comorbidity, drug interactions, and opioid dynamics and/or kinetics. Informed health professionals are now better able to match patients with a selected treatment option to maximize safety, efficacy, and tolerability when prescribing opioid analgesics.

The important role of opioid analgesics is broadly accepted in acute pain, cancer pain, and palliative and end-of-life care, but it is controversial for the management of chronic noncancer pain [2]. In recent years, the climate surrounding opioid analgesics has become decidedly negative, a response to the excessive prescribing and increases in fatal overdose during the 2000s. This backlash has prompted concerted broadcasting of opioid analgesic public health hazards, culminating in the 2016 Centers for Disease Control and Prevention (CDC) opioid prescribing guidelines that focus on curtailing prescribing and patient access [3,4]. However, guidance on improving prescription opioid analgesia and tolerability by carefully matching the patient to the selected opioid, unaddressed in the CDC guidelines, is also essential for effective treatment of pain [5,6].

Prescription opioid analgesic use and overdose both appear to be in multi-year declines from their 2011 peak. This course will provide perspective and address common misperceptions of opioid analgesic safety and potential benefits in order to help establish the basis for a balanced risks/benefits discussion and convey that with appropriate due diligence, opioid analgesics can be prescribed safely to benefit patients in pain who lack response to, or are unlikely to benefit from, other analgesics [7,8].

Opioids are not a panacea for pain, nor are they safe and effective for every patient. However, they can be a useful tool, and knowledge of medical advances can give clinicians greater confidence to safely and effectively prescribe these drugs. In this course, chronic pain management is emphasized because the potential patient/opioid interactions are more complex and current guidance can be enhanced. Unless stated otherwise, this course focuses on noncancer pain.

2. DEFINITIONS

Acute pain: Pain from tissue injury that resolves with tissue healing [9]. Acute pain may be protracted without mechanistic conversion to chronic pain, resolving with treatment [10].

Addictive drug: A disproven concept that some drugs are inherently "addictive." Addiction results from individual susceptibility and not from a substance. Most people do not respond with addictive behavior when prescribed opioids with abuse potential, while predisposed persons may abuse any opioid analgesic [11,12,13].

Analgesic tolerance: Diminished or lost analgesia requiring dose titration to regain pain relief. A concerning complication in long-term opioid therapy, long-term trials of transdermal fentanyl or extended-release (ER) oxycodone suggest analgesic tolerance is much less frequent and clinically relevant than previously believed [14].

Centralized pain: Refers to peripheral and central sensitization without detectable peripheral origin and includes fibromyalgia, irritable bowel syndrome, and tension-type headache. Also known as dysfunctional pain.

Central sensitization: The process by which pain initially generated from peripheral injury becomes embedded in the central nervous system (CNS) through pathologic adaptation to become self-perpetuating and amplified, uncoupled from original tissue origin, very difficult to treat, and potentially intractable [15].

Chronic pain: Pain lasting longer than three months or longer than expected healing time. Previously, chronic pain has been conceptualized as merely the continuation of acute pain beyond a chosen temporal cut-off point, a notion now considered overly simplistic. The transition from acute to chronic pain is now understood to involve a shift in pathogenic mechanisms from that associated with early-phase tissue injury and healing to a later period of abnormal, maladaptive sensory processing and neuronal plasticity that develops within peripheral and central pain pathways. Importantly, psychological status, cultural background/beliefs, and relationships/interactions in the workplace, home, and healthcare environments contribute to development and persistence of chronic pain [16].

Inflammatory pain: Nociceptive pain with a localized immune response that generates pro-inflammatory mediators to facilitate tissue repair.

Neuropathic pain: Originates from injury to specific peripheral nervous system (PNS) or CNS structures or to all peripheral sensory nerves (e.g., with diabetes or postherpetic neuralgia).

Neuroplasticity: The capacity of nerve cells to adapt and regenerate.

Nociceptive pain: The normal acute response to peripheral tissue injury or damage.

Pain: Physical discomfort. Pain is classified into four types (nociceptive, inflammatory, neuropathic, and centralized); chronic pain usually involves multiple pain mechanisms [17,18,19].

Pseudoaddiction: An iatrogenic condition whereby patients display drug-seeking behaviors mimicking opioid use disorder but driven by intense need for pain relief. Resolves with adequate pain control [20].

3. OPIOID ANALGESIC SAFETY, RISKS, AND BENEFITS: FACTS VERSUS FALLACIES

Safety considerations are the foundation of opioid analgesic prescribing, reflecting the basic principles of good medical practice [21]. As such, any comprehensive review of opioid analgesic therapy should address the assumptions that surround opioid analgesic prescribing for pain.

From the late 1990s through 2011, opioid analgesic prescribing and fatal overdose greatly increased [22]. The CDC identified this pattern, and their prompt attention and broadcasting elevated physician and public awareness and assisted in closing "pill mills" that served as conduits for millions of opioid doses into illicit markets [3]. The reaction to opioid overprescribing and overdose prompted efforts to curtail opioid prescribing, in part, by swaying physician and public opinion against opioids [6,7,23,24,25]. As of 2020, the total volume of opioid prescriptions nationally had dropped to the lowest rate in the 15 years for which data are available, to 43.4 prescriptions per 100 persons (a total of more than 142 million opioid prescriptions) [26]. This section addresses common misperceptions about opioid analgesics.

PRESCRIPTION OPIOID ANALGESIC FATAL OVERDOSE RATES

There is a misperception that overdose deaths from legally obtained prescription opioid analgesics continue rising, perpetuating an opioid epidemic. In fact, prescription opioid analgesic overdose deaths have steadily declined since 2012.

This perception is in part the result of CDC data indicating 18,893 prescription opioid overdose deaths in 2014, up sharply from 16,300 deaths in 2013 [27]. However, the 2014 increase was the result of a change in reporting standards. Starting in early 2014, the CDC began classifying all fentanyl overdoses as prescription opioid analgesic deaths, because laboratory tests were unable to distinguish clandestine from pharmaceutical fentanyl [28]. Also in 2014, there was an influx of fentanyl into the illicit opioid market, largely from Mexico and often sold as heroin or oxycodone. This resulted in a significant increase in fentanyl overdose deaths.

However, the total number of prescribed fentanyl dose units in 2014 (6.7 million) and 2013 (6.8 million) was unchanged [29]. In 2016, the CDC stated that the increase in overdose deaths in 2014 was mainly from adding fentanyl overdoses, almost all from clandestine fentanyl [30]. The CDC also provided an adjusted 2014 estimate (14,000 opioid overdose deaths), which was a continued decrease from the prescription opioid analgesic overdose deaths peak in 2011 (16,917 deaths) [31].

In 2018, there were 67,367 drug overdose deaths in the United States, a 4.1% decline from 2017 [32]. In 2021, 106,699 drug overdose deaths occurred [33]. Increases in rates (from 2020 to 2021) occurred for drug overdose deaths involving psychostimulants with abuse potential (from 7.5 to 10.0), synthetic opioids other than methadone (17.8 to 21.8), and cocaine (6.0 to 7.3). Rates were similar for drug overdose deaths involving natural and semisynthetic opioids, as well as deaths involving methadone. Of the drugs examined, only drug overdose deaths involving heroin had a lower rate in 2021 than in 2020 (2.8 and 4.1, respectively) [33].

It should also be noted that heroin overdose deaths are often undercounted, and morphine deaths overcounted, because heroin rapidly metabolizes into morphine. Many medical examiners are reluctant to label a death heroin-related without 6-monoaceytlmorphine present. However, this metabolite, unique to heroin, quickly metabolizes into morphine. The actual figures of heroin overdose reported as morphine are unknown, but when heroin overdose deaths increase, morphine overdose deaths also tend to increase [34].

PRESCRIPTION OPIOID ANALGESIC PRESCRIBING RATES

Many healthcare professionals believe that continued increases in opioid analgesic prescribing are fueling the opioid epidemic. In fact, the prescription rates of several opioid products are in multi-year declines. Total dispensed opioid prescriptions decreased 37.6% between 2011 and 2020 [26].

In late 2010, oxycodone ER was introduced as an abuse-deterrent formulation (ADF) to reduce abuse and overdose. After this product was released, there was a 39% prescribing decrease between 2010 and late 2012 [35]. In addition, oxycodone "doctor shopping" decreased 50% and overdose fatalities reported to the manufacturer decreased 65% [36].

Though it is still early, hydrocodone/acetaminophen combination product prescribing appears to be decreasing after it was rescheduled as a Schedule II controlled substance in 2014. After one year, there were 26.3 million fewer (-22%) prescriptions and 1.1 billion fewer (-16%) dispensed tablets [37]. Decreased hydrocodone/acetaminophen prescribing by primary care physicians during this period is also notable, with a 33% decrease from 2011 (144.5 million) to 2015 (97 million) [29,38,39].

After a steady increase in the overall national opioid prescribing rate starting in 2006, the total number of prescriptions dispensed peaked and leveled off in 2010–2012 at more than 255 million annually and a prescribing rate of 81 prescriptions per 100 persons [40]. The opioid prescribing rate declined from 2012 to 2020, and in 2020, the prescribing rate had fallen to the lowest in 15 years, totaling 142 million opioid prescriptions (43.3 prescriptions per 100 persons) [26].

While it is true that the United States uses 99% of global hydrocodone, this is partially due to the fact that the few countries with adequate opioid access prefer dihydrocodeine or low-dose morphine for moderate/moderately severe pain [41]. Liberal opioid analgesic prescribing in some European countries has not led to the addiction and overdose rates seen in the United States, which reflects contribution from uniquely American factors beyond opioid analgesic exposure [42,43,44].

PRESCRIPTION OPIOID ANALGESICS AND HEROIN

The use of prescription opioid analgesics has long been proposed as a "gateway" to heroin. However, progression from opioid prescription misuse to heroin initiation is infrequent. Among non-medical users of opioid analgesics, 3.6% initiate heroin use within five years of initial abuse of prescription opioids [45]. Although most persons who misuse opioids do not progress to heroin use, it is also true that the majority of current heroin users initially misused prescription opioids.

EVIDENCE OF LONG-TERM OPIOID BENEFIT FOR CHRONIC PAIN

No analgesic used for the treatment of chronic pain (opioid or other class) has evidence of long-term safety and efficacy from randomized controlled trials lasting longer than one year [43]. Although this has been used to support the belief that opioids are unsafe for prolonged treatment of chronic pain, this level of evidence is lacking for any analgesic drug in use for chronic pain [31,43,46]. Thus, the absence of evidence is not evidence of absence [5,47]. Many non-randomized controlled trials of opioid analgesics lasting one year or longer have substantive clinical value.

In general, opioid and other analgesic drug trials are seldom longer than 12 weeks in duration, and many obstacles interfere with the ability to conduct long-term opioid trials [48,49]. First, ethical standards prohibit randomizing 50% of subjects in substantial pain to placebo. In addition, complexity and expense deter researchers from using active-drug controls in randomized controlled trials; these trials are unattractive to industry funding. There are also very high dropout rates of subjects with chronic pain randomized to placebo.

Several factors make analgesic efficacy of opioid analgesics difficult to demonstrate in tightly controlled randomized trials [14,47,48]. Studies report average opioid response of large patient numbers under rigid, predetermined starting dose and titration. However, opioid response in chronic pain is bimodal and not normally distributed; patients primarily show substantial or negligible analgesic response. When individual patient response is pooled and averaged, modest benefit is reported.

The strict, inflexible dosing parameters in randomized controlled trials lead to high dropout rates from analgesic failure or intolerability. This underestimates efficacy and overestimates toxicity. Many such patients would gain analgesia and tolerability using an approach tailored to patient factors that influence opioid response.

PRIMARY CONTRIBUTORS TO OPIOID ANALGESIC-RELATED FATALITIES

Misuse or abuse of prescribed opioid analgesics may account for a smaller proportion of poisoning overdoses than assumed. Data from Florida during 2007–2013 found 12% of 5,254 patients treated for non-fatal prescription opioid overdose in Broward County were diagnosed with opioid use disorder; 88% were legally prescribed users without diagnosable opioid use disorder [50]. These findings suggest prescription opioid abuse may be a less frequent cause of overdose than commonly assumed.

Studies show that the majority of opioid analgesic deaths stem from combining opioids with sedative hypnotics and/or alcohol [6,51]. The extent to which contributing factors drive overdose rates is a more complex problem.

Methadone

Methadone analgesic prescribing began in the late 1990s [52]. In 1999, 784 overdose deaths were attributed to methadone. By 2021, this number was 3,678 [53]. Factors that have contributed to increased methadone deaths include prescriber knowledge deficits of its complex pharmacology and its designation by insurer/third-party payers as the first-line chronic pain drug on the sole basis of cost savings [7,54,55].

Benzodiazepines

Benzodiazepines contribute to a significant number of opioid analgesic deaths, particularly with higher-dose opioid prescribing [51]. In 2011, benzodiazepines were associated with 31% of opioid analgesic fatalities, compared with 18.4% in 2004 [56]. However, this 2011 figure may understate the true benzodiazepine contribution. In a study of 607,156 people 15 to 64 years of age, 84.5% of those prescribed opioids for pain who died of opioid analgesic overdose were co-prescribed benzodiazepines [57]. In another study of more than 2 million North Carolina residents receiving one or more opioid analgesics, benzodiazepines were present in 61.4% who fatally overdosed. The potential role of other psychoactive substances used in combination with prescription opioids was further examined using data from the National Multiple-Cause-of-Death Files for the periods 2002–2003 and 2014–2015. This study showed that among persons dying of opioid analgesic overdose the most frequent combination was with benzodiazepines [58]. Furthermore, the proportion of opioid overdose deaths in combination with benzodiazepines increased from 16.8% in 2002–2003 to 27.9% in 2014–2015 in spite of the fact, as noted, that the opioid prescribing rate had been declining during the latter period.

Alcohol

Alcohol coingestion may also contribute to opioid analgesic-related deaths. In 2010, 20% of opioid overdose deaths involved alcohol [59].

Prescriber Knowledge Deficits

Studies indicate that fatal respiratory depression events often occur in the first five days of initial opioid therapy, with most in the initial 24 hours. This reflects initiation of therapy at too high a starting dose or failure to consider other risk factors, such as co-prescribed CNS sedatives [60].

4. EPIDEMIOLOGY OF PAIN

Persistent pain has been reported to affect one in three adults in the United States and to cost more than $600 billion annually [2]. In 2011, the Institute of Medicine (IOM) estimated that more than 100 million Americans suffer from persistent or chronic pain, with roughly 10% experiencing chronic, disabling pain [2]. The CDC analyzed data from the 2019–2021 National Health Interview Survey to determine a more current and precise estimate of the prevalence of chronic pain in the United States, where chronic pain was defined as pain on most days or every day in the past six months. Based on this survey, an estimated 51.6 million adults experience chronic pain, with 17.1 million reporting high impact pain that limits life or work activities on most days [61]. These estimates indicate that chronic pain is experienced by 20% to 30% of adults in the United States, similar to the rates reported in Canada, Australia, and European countries.

Pain is a leading cause of chronic illness in persons older than 60 years of age, a major cause of disability, and the cardinal feature of arthritis, migraine, cancer, metabolic disorders, and neuropathies. Pain control in these diseases is notoriously difficult and often requires opioids [62,63]. Neuropathic pain, which includes diabetic neuropathy, complex regional pain syndrome, radiculopathy, phantom limb pain, human immunodeficiency virus (HIV) sensory neuropathy, multiple sclerosis-related pain, and post-stroke pain, affects 5% to 10% of the U.S. population [64].

Chronic pain prevalence varies by subgroup. In general, older adults have a much greater prevalence than younger adults. Higher rates of chronic pain are found among those living in poverty, in women, those recently hospitalized, obese individuals, and those who never graduated high school [61]. Roughly 50% of adults rating their health as fair or poor suffer from chronic pain [65].

Chronic pain rates are likely to continue increasing as the population ages and more people develop pain-associated conditions such as obesity, diabetes, cardiovascular disorders, arthritis, and cancer. Other contributors to chronic pain include improved trauma care (with more surviving with chronic pain), the increase in surgical procedures, and greater public understanding of chronic pain and access to health insurance [2].

The most common anatomic locations of pain in U.S. adults are the low back (28.1%), knee (19.5%), severe headache or migraine (16.1%), neck (15.1%), shoulder (9.0%), finger (7.6%), and hip (7.1%). The lifetime prevalence of spinal pain ranges from 54% to 80% [2]. In patients with low back pain or neck pain, 25% to 60% report pain lasting longer than one year from onset; high pain and disability levels were found in 23% of patients with low back pain and 15% of patients with neck pain. Low back pain is linked to greatest declines in function and quality of life [66].

As noted, adult women have an overall higher prevalence of chronic pain than men [67]. Some chronic pain syndromes occur only, or predominantly, in women, including chronic fatigue syndrome, endometriosis, fibromyalgia, interstitial cystitis, vulvodynia, and temporomandibular disorders. Roughly 50 million women have one or more of these conditions, which frequently co-occur [2].

5. CONSEQUENCES OF UNTREATED OR UNDERTREATED CHRONIC PAIN

Pain is a distressing sensory and emotional experience for the patient, imposing potentially life-altering physiologic, psychosocial, and quality of life alterations [2]. The negative impact of chronic pain on quality of life is more severe than heart failure, renal failure, or major depression and comparable to terminal cancer [68,69].

Failure to manage pain has serious pathophysiologic consequences, including cardiovascular (hypertension, myocardial ischemia, cardiovascular collapse) and physiologic (appetite loss, failure to thrive, immune dysfunction, endocrine failure) consequences, suppression of physical activity leading to joint and muscle deterioration, chronic sleep disturbance, dementia, and premature death [2,17,70]. Among 6,940 primary care patients followed over 10 years, those with poorly controlled moderate-to-severe chronic pain had a 68% greater risk of death than those with cardiovascular disease and 49% greater risk than all other causes combined [71].

Psychosocial consequences of unmanaged pain can be severe, with adverse psychological (impaired cognitive function, pathologic anxiety/depression, suicidal ideation, despair, hopelessness) and social/interpersonal (relationship disruption, loss of employment, financial difficulties) outcomes [2,17,72,73,74]. Chronic pain is second only to bipolar disorder as a medical cause of suicide [75,76,77].

Chronic undercontrolled pain activates CNS glial cells and leads to neuroinflammation, tissue destruction, loss of CNS tissue mass and receptors, and unresponsiveness to usual-dose opioids and other analgesics. These patients often require higher-dose opioids; the modest analgesic response can reduce suffering and prevent suicide [78].

Negative attitudes by primary care providers and other clinicians toward patients with chronic pain who use/misuse illicit or prescription drugs are widespread, with hedonistic pursuit the assumption. Reality may be more complex, as patients with chronic pain potentially use substances to alleviate poorly controlled pain. This was explored in a study of adult primary care clinic patients who tested positive for illicit drug use or prescription drug misuse. Of the 589 patients [79]:

- 87% reported chronic pain (13% mild, 24% moderate, 50% severe)

- 74% reported impairment from pain (15% mild, 23% moderate, 36% severe)

- 51% of those who used illicit drugs (cannabis, heroin) stated they did so to treat pain

- 81% of those who misused prescription drugs stated they did so to self-medicate pain

- 38% of those who reported past three month heavy drinking stated they did so to treat pain

Chronic pain and impairment from pain were the norm in primary care patients with positive drug screens. Nearly one-third reported both severe pain and disabling impairment. This study suggests that poor pain control is common, apparent substance use disorder may reflect pseudoaddiction, and pain requires attention in patients counseled about their substance use [79].

6. RISK FACTORS FOR CHRONIC PAIN

PSYCHOSOCIAL RISK FACTORS

Intense persistent pain and persistent emotional distress are both powerful physiologic stressors that activate the hypothalamic-pituitary-adrenal (HPA) axis, the body's primary stress-control mechanism. The HPA axis becomes dysregulated from prolonged activation, causing a cascading effect that activates immune and inflammatory factors and glutamate receptor complex elements [70]. Neuroplasticity, the alteration in activity and function of synapses and neuronal networks, mediates the development, chronicity, and treatment resistance of pain and psychiatric conditions through diminished neurogenesis, synaptic deficits, decreased neurotrophic factors (e.g., brain-derived neurotrophic factor), and dendritic pathology [80]. Neuroplastic changes lead to central sensitization and hyperalgesia in patients with chronic pain and in patients with major depression even when ongoing pain is absent [81].

Abuse and Trauma

Early childhood trauma greatly influences experiences of pain, and childhood physical and sexual abuse negatively and independently influences adult health status, even after controlling for psychiatric disorders [67]. Abuse in childhood strongly predicts depression and pain in adulthood, and childhood sexual abuse highly predicts later chronic pain.

Childhood trauma stimulates the release of inflammatory cytokines and the development of central sensitization, greatly elevating later risks of immune, endocrine, and nervous system dysregulation [82]. Adults with depression and a history of childhood abuse show amplified stress response and altered adrenocorticotropic hormone and cortisol release. Glucocorticoid receptor dysfunction and downregulation is a bidirectional cause/effect of abnormal HPA-axis regulation in patients with depression [83]. Neuroinflammation is the common mediator of comorbid chronic pain and depression [84].

Coping and Social Support

Multiple psychological mechanisms can alter pain outcomes and facilitate the progression of acute pain to chronic pain. Pain tolerance is adversely affected by mood, and factors such as pain coping skills and social support can affect pain and functionality [85,86]. Low socioeconomic status, characterized in part by lower education level and inequality in healthcare access, also correlates with chronic pain [67].

The presence of maladaptive coping styles such as catastrophizing, kinesophobia (i.e., fear of movement), and somatization (i.e., emotional distress expressed through physical symptoms) predicts development of chronic pain [66]. Craving is strongly associated with drug misuse in patients prescribed opioids for chronic pain, and pain catastrophizing is associated with craving even after controlling for demographic, psychological, medical, and medication regimen variables. This underscores the importance of including psychological interventions in the overall pain care [87].

Passive avoidant behavioral patterns, lack of engagement in self-care, and job dissatisfaction also elevate the risk of chronic pain [88,89]. Emotions and expectancies are strongly linked; negative emotions are associated with a generalized expectation of negative outcomes. The goal to avoid pain is often pursued with concurrent and often competing goals. Patients with chronic pain frequently weigh the value of pain avoidance against the costs related to loss of desired activities [85].

Neurobiologic mediation of social pain overlaps with physical pain. Social exclusion, bullying, isolation, and lack of support cross-sensitizes and amplifies physical pain. This relationship is bidirectional and highly relevant to patients with chronic pain who commonly encounter a process of rejection and social separation [67]. Passive pain coping and low levels of social support predict functional disability in patients with arthritis-related pain [90].

Addressing coping skills and bolstering social support can improve long-term pain outcomes and mitigate problematic medication use [86]. Patients with chronic pain and a history of prescription opioid use disorder who do not abuse their prescribed opioids are more likely to be active members of 12-step groups and have stable support systems [91].

MEDICAL RISK FACTORS

Obesity

Obesity is a pro-inflammatory state, and adipose tissue releases inflammatory mediators that increase chronic pain risks. Increased body weight and joint load can also promote or exacerbate painful conditions such as osteoarthritis [92].

Past Surgeries

Of patients undergoing surgery, 10% to 50% experience persistent pain and 2% to 10% experience severe pain. Inadequately treated postsurgical acute pain is common and increases the risk for developing chronic pain [2]. Chronic pain develops after thoracic surgery in 25% to 60% of patients and after herniorrhaphy in 14% [86].

COMMON COMORBID CONDITIONS

Major Depressive Disorder and Anxiety Disorders

Major depressive disorder is the single most important and prevalent chronic pain comorbidity. It is difficult to treat and renders pain control nearly impossible; anhedonia (i.e., inability to feel pleasure) is a frequent symptom [14,67]. Primary care patients with muscle pain, headache, or stomach pain complaints are 2.5 to 10 times more likely to have diagnosable panic disorder, generalized anxiety disorder, or major depressive disorder than those without pain. Patients whose pain level results in work interference show elevated risk of panic disorder and major depressive disorder. Conversely, major depressive disorder increases the odds of muscle pain complaints, headache, stomach pain, and pain interference with daily functioning. These results reflect the complex interaction between pain and medical/psychiatric comorbidities [93].

Sleep Impairment

Disturbed phase 2/3 and rapid eye movement sleep decreases pain threshold, impairs immune function, decreases insulin sensitivity, and undermines pain treatment response. Roughly 50% to 70% of patients with chronic pain experience sleep disturbance, and pain, sleep, and mood are connected and mutually reinforcing—sleep disturbance exacerbates pain, and pain disrupts sleep. The bidirectional association results from lowered pain threshold, promotion of hyperalgesia, and increased release of inflammatory cytokines [14,94]. Sleep recovery has an analgesic effect [86].

Medical Comorbidity

The presence of chronic pain is substantially elevated in patients with chronic respiratory disease, cardiovascular disease, or neurologic, metabolic, endocrine, and gastrointestinal (GI) disorders [95]. Among multi-morbid primary care patients older than 65 years of age, chronic low back pain was the most prevalent pain condition, significantly associated with cardiometabolic conditions in both sexes and depression in women [96].

7. BARRIERS TO ADEQUATE PAIN CARE

Pain arises in the nervous system but represents a complex, evolving interaction of biologic, behavioral, environmental, and societal factors. Biopsychosocial factors greatly influence pain perception, persistence, and treatment outcomes in patients with chronic pain [2]. As such, a coordinated multimodal approach with pharmacopoeia, cognitive-behavioral or other coping skills therapy, and a progressive strengthening or functional restoration modality is recommended [97,98]. Despite substantially greater efficacy than uncoordinated symptomatic care, few patients with chronic pain receive multidisciplinary pain care [86].

Chronic pain affects all domains of life, and clinicians have few effective tools at their disposal to help these patients [99]. Opioids remain the strongest group of analgesic drugs available [100]. Millions of patients are safely and effectively maintained on relatively high-dose opioids for chronic, severe pain and require these medications to function. Public pressure and the mischaracterization of patients as "drug addicts" has increasingly deterred prescribers from treating patients with chronic pain successfully managed with opioids for years or decades rather than improving safety practices [23,101]. However, opioids, like many medications, have serious risks and should not be treated like a cure-all [102]. This dichotomy has resulted in many patients for whom opioid analgesics are appropriate increasingly experiencing barriers to pain relief.

The IOM has stated that the uncertain diagnosis in many chronic pain cases, combined with stigma toward patients in pain, interferes with treatment seeking and adherence to follow-up. Negative provider interactions are powerful deterrents to future help-seeking by adults with chronic pain, particularly the elderly. Patient perception of having their pain complaint dismissed or of not being listened to by their initial pain provider can discourage subsequent care seeking or result in changing providers [2].

These observations are echoed by the National Pain Strategy (NPS), adding that in addition to prevalent stigma, increasing reluctance of many clinicians to prescribe opioids jeopardizes adequate pain control for patients with chronic pain. For most pain conditions, medications (including opioids) may be essential for improved quality of life, and rationing, medication shortages, and inadequate reimbursement decreases patients' access to medications, causing considerable hardship in this vulnerable population [103].

At greatest risk of unrelieved pain from stigma and bias are children, the elderly, racial and ethnic minorities, active duty or military veterans, and those with cancer, HIV, or sickle cell disease. Pain undertreatment in Black patients is especially widespread, from prevalent misperceptions that this group has higher pain tolerance and is more likely to abuse their opioid prescription [104].

The CDC guideline recommends that pain specialists, not primary care providers, manage patients requiring >90 mg daily morphine equivalent dosage (MED), but this is often unrealistic in practice. The number of pain specialists is inadequate to manage the large number of patients with pain severity and disability that requires >90 mg MED. Patients may feel abandoned or panicked about the potential loss of effective pain control. Adherence to this recommendation can therefore have potentially serious consequences for patients requiring opioids, and the growing problem of opioid medication access is likely to worsen [102]. Certain states require clinicians to implement clinical protocols at specific dosage levels. For example, before increasing long-term opioid therapy dosage to >120 MME/day, clinicians in Washington state must obtain consultation from a pain specialist who agrees that the increase is indicated and appropriate. Clinicians should be aware of policies related to MME thresholds and associated clinical protocols established by their state [102].

8. THE ENDOGENOUS OPIOID SYSTEM AND OPIOID ANALGESIC MECHANISMS

Opioid analgesics produce therapeutic and side effects by mimicking endogenous opioid activity, although some opioids produce analgesia by activity outside the opioid receptor complex. Opioids widely differ in levels of affinity and activation of opioid receptor subtypes. In addition, inter-individual variation in analgesic response and side effects is significant, largely driven by genetic factors [105]. The complex interaction between unique opioid properties and individual patient characteristics dictates that a patient-tailored approach is required for opioid selection, dose initiation, and titration to optimize safety, analgesia, and tolerability.

Naturally occurring opioid compounds are produced in plants (e.g., opium, morphine) and in the body (the endogenous opioids) [106]. Endogenous opioids are peptides that bind opioid receptors, function as neurotransmitters, and help regulate analgesia, hormone secretion, thermoregulation, and cardiovascular function. The three primary endogenous opioid peptide families are the endorphins, enkephalins, and dynorphins, and the three primary opioid receptor types are mu, kappa, and delta [107,108]. A quick overview of this complex pain modulation system is helpful in understanding how opioid analgesics work.

ENDOGENOUS OPIOID PEPTIDES

Endogenous opioid peptides are neurotransmitter molecules in the opioid receptor complex that produce specific physiologic effects determined by neuronal distributions of the activated opioid receptor type [109]. The endogenous opioid peptides are cleaved from the pro-hormone precursors proenkephalin, pro-opiomelanocortin, and prodynorphin. The endogenous delta opioid receptor peptides are met-enkephalin and leu-enkephalin, cleaved from proenkephalin. Prodynorphin gives rise to kappa opioid receptor agonists dynorphin A and B. Pro-opiomelancortin encodes the peptide beta-endorphin, which has agonist activity at all three classical opioid receptors. Some endogenous opioid ligands lack specificity for opioid receptor subtypes, such as b-endorphin and the enkephalins [110,111].

Endorphins

Endorphins are synthesized in the hypothalamus and the pituitary gland. Pain, strenuous exercise, excitement, and orgasm stimulate their release, binding, and activation. Endorphins are popularized as the "natural pain killers" from their ability to induce analgesia and a general feeling of well-being. They are thought to largely mediate analgesia from acupuncture, massage, hydrotherapy, and transcutaneous electrical nerve stimulation therapy [112].

Dynorphins

Dynorphin peptides are synthesized from the precursor pro-dynorphin and have primary affinity and binding at the kappa opioid receptor. Dynorphins are distributed throughout the CNS, with highest concentrations in the brain stem, hypothalamus, and spinal cord. Their physiologic actions are diverse, and their primary function is the modulation of pain response, appetite and weight, circadian rhythm, and body temperature. Dynorphins are linked to stress-induced depression and drug-seeking behavior, and drugs that inhibit dynorphin release are under evaluation for possible use in the treatment of depression related to drug addiction [112].

Enkephalins

Enkephalin peptides, derived from pro-enkephalin, are located throughout the brain and spinal cord and are involved in regulating nociception. Enkephalins inhibit neurotransmission in pain perception pathways, reducing the emotional and physical impact of pain. Enkephalins also reside in the GI tract, where they help regulate pancreatic enzyme secretion and carbohydrate metabolism [112].

OPIOID RECEPTORS

Opioid receptors are expressed throughout the CNS and PNS on key nodes within the pain pathway and are highly concentrated in areas involved with integrating pain information [62]. Opioids vary greatly by receptor affinity, binding, and activity and can bind to produce agonist, partial agonist, or antagonist receptor activity [107]. As noted, the analgesic activity and the side effects result from mimicry of endogenous opioids, achieved by the beta-phenylethylamine group moiety shared by endogenous and exogenous opioid receptor ligands that facilitate opioid receptor binding [113].

Mu Opioid Receptors

Mu receptors are the primary mediators of analgesia produced by opioid analgesics in clinical use. Their greatest CNS concentration is in the thalamus, medulla, periaqueductal gray area, neocortex, amygdala, dorsal horn, inferior and superior colliculi, and brain stem [107,112,114]. PNS occupancy includes the peripheral sensory neuron dorsal root ganglion, stomach, duodenum, jejunum, ileum, and proximal and distal colon. Mu receptors in non-neural tissue are found in the vascular and cardiac epithelium, keratinocytes, vas deferens, and Sertoli cells [115].

Mu opioid receptors in the amygdala and nucleus accumbens mediate opioid reward response (e.g., euphoria). In this brain region, opioids bind to and activate mu receptors, which inhibit gamma-aminobutyric acid (GABA) to increase dopamine transmission [62]. Mu opioid receptors broadly distributed in the limbic system mediate emotional response to pain and analgesia. In the medial thalamic nuclei, they relay spinothalamic inputs from the spinal cord to the cingulate gyrus and limbic structures [116].

Kappa Opioid Receptors

Kappa opioid receptors bind dynorphin as the primary endogenous ligand. In the CNS, they are highly concentrated in the caudate-putamen, nucleus accumbens, amygdala, brain stem, neural lobe of the pituitary gland, and hypothalamus. In the PNS, these receptors are found in the sensory neuron dorsal root ganglion, stomach, duodenum, jejunum, ileum, and proximal and distal colon. They are primarily found in the limbic system, brain stem, and spinal cord. Their major effects include spinal analgesia, sedation, dyspnea and respiratory depression, dependence, and dysphoria [115]. The kappa opioid receptor subtype k3 is considered the primary analgesic mediator [54].

Delta Opioid Receptors

Delta receptors are mostly confined to CNS structures of the pontine nuclei, amygdala, olfactory bulbs, and deep cortex, but are also found in the GI tract and the lungs. They mediate spinal and supraspinal analgesia and the psychomimetic and dysphoric effects of opioid analgesics [9,112].

Other Potential Opioid Receptors

Other opioid-like receptors have been identified in the CNS, including the opioid receptor like-1 (ORL-1). In contrast to the classic opioid receptors, the ORL-1 receptor is insensitive to the opioid antagonist naloxone. Opioids can bind to and activate the toll-like receptor 4 (TLR4), an innate immune pattern-recognition receptor [62].

OPIOID ANALGESIC MECHANISM

Opioid analgesia results from a complex series of neuronal interactions, largely mediated by the high density of opioid receptors in the dorsal horn of the spinal cord and in subcortical regions of the brain [109]. The analgesic effects of opioids result from two general processes: 1) direct inhibition of ascending transmission of pain signaling from the dorsal horn of the spinal cord, and 2) activation of descending pain control circuits from the midbrain to the dorsal horn of the spinal cord [112]. All three opioid receptor types mediate spinal analgesia. Supraspinal analgesia is primarily mediated by mu opioid receptor subtype 1. Opioid receptors are coupled to the superfamily of inhibitory G proteins. Receptor activation inhibits adenylate cyclase, reducing generation of cyclic adenosine 3,5 monophosphate and other second messengers. Potassium conduction is activated, inhibiting calcium influx to hyperpolarized target cells and reducing their response to depolarizing pulses. Neurotransmitter release is inhibited, and generation of postsynaptic impulses is decreased [62,109].

Although drugs such as morphine are highly selective for mu opioid receptor and bind multiple mu receptor subtypes, mu opioid agonists greatly differ by interaction with different receptor variants and other opioid and non-opioid receptors [108].

Spinal Level

The spinal cord dorsal horn is a primary analgesic site of opioids and is densely populated with mu (70%), delta (20%), and kappa (10%) opioid receptors. Opioid receptors are localized on presynaptic afferent fibers, interneurons, and postsynaptic projection neurons [62]. Opioids bind to and activate mu receptors, which inhibit the release of pain mediators such as substance P, glutamate, and nitric oxide from nociceptive afferent neurons. Spinal level analgesia appears to elevate pain thresholds [109].

Supraspinal Level

At supraspinal levels, opioids produce analgesia by attenuation of the subjective evaluation of pain. After morphine is given for severe pain, patients report pain but without the associated anguish and distress. Conscious awareness and pain response are retained but modified by changes in emotional response to pain, mediated in part through opioid receptors in the limbic system [109].

Opioid receptors are highly concentrated in the medial thalamus, where incoming sensory information associated with intense and deep pain is filtered and then relayed to the cerebral cortex. This opioid effect on medial thalamus pain signal filtering greatly contributes to analgesia [109].

Opioid receptors are highly localized in subcortical brain regions where descending pain-modulating pathways originate. Normally, these pathways are inhibited by GABAergic neurons that project to descending inhibitory neurons of the brain stem. Opioid analgesics bind to and activate mu receptors on GABAergic neurons; this inhibits GABA to activate descending pain-modulating pathways [62,109]. In addition, opioids activate ascending serotonin/norepinephrine pathways that project to forebrain centers to regulate the emotional response to pain [107].

The greatest factor that contributes to opioid analgesia is concentration of the drug on the mu receptor, which can be altered by pharmacokinetic processes that influence plasma concentration of the opioid by impacting its absorption, distribution, metabolism, or excretion. Intrinsic properties of the opioid, such as lipid solubility, also contribute to opioid receptor concentration [117].

Neuropathic Pain

Opioid analgesics have historically been considered less effective in neuropathic pain, but more recent evidence provides some support for their use. The extent of neuropathic pain reduction correlates with the duration of opioid therapy, possibly accounting for the mixed results in short-term studies [118,119]. A 2011 study discovered previously unknown mu and kappa receptor expression on numerous peripheral tissues, immune cells, and joint capsules/synovium. The administration of opioids by injection into painful peripheral tissue sites results in pain relief in the absence of CNS activity, which supports the existence of localized peripheral opioid receptors [120].

Opioid effectiveness in neuropathic pain may be influenced by the capacity to inhibit voltage-gated sodium channels and individual channel type. Buprenorphine is more effective in blocking sodium channels than meperidine, lidocaine, and bupivacaine, possibly from greater lipophilicity, as this is a major factor in local anesthetic potency [119]. Sufentanil, fentanyl, and tramadol, but not morphine, are effective in blocking neuronal Nav 1.2 and may have greater clinical effect in some forms of neuropathic pain [121].

Inflammation enhances opioid anti-nociceptive action by peripheral mechanisms that activate during later (but not early-stage) inflammation, suggesting that timing of opioid administration contributes to analgesic efficacy in inflammatory pain [120]. Opioids are also effective in reducing the "air hunger" of dyspnea in patients suffering from cancer or respiratory or cardiovascular insufficiency [107].

9. OPIOID ANALGESIC PHARMACOLOGY

Opioids have been a mainstay of pain treatment for thousands of years and remain so today. The opium poppy, Papaver somniferum, is the oldest and most prevalent source of opium and opioid analgesics. The opium poppy was grown in the Mediterranean region at least as early as 5000 B.C.E. and has since been cultivated in a number of regions throughout the world.

The first historical medical reference to opium dates back to the 3rd century B.C.E. by Arab physicians experienced in its therapeutic uses. In 1806, Friedrich Sertürner reported the isolation of a pure substance in opium that he named morphine, after Morpheus, the Greek god of dreams [112]. Sertürner also published the first report of morphine toxicity in 1817. In this account, he discussed his experimentation of administering the alkaloid to himself, three young boys, three dogs, and a mouse. One of the dogs died, and the effects of morphine on Sertürner and his three young volunteers were described as "near-fatal." In the 1850s, the first recorded morphine overdose fatality was reported by Alexander Wood when performing one of the first morphine injections on his wife, who subsequently died of respiratory depression [122].

Raw opium contains numerous alkaloids, but only morphine, codeine, thebaine, and papaverine have an identified use in medicine. Because the synthesis of morphine is difficult, the opium poppy plant remains the primary source of morphine [107]. Thebaine is a minor constituent of opium that chemically resembles morphine and codeine but produces a stimulant, rather than calming, effect. Thebaine is not used medicinally but is converted into oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, and buprenorphine [123].

The numerous synthetic derivatives of morphine and thebaine are produced by relatively simple modifications of the parent molecule. For example, morphine is transformed into codeine by methyl substitution on the phenolic hydroxyl group and into diacetylmorphine by acetylation at the 3 and 6 positions (to produce heroin). Structural alteration of opioid molecules has been performed with the goal of producing an opioid molecule with greater opioid receptor affinity, to alter drug activity from agonist to antagonist, to change lipid solubility, and to increase resistance to metabolic breakdown. Although numerous opioid analgesics have been developed with clinical effects similar to morphine, morphine remains the criterion standard by which the analgesic efficacy of new opioids is measured [107].

There are several ways to classify the various opioids (Table 1). The traditional approach to opioid classification is grouping by analgesic potency into strong, intermediate, and weak subgroups [9]. Opioids may also be grouped into chemical classes, including phenanthrenes (the prototypical opioids), benzomorphans, phenylpiperidines, diphenylheptanes, and phenylpropyl amines [106]. A more pharmacologically and clinically relevant classification approach is grouping by functional interaction as mu receptor agonists, partial agonists, mixed agonists-antagonists, or antagonists. For the purposes of this course, currently available opioids will be grouped and discussed by functional class.

Table 1: OPIOID ANALGESIC CLASSIFICATION SCHEMES

Category

Example Drugs

Analgesic Potency

Weak

Codeine

Intermediate

Buprenorphine

Pentazocine

Butorphanol

Nalbuphine

Hydrocodone

Tramadol

Tapentadol

Strong

Morphine

Oxycodone

Hydromorphone

Oxymorphone

Levorphanol

Fentanyl and analogs

Methadone

Meperidine

Chemical Classa

Phenanthrenes

Morphine

Codeine

Hydromorphone

Levorphanol

Oxycodone

Hydrocodone

Oxymorphone

Buprenorphine

Nalbuphine

Butorphanol

Benzomorphans

Pentazocine

Phenylpiperidines

Meperidine

Fentanyl and analogs

Diphenylheptanes

Methadone

Phenylpropyl amines

Tramadol

Tapentadol

Functional Activityb

Full agonist

Morphine

Codeine

Hydromorphone

Levorphanol

Oxycodone

Hydrocodone

Oxymorphone

Methadone

Fentanyl and analogs

Meperidine

Tramadol

Tapentadol

Partial agonist

Buprenorphine

Mixed agonist/antagonist

Pentazocine

Nalbuphine

Butorphanol

Antagonist

Naloxone

Naltrexone

Alvimopan

Methylnaltrexone

aUnder each class, the first listed opioid is the prototypical agent

bAt the mu opioid receptor

Source: [9,106]

Each opioid has a unique analgesic and adverse effect profile that reflects differences in opioid receptor selectivity, binding affinity, and activity (Table 2) [117]. Understanding the unique receptor activity profile of individual opioids can assist in the selection process. These inter-opioid differences help account for incomplete cross-tolerance, the basis for opioid rotation [124].

Table 2: RECEPTOR BINDING AFFINITY OF OPIOID ANALGESICS

Opioid Analgesic

Opioid Receptor

Other Receptors

Mu

Kappa

Delta

NE

5-HT

NMDA

Agonists

Codeine

+

+

Hydrocodone

+

+

+

Morphine

+++

+

+

Fentanyl

+++

Hydromorphone

++

+

Oxycodone

++

+

+

Oxymorphone

+++

Methadone

++

+

+

+

--

Meperidine

+

++

+

Levorphanol

+++

+

+

+

--

Tapentadol

+

+

Tramadol

+

+

+

Partial agonist

Buprenorphine

+

-

--

Agonist-antagonists

Pentazocine

-

++

Nalbuphine

-

+

+

Butorphanol

+

Antagonist

Naltrexone

---

---

-

+ = Low/moderate agonist

++ = Moderate/high agonist

+++ = High-affinity agonist

- = Low/moderate antagonist

-- = Moderate/high antagonist

--- = High-affinity antagonist

5-HT = serotonin, NE = norepinephrine, NMDA = N-methyl-D-aspartate.

Source: [9,117,119]

MU OPIOID RECEPTOR FULL AGONISTS

Mu opioid receptor agonists include the most powerful analgesics used in medicine and possess the greatest analgesic potency among opioids. Properties of opioids in this group include increasing efficacy with dose escalation, absence of a ceiling effect (defined as further dose increases failing to increase analgesia beyond a certain level), and lack of antagonism of other concurrently administered mu opioid receptor agonists. Despite these shared properties, substantial pharmacologic and clinical differences are found among these agents [9,125].

Morphine

Morphine (Roxanol, MS Contin, Avinza, Kadian, MorphaBond, Embeda) was first isolated from raw opium in 1803 and introduced as an analgesic in the United States in 1830. Hypodermic syringes were introduced in the mid-19th century, making morphine available for parenteral use with improved analgesic, sedative, and antitussive properties [126,127]. Morphine is the prototypical opioid and remains one of the most effective drugs for alleviating severe pain, remarkable given its clinical use spanning almost two centuries. The World Health Organization has designated morphine as a drug of choice for moderate-to-severe pain [105].

Morphine is a strong mu opioid receptor agonist and a weak kappa and delta receptor agonist. It can be administered intramuscularly (IM), intravenously (IV), subcutaneously (SC), rectally, epidurally, intrathecally, or orally. With IM/SC injection, the onset of effect occurs after 15 to 30 minutes, peak effect in 45 to 90 minutes, and duration of effect in roughly 4 hours. Following IV injection, the peak effect occurs in 15 to 30 minutes. When given IV, only a small portion of morphine reaches the CNS due to poor lipid solubility, a high degree of ionization at physiologic pH, protein binding, and rapid metabolism [117]. Morphine produces analgesia, euphoria, and a sensation of warmth. It increases pain threshold and alters the perception of noxious stimuli, even at low doses. Continuous, dull pain and pain originating in visceral organs, skeletal muscles, joints, and bone are most responsive to morphine [112].

The analgesic and respiratory depressant effects of morphine may not correlate with plasma concentrations, because CNS concentration peaks later and decays more slowly than plasma concentration. When given orally, morphine undergoes extensive first-pass hepatic metabolism, resulting in 40% to 50% of the oral dose reaching the CNS [117]. The elimination half-life of approximately two hours is independent of route of administration or formulation. Morphine administered by sublingual and buccal routes has a delayed onset of action compared with oral morphine (due to smaller peak plasma levels, lower bioavailability, and larger interpatient variability). Compared with the oral form, intrathecal morphine is 100 times more potent and epidural morphine is 10 times more potent (i.e., 0.5 mg intrathecally equals 5 mg epidurally) [105].

Oral morphine preparations are available in short-acting (SA) and ER formulations, including an ER formulation containing naltrexone to discourage tampering and diversion [117].

Hydromorphone

Hydromorphone (Dilaudid, Exalgo) is a semi-synthetic hydrogenated ketone of morphine with primary activity as a mu receptor agonist. It has roughly five to seven times the potency of morphine, with similar effects but possibly less sedation and greater euphoria [112]. Hydromorphone can be administered by parenteral, IV, rectal, and oral routes and is considered the best opioid for SC administration. Oral hydromorphone has a bioavailability of 50% and plasma elimination half-life of 2.5 hours [105]. Its high water solubility permits very concentrated formulations. A meta-analysis found significantly better analgesia with hydromorphone than morphine for acute pain, without significant differences in adverse effects [128].

Following oral administration of conventional-release hydromorphone, the drug is rapidly absorbed and undergoes hepatic first-pass elimination of approximately 50%. The terminal elimination half-life after IV administration is 2.5 to 3 hours, and the primary mode of elimination is through urinary elimination in the form of hydromorphone-3-glucuronide, the primary metabolite. Some metabolites may have greater analgesic activity than hydromorphone itself but probably do not contribute to its pharmacologic activity. The side effects are similar to morphine [129].

The first ER formulation of hydromorphone (Palladone) was approved for marketing in 2004. However, at the request of the FDA, Palladone was withdrawn from the U.S. market in 2005 by its manufacturer, Purdue Pharma, over the potentially fatal interaction with alcohol [130]. Another ER formulation, Exalgo, has since been introduced without this liability [131].

Codeine

Codeine (Tylenol with Codeine, Capital with Codeine, Vopac) produces analgesia solely through enzymatic conversion into morphine, so it is considered a pro-drug. A pro-drug is a drug ingested in a biologically inactive (or less active) form and biotransformed into an active (or more active) metabolite [132].

The oral bioavailability of codeine is 50%, with roughly 10% metabolized to morphine. However, at least 10% of individuals possess deficient activity of the hepatic enzyme necessary to metabolize codeine to morphine due to genetic variation or polymorphism. In these individuals, codeine has no analgesic effect and should be avoided.

Codeine can be used orally or IM for mild-to-moderate pain but has very limited use in severe pain. Codeine is also used as an antitussive and antidiarrheal. Codeine produces minimal euphoria, has low abuse liability, is less sedating, and is less likely to result in respiratory depression than morphine. Constipation is a common side effect. Because commercially available codeine is combined with acetaminophen or acetylsalicylic acid (ASA), the dosage should be monitored to ensure daily safe limits are not surpassed [106]. Codeine has an analgesic ceiling, with no additional analgesic benefit from doses greater than 60 mg [133].

Oxycodone

Oxycodone (Oxy IR, Percocet, Tylox, OxyContin, Xtampza ER, Targiniq ER) is a semisynthetic opioid analgesic derived from the natural alkaloid thebaine and has been in medical use since 1917. Although oxycodone mu opioid receptor affinity is at least 20 times less than morphine, oxycodone possesses high oral bioavailability and delivers analgesia and other subjective effects comparable to oral morphine [105]. Unlike morphine, oxycodone has moderate affinity and agonist activity at the kappa-2b opioid receptor, which contributes to its efficacy in neuropathic pain [119].

Oxycodone is available in SA and ER oral formulations. Oxycodone SA has a half-life of approximately two to four hours and a bioavailability of 50% to 60%. The overall clinical effects of oxycodone reflect primary mu receptor activity, with analgesia, respiratory depression, euphoria, and abuse liability comparable to other mu agonists. Oxycodone differs from morphine by producing less dysphoria and by more rapid transport through the blood-brain barrier, resulting in greater CNS than plasma concentrations, the reverse of morphine [119].

In addition to its low-dose combination with acetaminophen, oxycodone is formulated as the sole analgesic in 10-, 20-, 40-, and 80-mg controlled-release (CR) tablets and 5-mg SA capsules. Sales of oxycodone CR (OxyContin) 160 mg were discontinued by Purdue Pharma in 2001 over abuse and diversion concerns [134].

Oxymorphone

Oxymorphone (Numorphan, Opana) was first synthesized in Germany in 1914, patented in the United States in 1955, and introduced in 1959 for parenteral injection and in suppository form. It then became available as an oral SA opioid, but this was withdrawn from the U.S. market in the early 1970s. Following reintroduction in 2006 in oral SA and ER formulations, its use in the treatment of noncancer pain has steadily increased [135].

Oxymorphone is a semisynthetic derivative of the parent compound morphine and has a high affinity for the mu opioid receptor and negligible interaction with kappa and delta opioid receptors [136]. The potency is roughly 1.2 times that of morphine, but with less sedative effects [9]. Oxymorphone possesses less protein binding (10% to 12%) than morphine (30% to 35%) and oxycodone (45%), and its highly lipophilic properties provide ease in blood-brain barrier penetration [131]. The oral bioavailability of oxymorphone is approximately 10%, the lowest of the full agonists. In healthy volunteers, the half-life ranges from 7.2 to 9.4 hours, longer than that of morphine, hydromorphone, and oxycodone. Oxymorphone SA tablets may be given at six-hour intervals, whereas the ER formulation is dosed twice daily. Steady-state conditions are achieved after three to four days. Oxymorphone is subject to hepatic first-pass effects and is excreted by the kidneys. As such, this agent has a prolonged half-life and accumulates in patients with renal failure. In patients with hepatic insufficiency, increasing the dosing interval is recommended [105].

Oxymorphone is an effective opioid analgesic with a safety profile comparable to other mu agonist opioids. It may have a safety advantage in elderly or frail patients for whom adverse drug interactions are concerning [137]. However, in 2017, the FDA requested Opana ER be removed from the market amid abuse concerns [138].

Hydrocodone

Hydrocodone (Zohydro ER, Hysingla ER, Lortab, Vicodin) is a semi-synthetic codeine derivative that more closely resembles morphine in its pharmacologic profile. Hydrocodone was first used medically as a cough suppressant and analgesic in the 1920s [123,139]. It exhibits a complex pattern of metabolism, including demethylation at the 3-carbon position into hydromorphone, which has stronger mu receptor binding than the parent drug. Thus, similar to codeine, hydrocodone is suggested to be a pro-drug. Its analgesic properties are similar in potency to codeine [9].

Hydrocodone is effective as a cough suppressant and as an analgesic for moderate to moderately severe pain. It is most frequently prescribed in combined formulations with acetaminophen (Vicodin, Lortab), aspirin (Lortab ASA), ibuprofen (Vicoprofen), and antihistamines (Hycomine) and as an antitussive liquid formulation [123]. The hydrocodone/ibuprofen product is intended for short-term (generally less than 10 days) management of acute pain from trauma, musculoskeletal or back pain, postoperative pain, abdominal pain, or dental pain. Two single-entity hydrocodone ER products are now available; in addition to sparing patients with comorbidity or who require long-term use from acetaminophen or nonsteroidal anti-inflammatory drug (NSAID)-related adverse effects, these products are thought to provide more stable analgesic with slow release and less euphoria [140].

Methadone

Methadone (Dolophine, Methadose) was first synthesized as an analgesic in Germany during World War II in response to the difficulty obtaining raw opium to synthesize morphine [141]. Although chemically unlike morphine or heroin, methadone produces many of the same pharmacologic and clinical effects. It was introduced into the United States in 1947 as the analgesic Dolophine.

High-dose methadone can block the effects of heroin and other opioid drugs by diminishing reward and reinforcement effects, and this has been the primary use of methadone in the United States over the last five decades. In the late 1990s, methadone entered clinical use as an analgesic [123].

Evidence Based Practice Recommendation

The American Society of Interventional Pain Physicians recommends methadone for use after failure of other opioid therapy and only by clinicians with specific training in its risks and uses.

https://painphysicianjournal.com/current/pdf?article=NDIwMg%3D%3D&journal=103

Last Accessed: May 22, 2023

Level of Evidence: I (Evidence obtained from multiple relevant high quality randomized controlled trials for effectiveness)

Methadone is available in racemic form with a 50:50 mixture of two enantiomers: a levo-(R)-enantiomer and a dextro-(S)-enantiomer. The 1(R)-enantiomer produces opioid analgesia as a mu opioid receptor agonist, while the d(S)-enantiomer functions as an N-methyl-D-aspartate (NMDA) receptor antagonist and reuptake inhibitor of serotonin and norepinephrine. These pharmacologic properties expand indications for its use beyond those of most other mu receptor agonists [119]. Methadone produces analgesia very similar to other commonly used opioids, but its lack of euphoric effects relative to other agents can make it advantageous in some patient populations. NMDA receptor antagonism can make methadone highly beneficial in managing patients with a history of prolonged opioid use with high opioid tolerance or opioid-induced hyperalgesia [112].

In the inpatient setting, IV methadone can be very effective in managing patients with true morphine allergies. Patients predicted to have long-term opioid requirement can initiate with IV methadone and are easily transitioned to oral methadone [112]. The highly variable elimination half-life is 8 to 60 hours, and single-dose analgesia lasts 4 to 8 hours. This necessitates great caution during initiation and titration, because patients may re-dose when analgesia wears off and pain reappears, leading to accumulation, toxicity, and overdose [112]. Methadone requires a thorough understanding of its pharmacokinetic properties to safely prescribe.

Levorphanol

Levorphanol is the only commercially available opioid agonist of the morphinan series and the levo-enantiomer of dextrorphan, a potent NMDA receptor antagonist [142]. Levorphanol was first synthesized more than 40 years ago as an alternative to morphine, and it produces effects very similar to morphine, with greater potency. Analgesia is produced by activity as a mu, delta, and kappa opioid receptor agonist, NMDA receptor antagonist, and norepinephrine and serotonin reuptake inhibitor. The NMDA receptor antagonist potency of levorphanol is equivalent to ketamine and superior to methadone [54]. Single-dose analgesic duration is 6 to 8 hours, and the elimination half-life is 11 hours. This increases the potential for drug accumulation, and patients should be observed for toxicity during the initial two to five days. Roughly 50% of oral levorphanol clears first-pass metabolism and is bioavailable [143]. Initiate dosing every four hours, and every six to eight hours when steady state is reached (after one to two weeks) [19,143].

During the 1980s, levorphanol fell into disuse with the introduction and aggressive marketing of ER forms of morphine, oxycodone, and fentanyl. Renewed interest in this drug was prompted by recognition that many patients with neuropathic pain do not obtain pain control with standard full-agonist opioids. Levorphanol shows promise in treating neuropathic pain, severe pain in hospice patients, and severe pain in patients with chronic noncancer pain uncontrolled by other mu opioid receptor agonists. With empirical confirmation, levorphanol has potential as first-line or second-line therapy for these indications, but little research has been published on this drug [49,54,143,144].

The brand-name drug Levo-Dromoran is discontinued, and no parenteral form is available. The sole available dose and formulation for levorphanol is an oral 2-mg tablet [143]. As a generic drug, levorphanol has not been promoted or marketed [144].

Roxane Pharmaceuticals stopped manufacturing levorphanol in 2015. Shortly thereafter, Sentynl Therapeutics, Inc., released a "new" levorphanol to the market. Unfortunately for pain sufferers who responded well to levorphanol, the average wholesale price of 2-mg tablets increased 2,073%, from $214/100 tablets to $4,650/100 tablets [145].

Fentanyl and Analogs

Fentanyl (Duragesic) is a phenylpiperidine-class opioid and is structurally similar to meperidine. Fentanyl was first synthesized in Belgium in the late 1950s and introduced to the U.S. market in the 1960s as an IV anesthetic. Other fentanyl analogues were subsequently introduced, including alfentanil, an ultra-short acting (5 to 10 minutes) analgesic; sufentanil, an exceptionally potent analgesic (1,000 times more potent than morphine) for use in cardiac surgery; and remifentanil, with similar potency to fentanyl and ultra-short duration of 3 to 10 minutes [107].

Fentanyl has an analgesic potency 80 to 100 times that of morphine. The highly lipophilic nature of the molecule allows rapid blood-brain barrier penetration and quick onset of action (two to three minutes with IV administration). Primary clinical effect comes from mu receptor agonist activity and to a lesser extent from kappa and delta receptor activity [146]. The pharmacologic profiles of fentanyl and its congeners (sufentanil, remifentanil, and alfentanil) are similar to other mu-receptor agonists, although fentanyl produces fewer side effects of sedation, nausea and vomiting, urinary retention, and pruritus than morphine or hydromorphone [112]. The fentanyls are distinguished from other mu opioid receptor agonists by shorter time to peak analgesic effect, rapid termination of effect after small doses, and relative cardiovascular stability, making them very popular for surgical use. The respiratory depression potential is similar to other mu receptor agonists, with a more rapid onset [107]. Fentanyl formulations include several transmucosal and buccal preparations for rapid-onset analgesia in breakthrough pain, and a transdermal preparation for sustained analgesia in chronic pain.

Transmucosal immediate-release fentanyl formulations are approved by the FDA for use in breakthrough pain. Transdermal fentanyl was developed to circumvent unsuitability for oral use and is indicated for continuous sustained-release analgesia in the treatment of chronic pain [147]. With initial use, the 6- to 12-hour lag time from application to onset of action requires the use of short-acting opioids for analgesic coverage and for breakthrough pain; morphine, tapentadol, or oxycodone are preferred. Steady state is usually achieved in three to six days. With patch removal, a subcutaneous reservoir remains, and up to 24 hours is usually needed for drug clearance [9,117].

Tramadol

Research efforts into mechanisms of pain relief during the 1990s focused on centrally mediated monoamine transmission and its influence on chronic and neuropathic pain. Clinical evidence demonstrated that increasing the extracellular concentrations of serotonin and norepinephrine in descending pain inhibitory pathways produced an analgesic effect. Norepinephrine is the primary monoamine contributor to pain signal attenuation and is especially useful in neuropathic pain. Combining an opioid agonist with a monoamine reuptake inhibitor was hypothesized to produce opioid-sparing effects, increased pain control, and decreased adverse effects. These efforts led to the development of tramadol and tapentadol [54].

Tramadol (Ultram, ConZip) is a synthetic codeine analog from the aminocyclohexanol structural group and a racemic compound. The positive enantiomer acts as a serotonin reuptake inhibitor, with 30% of total analgesic effect from weak mu opioid receptor agonism; the negative enantiomer inhibits norepinephrine reuptake [119]. Tramadol has greater efficacy in neuropathic than nociceptive pain. Monoamine reuptake inhibition accounts for tramadol's efficacy in neuropathic pain [119].

The primary metabolite, O-desmethyltramadol, has higher mu opioid receptor affinity and two to four times greater analgesic potency than the parent drug. Tramadol is as effective as morphine in mild-moderate pain. Its bioavailability is 68% following an oral dose and 100% following IM administration [148].

Tramadol has lower abuse potential than other opioids but is associated with the significant adverse drug reactions of serotonin syndrome and seizures. Dosage should not exceed 400 mg/day due to the seizure risk, and even doses less than 400 mg/day can increase seizure potential in patients with epilepsy or risk factors for seizure [119]. Seizure risk is elevated by concurrent use of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), cyclobenzaprine and other tricyclic compounds, other opioids, neuroleptics, and certain other drugs. Tramadol should not be used within 14 days of monoamine oxidase inhibitors (MAOIs), as this increases risk of seizures or serotonin syndrome [9].

Tapentadol

Tapentadol (Nucynta) is a novel synthetic opioid structurally related to tramadol that was approved in 2009. It was intentionally designed to overcome the barriers to efficacy associated with tramadol, such as the potential risk for serotonin syndrome [54]. Tapentadol has 18 times less affinity for mu opioid receptor than morphine and is 5 times less potent than oxycodone (i.e., 50 mg tapentadol is equivalent to 10 mg oxycodone) [149,150]. Tapentadol has an oral bioavailability of 32%, and plasma protein binding is 20%. Time to maximum serum concentration is achieved in 1.25 to 1.5 hours, and the half-life is 24 hours [105].

Tapentadol has no active metabolites and primarily undergoes hepatic metabolism via phase II conjugation. Tapentadol selectively inhibits norepinephrine reuptake with affinity and potency comparable to venlafaxine, which increases efficacy and avoids the potential risk for serotonin syndrome. In a study of patients with chronic pain receiving tapentadol for up to two years, 88% did not experience opioid withdrawal symptoms on abrupt withdrawal and symptoms were mild-to-moderate among those who did [151].

Analgesic tolerance develops at significantly lower rates with tapentadol than with morphine. It has a low risk for drug interactions, does not depend on metabolic activation for efficacy, and shows a lower incidence in adverse GI effects such as nausea, vomiting, and constipation relative to other opioids [54,152].

A review of prolonged-release (PR) tapentadol concluded its broad analgesic efficacy, ease of initiating and titrating in opioid-naïve and opioid-experienced patients, favorable pharmacokinetic profile with few medication interactions, low abuse potential, and low risk of withdrawal after cessation may offer significant advantages over classic opioid analgesics. Tapentadol is not recommended in patients with severe renal or hepatic impairment, because studies are lacking in these patient populations [153].

Meperidine

Meperidine (Demerol, Meperitab) is a synthetic phenylpiperidine derivative with weak mu and kappa receptor agonist activity. It has roughly one-tenth the potency of morphine. The structural similarity to atropine is consistent with its original development as an anti-muscarinic agent. The effects are similar, but not identical, to morphine, with shorter analgesic duration and less antitussive and antidiarrheal efficacy. In equivalent analgesic doses, meperidine produces comparable sedation and respiratory depression and possibly greater euphoria than morphine, although some patients experience dysphoria. Pharmacologic differences from morphine include increased risk for tachycardia and dry mouth and less biliary tract spasm and miosis. Meperidine may significantly decrease blood pressure, especially when administered to elderly or hypovolemic patients [106,125].

The short analgesic duration (2.5 to 3.5 hours) makes meperidine impractical for persistent pain, although it is a useful analgesic in labor and delivery and uniquely effective in treating post-operative shivering. Accumulation of the neurotoxic metabolite normeperidine contraindicates its use for longer than 48 hours or at doses of 600 mg or greater over 24 hours in any context. Normeperidine accumulation is especially likely in patients with impaired renal function. The neuroexcitatory properties of this metabolite can cause tremors, muscle twitches, delirium, or seizures; multifocal myoclonus develops before seizures and can serve as a warning sign. Normeperidine toxicity is not reversible with naloxone. Administration of meperidine to patients receiving MAOIs can lead to profound and possibly fatal autonomic instability [9,112,125]. Clinical use of meperidine has declined into virtual disuse in recent years [117].

Propoxyphene

Propoxyphene (Darvon, Darvocet) was first marketed in 1957 to treat mild-to-moderate pain. Propoxyphene primarily binds to mu opioid receptors to produce mild analgesia, with potency one-half to one-third that of codeine [9]. Propoxyphene also became a popular drug of abuse. In 2010, the FDA requested the removal of propoxyphene from the U.S. market due to new data showing increased risk for serious abnormal heart rhythms with its use, even at therapeutic doses [154]. This drug is no longer available domestically.

Levo-Alpha-Acetylmethadol

Levo-alpha-acetylmethadol (LAAM) is a synthetic mu opioid receptor agonist closely related to methadone, but with a longer duration of action (48 to 72 hours). LAAM was originally developed by German chemists in 1948 and as early as 1952 was identified as an agent that could prevent opioid withdrawal symptoms for more than 72 hours. In 1993, the FDA approved LAAM for the treatment of opioid addiction, with the intent to build on the strengths and improve on the drawbacks of methadone [123,155]. However, concerns over cardiovascular toxicity and subsequent under-utilization led to its withdrawal from the market in 2004 by the manufacturer, and LAAM is no longer commercially available in the United States [141].

PARTIAL AGONIST OPIOIDS

Partial agonists possess mu opioid receptor binding and activity, but to a lesser extent than full agonists such as morphine. Buprenorphine is the only commercially available partial agonist in the United States.

Buprenorphine

Buprenorphine (Belbuca, Suboxone, Subutex, Butrans) is a semi-synthetic opioid first derived from thebaine in 1966, initially as an alternative to methadone therapy for heroin addiction [156]. Injectable buprenorphine (Buprenex) was approved in 1981 for acute pain, and two sublingual formulations (Suboxone and Subutex) were approved for treating opioid addiction in 2002 [54]. The buprenorphine transdermal system was approved by the FDA in 2010 for the management of moderate-to-severe chronic pain in patients requiring continuous opioid analgesia for an extended time period. More recently, buprenorphine buccal film (Belbuca) was approved for the same indication. The transdermal and buccal products were developed to overcome the very low oral bioavailability resulting from substantial first-pass intestinal and hepatic metabolism [119].

The mu opioid receptor-binding kinetics of buprenorphine are unique. Receptor affinity is high, but buprenorphine associates and dissociates slowly (30 and 166 minutes, respectively) and incompletely (50%). This receptor saturation is particularly important with buprenorphine, because its high affinity and robust binding capacity make displacement by naloxone difficult or impossible. The relative resistance to naloxone antagonism requires higher doses for successful reversal [54].

The analgesic properties of buprenorphine mostly originate from mu opioid receptor interaction with high binding affinity and low efficacy, yielding partial agonist effects. Other contribution comes from activity as a nociceptin opioid peptide receptor partial/full agonist and kappa opioid receptor antagonist [119]. Prolonged analgesia can be achieved with buprenorphine from its highly lipophilic properties and prolonged receptor occupancy. It may have superior efficacy in neuropathic pain due to its pharmacologic profile and has also shown anti-hyperalgesic effects [119,148]. A high-dose (15 mg) analgesic ceiling effect can occur, but this dose level is infrequent with analgesic use [123,148]. Buprenorphine may act as a mu opioid receptor antagonist at high doses [119].

After application of the transdermal patch, plasma concentrations steadily increase, and the minimum effective analgesic dose is reached more rapidly with higher-dose patches. Steady state is reached after the third consecutive application. Bioavailability of the transdermal formulation is 60% compared with the IV route. Effective plasma levels occur within 12 to 24 hours and last for 72 hours. It takes 60 hours to reach maximum concentration. After patch removal, concentrations decrease by 50% in 12 hours, and then decline more gradually [105]. Transdermal buprenorphine has a maximum dose limited to 20 mcg per hour due to the potential for prolonged QTc wave interval at higher doses [9,125].

Buprenorphine possesses a dose-ceiling effect for respiratory depression, reducing the likelihood of this potentially fatal consequence. Importantly, this applies only in the absence of co-ingested CNS or respiratory depressants. Side effects are similar to other opioids, but it is important to remember that as a result of its antagonist properties, buprenorphine can precipitate withdrawal symptoms in patients who are physically dependent on other commonly used opioids [112].

MIXED AGONIST/ANTAGONIST OPIOIDS

For more than 70 years, the ultimate goal of analgesic research has been the discovery of an opioid agent producing effective analgesia without respiratory depression or abuse/addiction potential [157]. Earlier efforts in this quest led to synthesis of the first mixed agonist-antagonist, N-allylmorphine (nalorphine), in 1942. Although nalorphine was a potent analgesic and antagonist to most morphine effects, dosing sufficient for analgesia produced severe psychotomimetic effects that made the drug unsuitable for clinical use. However, discovery and development of this opioid lay the groundwork for subsequent synthesis of several mixed agonist-antagonists that have entered clinical use [9,158].

Available mixed agonist-antagonists act as mu receptor antagonists and kappa receptor agonists. Those in current clinical use share the characteristics of an analgesic ceiling effect, whereby dose escalation beyond a certain point will not increase analgesia but increases side effects. These agents have a greater likelihood of the side effects of dysphoria, delusions, and hallucinations than full mu agonists and an increased risk of triggering an opioid withdrawal crisis in patients with physiologic dependence to full mu agonists. Kappa receptor agonist activity contributes to the analgesic and side effect profile.

These drugs should be used with caution in any patient currently receiving opioid agonists [9,117,125]. Practice guidelines recommend against using mixed agonists/antagonists in cancer pain, and their absence from practice guidelines for chronic noncancer pain reflects discouragement for use in these patients as well [19,159,160]. However, several niche indications for pain have emerged.

Pentazocine

Pentazocine (Talwin) was the first opioid in this class to enter clinical use following the development of nalorphine; it was introduced to the U.S. market as an analgesic in 1967 [123]. Kappa opioid receptor activation accounts for the analgesic effects and potential side effects of dysphoria and psychotomimesis [127]. The analgesic potency is 25% to 50% of morphine. Moderate analgesia is produced by an oral dose of 50 mg; with doses greater than 70 mg, an analgesic and respiratory depression ceiling occurs. Pentazocine has lower abuse potential than morphine, but prolonged daily use can lead to physical dependence. Dysphoric and psychotic side effects are dose proportional and reversed with naloxone. Pentazocine can increase serum catecholamine levels. Clinical use is restricted by limited analgesia, antagonism of concurrent mu agonist opioids, and the potential for GI and cardiovascular adverse effects [158].

Butorphanol

Butorphanol (Stadol) is a morphinan congener with a pharmacologic profile similar to pentazocine. It is more suitable for acute than chronic pain. Side effects of drowsiness, weakness, sweating, sensation of floating, nausea, and psychotic-like effects are less frequent than with pentazocine. Physical dependence can develop from regular use [107]. Butorphanol was initially available as an injectable formulation (Stadol). More recently, a nasal spray (Stadol NS) became available, and the ensuing abuse and diversion of this product led to its designation as a Schedule IV controlled substance [123].

Butorphanol is a mu opioid receptor antagonist and kappa opioid receptor agonist, and the opioid receptor affinity ratio of 1:25:4 for mu, kappa, and delta receptors, respectively, indicates greater delta than mu opioid receptor affinity [161]. With parenteral administration, butorphanol has analgesic potency five to eight times greater than morphine. It has a rapid onset, with peak analgesia within 1 hour, plasma half-life of 2 to 3 hours, and elimination half-life of 4.5 to 5 hours. With oral administration, bioavailability is 17% that of a comparable IV dose. The intranasal formulation is commonly used in the treatment of migraine headache. The IV formulation is effective in moderate-to-severe pain and is typically used for postoperative pain and pain control during labor. With analgesia mediated by kappa and not mu receptor activation, butorphanol may be an effective analgesic option in patients with history of opioid use disorder [112]. At a dose of 10 mg IM, butorphanol induces respiratory depression similar to a comparable morphine dose, but the level of depression does not increase with dose escalation due to the ceiling effect [162,163].

Nalbuphine

Nalbuphine (Nubain) is similar in structure to naloxone, with primary activity as a kappa opioid receptor agonist, a mu opioid receptor partial antagonist, and delta receptor activity. On a per-milligram basis, analgesic potency is comparable to morphine, and opioid antagonist potency is one-fourth that of nalorphine and 10 times that of pentazocine. Respiratory depression is similar to morphine at equianalgesic doses, does not increase at doses greater than 30 mg, and is reversed by naloxone. With IV administration, onset is 5 to 10 minutes, duration is 3 to 6 hours, and elimination half-life is roughly 5 hours.

The most common side effect is sedation. Nalbuphine produces less dysphoria than other mixed agonist-antagonists and may produce euphoria; hemodynamic parameters are unaffected. Nalbuphine can reverse the respiratory depression and pruritus produced by mu agonists while maintaining analgesia; in this context, it is co-administered epidurally [112,164,165,166].

OPIOID ANTAGONISTS

A fourth group of opioids, opioid antagonists, bind and inactivate opioid receptors. Naltrexone and naloxone have traditionally been used to reverse potentially fatal overdose from opioid receptor agonists such as morphine or heroin. Opioid agonist molecules on mu opioid receptor are displaced, agonist effects on mu opioid receptor are abruptly halted, and opioid-dependent patients rapidly experience full alertness, analgesic loss, and opioid withdrawal [167].

Clinical trials with low-dose naltrexone have found unexpected and paradoxical enhancement rather than blockade of analgesia when co-administered with morphine and other opioid agonists in postoperative pain or severe intractable pain. Other evidence suggests analgesic efficacy as monotherapy in Crohn disease, irritable bowel syndrome, and fibromyalgia [168]. These findings led to the development and introduction of the peripheral-acting mu receptor antagonists alvimopan, methylnaltrexone, and naloxegol for severe opioid-induced constipation [169,170].

In addition to opioid-induced constipation, opioid antagonists are FDA-approved for the treatment of alcohol and opioid use disorder (naltrexone 50–100 mg/day oral) and opioid overdose (naloxone 0.4–1.0 mg/dose IV or IM). In pain medicine, the dose ranges of naltrexone and naloxone are substantially lower. Of the two, naltrexone is much more widely used, and published pain medicine studies have used dose ranges of 1–5 mg (termed "low-dose") or <1 mg in microgram amounts (termed "ultra-low-dose") [168]. For example, case studies have reported dramatic improvement in refractory pain with intrathecal administration of an opioid agonist combined with ultra-low-dose naloxone in the low nanogram range [171].

The mechanism of low-dose and ultra-low-dose opioid antagonists is not fully known and is the subject of investigation [168]. One explanation describes a sequential action, whereby binding and inhibition first occurs at excitatory receptors, followed by binding at inhibitory receptors. This decrease in excitation facilitates a broader clinical expression of inhibitory function, which potentiates analgesia and reduces adverse effects. For example, with opioid-induced hyperalgesia, ultra-low-dose naltrexone appears to act through excitatory blockade to promote analgesia and tolerability [172,173].

Naloxone

Naloxone (Narcan) is an allyl-derivative of noroxymorphone first synthesized in 1960. It acts as a competitive antagonist with slightly higher affinity for mu receptors over kappa and delta receptors, and inhibits the entire range of pharmacologic effects produced by mu agonists. Naloxone is efficiently absorbed after oral administration, but extensive hepatic first-pass metabolism (>95%) and low bioavailability makes it unsuitable for oral use [122,127]. Following IV or IM administration, peak plasma concentration occurs at 10 minutes, the duration of action is 1 to 4 hours, and the half-life is 30 to 81 minutes [168]. Peak effect is noted in 30 minutes following intranasal administration, with a half-life of approximately two hours.

Naltrexone

Naltrexone (ReVia, Depade) has activity comparable to naloxone but with a longer duration of action and higher oral bioavailability (40%) [127]. Following oral administration of naltrexone, the peak plasma concentration occurs at 1 to 2 hours, the duration of action is up to 24 hours, and the half-life is up to 14 hours [168].

Methylnaltrexone

Methylnaltrexone bromide (Relistor) is a naltrexone derivative with high peripheral opioid receptor selectivity resulting from low lipid solubility and poor blood-brain barrier penetration into the CNS. Methylnaltrexone is indicated for opioid-induced constipation refractory to conventional therapies in patients with advanced illness receiving palliative care. It binds and antagonizes mu opioid receptors in the GI tract. With little oral bioavailability, methylnaltrexone is administered by subcutaneous injection [174].

Alvimopan

Alvimopan (Entereg) is a mu opioid receptor antagonist with limited CNS penetration due to its large molecular weight and polarity that facilitates selective GI mu opioid receptor antagonist activity. Alvimopan was developed to address the problem of bowel dysfunction following intestinal surgery and opioid use for postoperative pain. It is FDA-approved only to accelerate the time to upper and lower GI recovery after partial large or small bowel resection surgery with primary anastomosis [174]. Concerns over the risk of serious adverse cardiovascular events led the FDA in 2012 to restrict its use to a maximum of 15 capsules, a seven-day maximum duration, used only in hospitalized patients and only in hospitals with documented registration and completion of the Entereg Access Support and Education (EASE) program, a risk management program specific to alvimopan [175].

Naloxegol

Naloxegol (Movantik) is a polymer conjugate of naloxone administered orally once daily. It is FDA-approved for the treatment of opioid-induced constipation in adults with chronic noncancer pain. The 25-mg dose appears similar in efficacy to the 12.5-mg dose, with greater side effects associated with the higher dose. In phase III trials, the most common side effects were abdominal pain (21%), diarrhea (9%), nausea (8%), flatulence (6%), vomiting (5%), headache (4%), and hyperhidrosis (3%) [174].

OTHER OPIOIDS IN CLINICAL USE

Diphenoxylate (Lomotil) and loperamide (Imodium) are meperidine congeners FDA-approved for the treatment of diarrhea. Both drugs bind intestinal opioid receptors to slow GI motility through action on intestinal circular and longitudinal muscles. At approved anti-diarrheal doses, both agents lack significant CNS effects [107].

10. PHARMACOKINETIC FACTORS IN OPIOID ANALGESIC RESPONSE

Pharmacokinetics is the process by which the body absorbs, distributes, metabolizes, and excretes a drug, and pharmacokinetic factors fundamentally influence the safety, efficacy, and tolerability of opioid analgesics. This is true with fatal toxicity, whereby rising serum opioid concentrations overwhelm a patient's physiologic capacity to clear the opioids through metabolism and elimination. Aside from high-dose ingestion, fatal and non-fatal toxicity results from interference with opioid metabolism and excretion from genetic factors, drug interactions, medical comorbidities, or opioid analgesic formulation and dosing. These risks can be mitigated by improved prescriber knowledge and skills.

ABSORPTION AND DISTRIBUTION

Most opioids, including morphine, oxycodone, hydromorphone, methadone, tramadol, tapentadol, fentanyl, sufentanil, buprenorphine, and codeine, possess high GI permeability and are completely absorbed from the GI tract following oral administration. However, fentanyl and buprenorphine, due to extensive hepatic first-pass metabolism, have very low oral bioavailability, rendering their oral use ineffective [1]. (This differs from sublingual and buccal administration.)

To produce analgesic action in the CNS after absorption, opioids must penetrate the blood-brain barrier; highly lipophilic opioids possess a more rapid onset due to greater ease of blood-brain barrier transport [1]. The basis for the widely variable duration of effect among opioids is complex, not always explainable by the rate of plasma clearance and terminal half-life. For example, at equivalent analgesic doses, morphine produces longer analgesia than fentanyl but has a shorter half-life. This may be explained by morphine's relatively low lipid solubility and slower diffusion out of CNS tissue [106].

METABOLISM AND ELIMINATION

Many drugs, including opioids, must undergo biotransformation to be readily eliminated from the body. Opioid analgesic molecules that produce CNS effects must be lipophilic to cross cell membranes in the blood-brain barrier, and metabolism is performed to convert lipophilic opioids into hydrophilic metabolic products for elimination. This is achieved through hepatic enzymes. The metabolic process ends when the opioid byproducts are sufficiently hydrophilic for urinary excretion [176]. Medications can be substrates at multiple cytochrome (CYP) isoenzymes, inducing one while inhibiting another.

Hepatic enzymes facilitate two forms of metabolism: phase I and phase II [176]. Phase I metabolism consists of modification of the drug molecular structure through chemical reactions such as oxidation, reduction, or hydrolysis. The predominant catalysts for phase I drug metabolism are found in the CYP450 enzymatic superfamily [132]. Phase I metabolism of some opioids produces active analgesic metabolites, as with conversions of codeine into morphine, hydrocodone into hydromorphone, and tramadol into O-desmethyltramadol [177]. The CYP system is comprised of more than 50 isoenzymes, but more than 90% of opioid metabolism involves the 3A4, 2D6, or 2C9 isoenzymes [148].

Phase II metabolism is a chemical reaction whereby a drug is conjugated with a chemical moiety (e.g., a glucuronide) to readily promote renal excretion. The most important Phase II conjugation reaction is glucuronidation, catalyzed by members of the uridine diphosphate glucuronosyltransferase (UGT) enzyme family. Within the UGT enzyme family, the most abundant enzyme involved in phase II opioid metabolism is UGT2B7. In most cases, the conjugated drug is rendered inactive and loses biologic activity. The exception is morphine; its conjugated metabolite, morphine-6-glucuronide, is analgesic. UGT2B7 is the primary enzyme that metabolizes morphine, hydromorphone, and oxymorphone [132].

Some opioids undergo both phase I and phase II metabolism; the breakdown products of both phases can be active or inactive. The process of metabolism ends when the molecule is sufficiently hydrophilic for efficient excretion [176].

The metabolic products of opioids differ in pharmacologic and clinical relevance. Some have analgesic activity, some are toxic with accumulation, and others are inactive. Active metabolites can bind to and activate opioid or other receptors, compete with co-administered drugs or their metabolites when metabolism involves a common pathway, or alter the activity of its CYP450 metabolic pathway.

ADVERSE DRUG INTERACTIONS

One challenge in safe opioid analgesic prescribing is avoiding adverse drug interactions. Opioids have a narrow therapeutic index, potentially fatal concentration-dependent toxicity, and wide inter-individual variability. As discussed, many fatalities associated with opioid prescribing involve at least one other offending drug, and numerous reports of fatal pharmacokinetic adverse drug interactions with opioids have been published [132]. Elderly patients and patients with medical comorbidities typically require multiple medications, termed polypharmacy, which increases the risk of adverse drug interactions. Understanding the underlying cause of these interactions can mitigate a major toxicity risk when prescribing opioids [147].

Factors that interfere with opioid metabolism or excretion can cause opioids or metabolites to accumulate (leading to toxicity) or can accelerate their elimination (leading to analgesic failure). Conditions that can lead to delayed opioid metabolism include genetic predisposition (CYP450 isoenzyme polymorphism), hepatic and/or renal dysfunction, and drug-drug interactions [167]. Adverse opioid-drug interactions can involve pharmacokinetic or pharmacodynamic interactions, and while pharmacokinetic interactions involving CYP isoenzymes (phase I) are well characterized, those involving the UGT enzyme family (phase II) are less understood.

Among opioid analgesics, CYP metabolism occurs by either the CYP206 or CYP3A4 pathway. The propensity for drug interactions is higher for opioids metabolized by CYP3A4, and this is the pathway by which most opioids in general use are metabolized [105,132,176]. Thus, drugs and other compounds that inhibit or induce CYP3A4 activity contribute to opioid adverse drug interactions. CYP3A4 inducers include rifampin, St. John's wort, troglitazone, and phenytoin; inhibitors include telithromycin, itraconazole, ketoconazole, miconazole, voriconazole, ritonavir, lopinavir, erythromycin, clarithromycin, and grapefruit juice. Adverse opioid-drug interactions from enzyme induction mostly involve CYP3A4 and, to a lesser extent, CYP2B6.

In April 2023, the FDA issued a drug safety communication to announce safety-related updates to the prescribing information for immediate-release and extended-release long-acting opioid analgesics, including updates to Boxed Warnings, Indications and Usage, Dosage and Administration, Warnings and Precautions, and the Medication Guide. These safety labeling changes are intended to provide clarity on appropriate patient populations for opioid treatment, appropriate dosage and administration, and updated information on the risks associated with opioid use [178].

Morphine

Morphine is believed to possess a low potential for adverse drug interactions, because UGT inhibition produces few relevant pharmacokinetic changes in morphine or its metabolites [132].

Codeine

Analgesia requires the conversion of roughly 10% of codeine via CYP2D6 into morphine, which is then converted to M3G and M6G by glucuronidation. Codeine is also metabolized by CYP3A4 to the inactive metabolite norcodeine [105].

CYP3A4 inducers speed the conversion of codeine to the inactive norcodeine and decrease conversion to morphine. Although codeine undergoes phase II metabolism to codeine-6-glucuronide, UGT2B7 inhibition or induction does not result in codeine adverse drug interactions [132].

Oxycodone

Oxycodone undergoes a complex hepatic metabolic process. CYP2D6 catalyzes oxycodone to oxymorphone (10% of metabolites), and UGT2B7 rapidly inactivates oxymorphone by conversion to oxymorphone-6-glucuronide; the analgesic contribution of oxymorphone is minimal. CYP3A4 catalyzes oxycodone to noroxycodone, the primary (90%), but inactive, metabolite. In addition, CYP2D6 converts noroxycodone to noroxymorphone. These metabolites have varying mu receptor potencies and affinities [100,179].

Many adverse drug interactions have been reported between oxycodone and other CYP3A4 substrates. CYP3A4 inhibitors can substantially increase oxycodone serum levels, reflected in the "black box warning" to not use oxycodone with CYP3A4 inhibitors due to the elevated risk of serious adverse effects, including potentially fatal respiratory depression. CYP3A4 inhibitors may elevate plasma oxymorphone to increase opioid effects, while CYP3A4 inducers may substantially decrease oxycodone (and potentially oxymorphone) serum levels, leading to analgesic failure. In general, concurrent use of oxycodone with CYP3A4 inhibitors or inducers is likely to result in adverse drug interactions.

The clinical effects of CYP2D6-mediated drug interactions with oxycodone are mixed, because overall analgesic contribution from the active metabolite oxymorphone is minimal [132].

Oxymorphone

Oxymorphone undergoes hepatic metabolism by phase II conjugation via glucuronide UGT2B7. The absence of CYP450 involvement minimizes adverse drug interactions with CYP substrates [117].

Hydrocodone

Limited clinical data have been published on drug interactions with hydrocodone metabolism. The overall evidence suggests concurrent use of CYP2D6 inhibitors diminish conversion of hydrocodone into the active metabolite hydromorphone [132].

Hydromorphone

The metabolites of hydromorphone are not thought to contribute to its pharmacologic activity. Minimal CYP450 involvement indicates a lack of adverse drug interactions impacting its pharmacokinetics [9,117].

Fentanyl

Fentanyl is metabolized primarily via hepatic CYP3A4 and is a weak CYP3A4 inhibitor. As such, many CYP3A4 substrates can interact with fentanyl. Elevated plasma fentanyl and decreased fentanyl clearance can result from coingestion of CYP3A4 inhibitors. CYP3A4 inducers can diminish fentanyl serum levels and analgesia and increase clearance. The adverse interactions between fentanyl and CYP3A4 inhibitors are potentially very serious, and a "black box warning" on all fentanyl products cautions against concurrent use of fentanyl and all CYP3A4 inhibitors because of the heightened risk of adverse effects, including fatal respiratory depression. CYP3A4 inducers may nullify fentanyl analgesia, and patients receiving fentanyl should avoid all CYP3A4 substrates [132].

Methadone

Methadone is associated with numerous potentially serious adverse drug interactions. CYP3A4 inhibitors can delay methadone clearance and potentially lead to toxicity. Methadone has been linked to the development of the ventricular arrhythmia torsades de pointes; additional reports suggest an association between methadone-induced torsades de pointes and CYP3A4 inhibition [132,180].

CYP3A4 inducers can reduce plasma methadone levels, leading to analgesic failure and opioid withdrawal. CYP2B6 inhibitors can decrease methadone metabolism to increase side effect risk, while CYP2B6 inducers delay metabolism to diminish its therapeutic effects [132,180].

Many members of specific drug classes adversely interact with methadone, and clinicians should carefully evaluate the interaction potential of any CYP3A4 or CYP2D6 inhibitor used with methadone [132,180].

The complex pharmacology of methadone makes the drug hazardous when prescribed without extensive knowledge and experience. With a half-life (15 to 60 or more hours) longer than analgesia (4 to 8 hours), risks of accumulation and fatal overdose are increased, as when analgesia wears off and pain returns followed by re-dosing. Other factors that contribute to the risk of toxicity include [54]:

- Metabolism by numerous CYP isoenzymes, which elevates the risks of drug-drug interactions, delayed clearance, and increased serum concentrations of methadone to fatal levels

- Prolongation of QTc interval, which may increase risk of life-threatening cardiac arrhythmias

- P-glycoprotein (P-gp) substrate, elevating risk of drug interactions that accelerate methadone blood-brain barrier penetration

Methadone requires metabolism by at least five fully active CYP450 isoenzymes for its efficient breakdown and elimination. This makes it the opioid with greatest susceptibility to adverse drug interaction. Concurrent use of common medications such as benzodiazepines, antihistamines, antidepressants, and antiviral agents may result in inhibition of CYP450-mediated breakdown and clearance of methadone, increased plasma levels, and serious risk of oversedation and suppression of CNS respiratory centers [177].

Toxicity risks of methadone can be mitigated with gradual titration and dose adjustment. Opioid-naïve patients should be started at a low dose, usually 2.5 mg every eight hours. The dose may be titrated by 10% to 20% increments, not less than three to four days apart except under inpatient or closely supervised settings. Once-daily methadone is ineffective for chronic pain; dosing at least every eight hours is required. When rotating patients from another opioid to methadone, it is important to consult the latest product information for dose equivalence and conversion; do not use published equianalgesic tables [105,177].

The increasing use of methadone treatment for chronic pain has led to high rates of fatal toxicity and concerns over its safe and appropriate use as an analgesic. Clinical practice guidelines have been developed to promote safer methadone prescribing for chronic pain [181]. The first step is careful patient assessment. From a thorough history, medical records review, physical examination, and possibly electrocardiography, stratify patients on risk for substance abuse, adverse reactions with other prescribed medications, and arrhythmia. Alternative opioids should be used in patients at high risk of QTc interval prolongation. If methadone is used, a low starting dose and slow titration are necessary, as are diligent monitoring and patient follow-up. All patients should receive education on methadone safety.

Levorphanol

No adverse interactions with CYP450 substrates have been noted with levorphanol. Interactions at glucuronidation enzyme sites are theoretically possible, but none have been substantiated [9].

Tramadol

CYP2D6 and CYP3A4 account for more than 70% of tramadol metabolism. CYP2D6 inhibitors reduce tramadol analgesia and concurrent use should be avoided. CYP3A4 inhibitors may increase exposure to tramadol, and their use should be avoided. CYP3A4 inducers can reduce plasma tramadol, and patients requiring CYP3A4-inducing medications should be monitored for inadequate analgesia [132].

Tapentadol

Clinically relevant drug interactions are unlikely with tapentadol [182].

PHARMACODYNAMIC DRUG-DRUG INTERACTIONS

Pharmacodynamic drug-drug interactions are possible with all opioid analgesics. Drugs with hypoventilatory or CNS depressant properties, such as benzodiazepines, sedative-hypnotics, and antihistamines, can act synergistically with opioids to increase sedation and risk of potentially lethal respiratory depression [176].

Some pharmacodynamic adverse drug interactions with opioids can be clinically advantageous. For instance, ibuprofen co-administration with hydrocodone or oxycodone potentiates the analgesia of the opioids in laboratory-induced moderate-to-severe pain, producing a 2.5-fold and 4.6-fold shift in the effective dose, respectively. Aspirin and ketorolac have no effect on hydrocodone analgesia, and ibuprofen has no effect on fentanyl or morphine analgesia [183].

11. CDC GUIDELINES FOR OPIOID PRESCRIBING IN CHRONIC PAIN

In 2016, the CDC published opioid prescribing guidelines for chronic pain by primary care physicians, not applicable to active cancer treatment, palliative care, or end-of-life care [46]. Release of the draft and final CDC guidelines provoked controversy and alarm from pain professionals and pain patient advocacy groups and serious concerns by the American Medical Association (AMA), the American Cancer Society (ACS), the American Academy of Pain Medicine (AAPM), and other prominent organizations [102,184].

In response to concerns raised and challenges encountered following implementation of the 2016 guidelines, in 2019 the CDC issued a clarification and cautioned against misapplication of the opioid prescribing guidelines in ways that could put patients at risk [185]. It is also important to note that the NPS, a comprehensive action plan to decrease the burden of undertreated pain, was also released in 2016. The NPS was developed in response to the 2011 IOM mandate for system-wide transformation of pain care but was largely overshadowed by the CDC guideline release [186].

Since release of the 2016 CDC guideline, new evidence has emerged on the benefits and risks of prescription opioids for both acute and chronic pain, comparisons with nonopioid pain treatments, dosing strategies, opioid dose-dependent effects, risk mitigation strategies, and opioid tapering and discontinuation [187]. Rates of opioid prescribing continue to vary across states, medical specialties, patient demographics, and pain conditions in ways that cannot be explained by the underlying health status of the population, and often are discordant with the 2016 guideline recommendations. Despite a decline in the prevalence of prescription opioid misuse and prescription opioid use disorder, in 2020, prescription opioids remained the most commonly misused prescription drug in the United States. These and other factors led the CDC in 2022 to publish an expanded, updated opioid prescribing guideline [187]. This guideline provides evidence-based recommendations for prescribing opioid pain medication for acute, subacute, and chronic pain for outpatients 18 years of age and older, excluding pain management related to sickle cell disease, cancer-related pain treatment, palliative care, and end-of-life care. Lessons learned from the development of the 2016 guideline informed the process used to generate the 2022 guideline [187].

The following recommendations are reprinted from the CDC 2022 guideline and represent a simple approach to opioid prescribing for chronic pain. While this may be helpful for primary care providers, it does not take into account many of the nuances of opioid use for chronic pain, including patient-specific response, side effects, comorbidities, and pharmacokinetics and pharmacodynamics. The guideline is not intended to replace clinical judgment and individualized, patient-centered decision making [187]. These issues will be discussed in detail later in this course.

The 12 recommendations found in the 2022 guideline are summarized by: determining whether or not to initiate opioids for pain; selecting opioids and determining opioid dosages; deciding duration of initial opioid prescription and conducting follow-up; and assessing risk and addressing potential harms of opioid use [187]. Each recommendation includes a recommendation category and type of evidence. The recommendation categories were determined on the basis of evidence type, balance between desirable and undesirable effects, values and preferences, and resource allocation (cost). Category A recommendation applies to all persons; most patients should receive the recommended course of action. Category B recommendation calls for individual decision-making. Different choices will be appropriate for different patients. Clinicians should help patients arrive at a decision consistent with patient values and preferences and specific clinical situations. Evidence types were designated based on study design and as a function of limitations in study design or implementation, imprecision of estimates, variability in findings, indirectness of evidence, publication bias, magnitude of treatment effects, dose-response gradient, and constellation of plausible biases that could change effects [187]:

- Type 1 evidence: Randomized clinical trials or overwhelming evidence from observational studies

- Type 2 evidence: Randomized clinical trials with important limitations, or exceptionally strong evidence from observational studies

- Type 3 evidence: Observational studies or randomized clinical trials with notable limitations

- Type 4 evidence: Clinical experience and observations, observational studies with important limitations, or randomized clinical trials with several major limitations

DETERMINING WHETHER OR NOT TO INITIATE OPIOIDS FOR PAIN (RECOMMENDATIONS 1 AND 2)

Evidence Based Practice Recommendation

The American Society of Interventional Pain Physicians asserts that a robust agreement, which is followed by all parties, is essential prior to initiating and maintaining opioid therapy, as such agreements reduce overuse, misuse, abuse, and diversion.

https://painphysicianjournal.com/current/pdf?article=NDIwMg%3D%3D&journal=103

Last Accessed: May 22, 2023

Level of Evidence: III (Evidence obtained from at least one relevant, high-quality nonrandomized trial or observational study with multiple moderate- or low-quality observational studies)

Nonopioid therapies are at least as effective as opioids for many common types of acute pain. Clinicians should maximize use of nonpharmacologic and nonopioid pharmacologic therapies as appropriate for the specific condition and patient and only consider opioid therapy for acute pain if benefits are anticipated to outweigh risks to the patient. Before prescribing opioid therapy for acute pain, clinicians should discuss with patients the realistic benefits and known risks of opioid therapy (category B, evidence type 3).

Nonopioid therapies are preferred for subacute and chronic pain. Clinicians should maximize use of nonpharmacologic and nonopioid pharmacologic therapies as appropriate for the specific condition and patient and only consider initiating opioid therapy if expected benefits for pain and function are anticipated to outweigh risks to the patient. Before starting opioid therapy for subacute or chronic pain, clinicians should discuss with patients the realistic benefits and known risks of opioid therapy, should work with patients to establish treatment goals for pain and function, and should consider how opioid therapy will be discontinued if benefits do not outweigh risks (category A, evidence type 2).

OPIOID SELECTION AND DOSAGE DETERMINATION (RECOMMENDATIONS 3, 4, AND 5)

When starting opioid therapy for acute, subacute, or chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release and long-acting (ER/LA) opioids (category A, evidence type 4).

When opioids are initiated for opioid-naïve patients with acute, subacute, or chronic pain, clinicians should prescribe the lowest effective dosage. If opioids are continued for subacute or chronic pain, clinicians should use caution when prescribing opioids at any dosage, should carefully evaluate individual benefits and risks when considering increasing dosage, and should avoid increasing dosage above levels likely to yield diminishing returns in benefits relative to risks to patients (category A, evidence type 3).

For patients already receiving opioid therapy, clinicians should carefully weigh benefits and risks and exercise care when changing opioid dosage. If benefits outweigh risks of continued opioid therapy, clinicians should work closely with patients to optimize nonopioid therapies while continuing opioid therapy. If benefits do not outweigh risks of continued opioid therapy, clinicians should optimize other therapies and work closely with patients to gradually taper to lower dosages or, if warranted based on the individual circumstances of the patient, appropriately taper and discontinue opioids. Unless there are indications of a life-threatening issue such as warning signs of impending overdose (e.g., confusion, sedation, or slurred speech), opioid therapy should not be discontinued abruptly, and clinicians should not rapidly reduce opioid dosages from higher dosages (category B, evidence type 4).

DECIDING DURATION OF INITIAL OPIOID PRESCRIPTION AND CONDUCTING FOLLOW-UP (RECOMMENDATIONS 6 AND 7)

When opioids are needed for acute pain, clinicians should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids (category A, evidence type 4).

Clinicians should evaluate benefits and risks with patients within 1 to 4 weeks of starting opioid therapy for subacute or chronic pain or of dosage escalation. Clinicians should regularly re-evaluate benefits and risks of continued opioid therapy with patients (cateogry A, evidence type 4).

ASSESSING RISK AND ADDRESSING HARMS OF OPIOID USE (RECOMMENDATIONS 8, 9, 10, 11, AND 12)

Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk for opioid-related harms and discuss risk with patients. Clinicians should work with patients to incorporate into the management plan strategies to mitigate risk, including offering naloxone (category A, evidence type 4).

Evidence Based Practice Recommendation

According to the American Society of Interventional Pain Physicians, presumptive urine drug testing should be implemented at initiation of opioid therapy, along with subsequent use as adherence monitoring, using in-office point of service testing, followed by confirmation with chromatography/mass spectrometry for accuracy in select cases, to identify patients who are noncompliant or abusing prescription drugs or illicit drugs. Urine drug testing may decrease prescription drug abuse or illicit drug use when patients are in chronic pain management therapy.

https://painphysicianjournal.com/current/pdf?article=NDIwMg%3D%3D&journal=103

Last Accessed: May 22, 2023

Level of Evidence: III (Evidence obtained from at least one relevant, high-quality nonrandomized trial or observational study with multiple moderate- or low-quality observational studies)

When prescribing initial opioid therapy for acute, subacute, or chronic pain, and periodically during opioid therapy for chronic pain, clinicians should review the patient's history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or combinations that put the patient at high risk for overdose (category B, evidence type 4).

When prescribing opioids for subacute or chronic pain, clinicians should consider the benefits and risks of toxicology testing to assess for prescribed medications as well as other prescribed and nonprescribed controlled substances (category B, evidence type 4).

Clinicians should use particular caution when prescribing opioid pain medication and benzodiazepines concurrently and consider whether benefits outweigh risks of concurrent prescribing of opioids and other central nervous system depressants (category B, evidence type 3).

Clinicians should offer or arrange treatment with evidence-based medications to treat patients with opioid use disorder. Detoxification on its own, without medications for opioid use disorder, is not recommended for opioid use disorder because of increased risks for resuming drug use, overdose, and overdose death (category A, evidence type 1).

CRITICAL RESPONSE TO CDC GUIDELINES

Experts argued that the dose levels established in the 2016 CDC guideline were arbitrary, ignoring the fact that millions of Americans receive 90 mg MED/day for needed pain control [102]. While the 2022 guideline no longer recommends dosage thresholds, it still urges practitioners to be cautious about prescribing more than 50 MME/day [187,188]. In addition, the opioid dosing limits for acute pain were based on emergency department prescribing guidelines for nontraumatic, nonsurgical pain, to provide analgesia until the acute pain resolves or the patient sees his or her primary care provider [5]. As such, the recommendation is unlikely to be helpful in a chronic pain guideline. Practicing pain management clinicians have expressed several specific concerns about the 2022 guideline recommendations [189].

12. GENERAL RECOMMENDATIONS FOR ANALGESIC PRESCRIBING

Evidence Based Practice Recommendation

The American Society of Interventional Pain Physicians recommends screening for opioid abuse, as it will potentially identify opioid abusers and reduce opioid abuse.

https://painphysicianjournal.com/current/pdf?article=NDIwMg%3D%3D&journal=103

Last Accessed: May 22, 2023

Level of Evidence: II (Evidence obtained from at least one relevant, high-quality randomized controlled trial or multiple relevant moderate- or low-quality randomized controlled trials)

As discussed, the CDC's opioid prescribing guidelines are strictly focused on curtailment and, as such, are less useful for guiding analgesic selection or patient matching [5]. Instead, this information may be obtained from practice guidelines from the FDA, the Federation of State Medical Boards, and the AAPM. These organizations state that opioid analgesics are generally not used as first-line analgesic therapy; non-drug and non-opioid drug alternatives should be considered first. Opioids may be initiated when benefits are likely to outweigh risks, when other approaches to analgesia are ineffective or unlikely to be effective, and with a treatment plan reasonably designed to mitigate the risks of addiction, toxicity, and other adverse effects [21,190,191].

Opioid therapy should be presented as a time-limited trial to evaluate pain, functioning and quality of life benefits, and adverse effects. Opioid-naïve patients should be started at the lowest dose, with titration to effect. In general, it is best to begin opioid therapy with an SA formulation and rotate to an ER/LA formulation, if indicated. Opioid therapy may be continued beyond the trial period after careful evaluation of benefits versus adverse effects and/or potential risks [21,191].

Fear of inducing respiratory depression has constrained opioid prescribing for patients with chronic pain, but this risk can be minimized by exercising caution and providing patient education regarding the risks of any concomitant use of CNS depressants, especially benzodiazepines and alcohol [21]. Caution should also be used with dosing and titration in patients with sleep apnea or end-stage respiratory disease. Emerging data suggest an association of chronic opioid therapy with central sleep apnea, but the direction and details of this association are unclear. Patients on long-term opioid therapy are at risk for hypoxia if respiratory infections or acute asthmatic attacks supervene; patients should be advised that opioid dosage adjustments may be necessary in the event of any intercurrent illness that affects breathing.

Previous assumptions that patients on chronic opioid therapy will invariably develop analgesic tolerance (i.e., decreasing pain control with the same dosage over time) have also constrained effective opioid prescribing practices. Chronic pain unresponsive to opioid dose escalation may reflect tolerance, but it may also be the result of disease progression, non-opioid responsive pain syndromes, or opioid-induced hyperalgesia. Tolerance is not usually an impediment to long-term opioid therapy [21].

The most recent comprehensive guidelines for neuropathic pain were published by the Canadian Pain Society in 2014. Common causes of peripheral neuropathic pain include diabetic neuropathy; postherpetic neuralgia; post-thoracotomy, post-breast surgery, and post-back surgery pain; phantom limb pain; and complex regional pain syndrome [192]. ER opioid analgesics are recommended as second-line options for moderate-to-severe neuropathic pain.

Although there are few class-wide contraindications for the use of mu opioid agonist analgesics, contraindications to ER/LA opioid prescribing exist by formulation and specific opioid [190]. Contraindications to any use of opioid analgesics include [193]:

- Respiratory instability

- Acute psychiatric instability

- Uncontrolled suicide risk

- Active, untreated alcohol or substance use disorder

- True opioid allergy

- Current medication use with potential for dangerous drug interactions

- Active diversion

- Prolonged QTc (≥500 ms) (with methadone)

- Codeine (in pediatric patients)

Contraindications to long-term opioid analgesic therapy include [43,194]:

- Primary headache

- Functional disorders

- Fibromyalgia syndrome (except tramadol)

- Chronic pain as prominent manifestation of a mental disorder (e.g., atypical depression, generalized anxiety disorder, post-traumatic stress disorder)

- Chronic pancreatitis, with the possible exception of brief (less than four weeks) treatment during an acute episode

- Chronic inflammatory bowel disease, with the possible exception of brief (less than four weeks) treatment during an acute episode

- Comorbid severe affective disorder and/or suicidality

- Current prescribed opioid abuse, diversion, and/or serious doubts over responsible use (e.g., unable to control opioid use, unwilling or unable to adhere to dosing schedule)

- Current or planned pregnancy

13. PATIENT FACTORS AND OPIOID ANALGESIC RESPONSE

Clinicians have long observed wide response variation in patients receiving opioids for pain. Patient factors, including age, medical comorbidity, and genetic differences, substantially contribute to this variation. Understanding how these factors influence opioid response can facilitate opioid selection and prescribing that mitigates side effects and toxicity while attaining adequate pain control.

AGE

By 2025, the number of adults 65 years of age and older in the United States is projected to increase 80% from 2010 estimates, comprising nearly 20% of the population. Understanding age-related physiologic changes and the complexity of pain management in elderly patients is essential for optimal efficacy, safety, and tolerability [54].

Independent of disease morbidity, aging elevates the risk of adverse events and associated opioid toxicity (Table 3). The elderly account for 49% of all hospitalizations due to medication adverse effects [195]. A variety of age-related physiologic changes account for this, including diminished gastric secretions and intestinal dysmotility; vitamin D deficiency, loss of appetite, and poor nutrition; and decreased bone density. Increased arterial thickening and rigidity elevate cardiac risk, while decreased lung elasticity may exacerbate respiratory disorders. Neurons become less stress-resilient. Reduced hepatic and renal blood flow diminish metabolism and filtration, increasing the risk for toxic substance accumulation [195]. Patients with dementia and/or cognitive deficits may have communication problems or confusion that render expression of pain severity, therapeutic response, and/or side effects difficult [196].

Table 3: CLINICAL RELEVANCE OF AGE-RELATED PHYSIOLOGIC CHANGES

Pharmacokinetic Impact

Reduced GI function and delayed absorption

Increased risk of opioid-related GI side effects

Alteration of drug absorption (little clinical effect)

Altered distribution

Reduced distribution of water-soluble drugs

Longer effective half-life of lipid-soluble drugs

Increased potential for drug-drug interactions

Reduced hepatic metabolism

Reduced first-pass metabolism

Oxidative reactions (phase I) may be reduced, prolonging half-life

Conjugation (phase II metabolism) usually preserved

Difficult to predict exact individual effects

Reduced renal excretion

Accumulation and prolonged effects of drugs and metabolites

Pharmacodynamic Impact

Decreased receptor density, increased receptor affinity

Increased sensitivity to therapeutic and side effects

Source: [197]

In older adults, heightened sensitivity to adverse effects results from physiologic changes, drug interactions, and drug-disease interactions [198]. Aging is associated with higher steady-state concentrations of water-soluble drugs and increased half-life of fat-soluble drugs. Consequently, opioid use in older adults may necessitate a lower than usual dose or longer dosage interval in order to maintain an appropriate balance between analgesia and side effect risk [199]. Other functional changes and comorbidities that impact opioid pharmacokinetics may also influence patient response and tolerability. Therefore, the selection and prescribed dosage of opioids in elderly patients must be considered carefully [196].

Older adults are also more likely to be prescribed multiple medications for a variety of chronic and acute conditions. In some cases of multimorbidity and chronic conditions (e.g., hypertension), the use of multiple medications may be unavoidable if one is to follow best practice clinical guidelines; this is referred to as "appropriate polypharmacy." However, even when the prescription of multiple medications is warranted, it raises the risks of drug-drug interactions, compliance issues, and adverse effects.

Elderly adults are more likely than younger adults to experience significant chronic pain because of the higher prevalence of rheumatic diseases, orthopedic conditions, and other debilitating illnesses. In many cases, opioid therapy with optimum patient-treatment matching is the safest analgesic option for elderly patients compared with oral NSAIDs, acetaminophen, antidepressants, or anticonvulsants [54].

MEDICAL COMORBIDITIES

Comorbid medical or neuropsychiatric conditions can affect opioid response or tolerability by interfering with opioid metabolism, elimination, efficacy, and adherence. Many patients require polypharmacy, especially the elderly and patients with psychiatric illness, cancer, cardiovascular disease, diabetes, and other chronic illnesses. As discussed, polypharmacy elevates risks of drug interactions that reduce efficacy or increase toxicity [200].

Cardiovascular, cerebrovascular, and respiratory disease all impact susceptibility to respiratory depression, bradycardia, or hypotension. Neurologic or neuropsychiatric conditions such as dementia, brain injury, or psychiatric illness may render the patient more susceptible to adverse CNS effects from opioids, such as cognitive impairment or sedation [200]. The presence of significant cognitive or intellectual disabilities can accompany sensory or communication disorders to interfere with verbal or nonverbal communication of pain to healthcare providers. In these patients, chronic pain can manifest in behavioral challenges or gradual declines in function. Appropriate treatment can greatly improve patient quality of life and caregiver stress [72].

Hepatic Dysfunction

Opioid biotransformation occurs in the liver, and any significant impairment in hepatic function will delay the metabolism and prolong the effect of opioids and their metabolites. Generally, CYP-mediated metabolism is affected more than glucuronidation, although opioids solely metabolized by glucuronidation also show altered pharmacokinetics. Morphine clearance is reduced ≥25%, and hydromorphone plasma concentrations are increased four-fold [200]. As such, it is important to avoid using oxymorphone and tapentadol and to use hydromorphone and oxycodone with great caution in these patients. Fentanyl is the first-choice opioid in patients with serious liver disease. Buprenorphine is safe in patients with mild-to-moderate liver disease, and methadone can also be used safely [105]. All opioids should be used with extreme caution with lowest-dose initiation [200].

Renal Dysfunction

Renal impairment can interfere with clearance of opioids and metabolites, which may lead to serum concentrations rising to dangerous levels. Delayed morphine elimination can lead to respiratory depression, excitotoxicity, and/or neurotoxicity. In these patients, morphine, hydromorphone, tramadol, tapentadol, and codeine should be avoided. Oxymorphone and oxycodone may be used with great caution. Fentanyl should be considered as the opioid of first choice for patients with renal impairment, followed by buprenorphine and methadone [105]. All opioids should be started at a low dose and slowly titrated [200].

Cardiovascular Disease

In patients with heart failure, special care should be taken with methadone. Some patients prescribed methadone for chronic pain may be at increased risk for developing prolonged QT interval or may already have a congenital QT prolongation.

Tramadol is recommended ahead of NSAIDs for patients with significant cardiovascular risk, and the same can be argued for tapentadol. Fentanyl, morphine, or oxycodone should be considered for these patients, as none are significantly associated with QT prolongation [199].

GENETIC FACTORS

Morphine, oxycodone, hydromorphone, and fentanyl have comparable population level efficacy but widely variable analgesic efficacy and tolerability at the individual level; the same drug/dose may be toxic in some patients and have little or no effect in others. For example, up to 30% of patients with cancer-related pain show poor morphine response from inadequate analgesia or intolerability, but most achieve pain control with alternative opioids. Genetic factors account for at least 25% of this response variation to opioids [100,201]. Genetic variations with greatest confirmation and relevance to opioid kinetics and dynamics include CYP450 enzymes, P-gp transporter ABCB1, catechol-O-methyltransferase (COMT) enzymes, and cytokine gene promoters (Table 4).

Table 4: PRIMARY PHARMACOGENETIC INFLUENCES IN OPIOID ANALGESIC RESPONSE

Site of Activity

Genes of Interest

Function

CYP450

CYP2D6

Involved in metabolism of several opioids analgesics, including:

- Codeine to morphine

- Oxycodone to oxymorphone

- Tramadol to O-desmethyltramadol

- Hydrocodone to hydromorphone

P-gp

ABCB1/MDR1

Decreased P-gp expression and activity can affect brain opioid levels and increase toxicity risk

COMT

COMT

Val158Met variant

May increase dopaminergic stimulation due to dysfunctional COMT activity, which upregulates mu opioid receptor expression and increases morphine efficacy

Mu opioid receptor

OPRM1

Codes the expression of higher mu opioid receptor binding affinity of b-endorphin

Kappa opioid receptor

MC1R

Sex-specific increase in pain perception and analgesic response via the kappa opioid receptor

COMT = Catechol-O-methyltransferase, P-gp = P-glycoprotein.

Source: [193,201]

P-glycoprotein (P-gp) Transporter ABCB1

The P-gp transporter ABCB1, encoded by the ABCB1 gene, regulates the cerebrospinal fluid and serum levels of drugs passing the blood-brain barrier. ABCB1 polymorphism alters P-gp transporter expression and activity at the blood-brain barrier to influence drug concentrations, CNS parent drug/metabolite ratios, and adverse effects. The impact of polymorphic ABCB1 varies with the particular opioid in use. With morphine, it is associated with increased systemic and CNS exposure and accumulation; with fentanyl, increased respiratory depression; and with oxycodone, greater pain reduction and adverse effects due to higher plasma concentrations [202].

Cytochrome P450 Enzymes

As discussed, CYP enzymes influence the concentration of circulating opioids. Polymorphism of genes that encode CYP isoenzymes can affect opioid metabolism by determining isoenzyme activity level [203]. Polymorphic CYP2D6 is the most important genetic determinant of opioid response [1].

Phenotypic variations due to CYP2D6 polymorphism are classed into four functional groups: poor, intermediate, extensive, and ultra-rapid metabolizers [177]. In the general population, polymorphic CYP2D6 results in ultra-rapid metabolism in 7%, poor metabolism in 10%, intermediate metabolism in 35%, and extensive metabolism in 48%. In White individuals, 77% to 92% are CYP2D6 extensive metabolizers. However, racial differences are found in polymorphic CYP2D6 distribution, with greater effects seen in certain groups (Table 5) [203].

Table 5: ETHNIC/RACIAL DISTRIBUTION OF POLYMORPHIC CYP2D6

Ethnicity/Race

Poor Metabolism

Intermediate Metabolism

Ultra-Rapid Metabolism

White

5% to 10%

2% to 11%

0.8% to 4.3%

Asian

1% to 2%

51%

0.9%

Black/African American

2% to 4%

30%

N/A

Hispanic

2.2% to 6.6%

N/A

1.7%

N/A = Not available.

Source: [202,203,204]

Inactive/Absent Activity (Poor Metabolizers)

In patients with CYP2D6 polymorphism resulting in poor metabolism, the opioid cannot undergo metabolism and is eliminated unchanged. Absence of metabolic activity delays clearance and elevates plasma opioid concentration. This phenotype is hazardous and especially dangerous in opioid-naïve patients. Another effect is analgesic failure with pro-drugs, from the inability to convert to the active metabolite [177,205].

Underactive Activity

In intermediate metabolizers, the isoenzyme functions at reduced activity level and the opioid is metabolized at a slower rate, delaying plasma clearance, elevating serum concentration, and increasing toxicity potential. In some patients, isoenzyme function is activated with high serum opioid concentration, but these patients have greater overall risk of adverse effects and require lower opioid dosing [177,203].

Full Activity

The greatest proportion of the population has extensive (full) opioid metabolism ability. With isoenzyme activity fully functional, patients show expected opioid dose response and the expected rate of opioid metabolism [203,206].

Overactive Activity

In overactive (ultra-rapid) metabolizers, accelerated opioid metabolism and clearance results in analgesic failure from serum concentrations not reaching analgesic threshold, leading to ongoing pain and frequent dose escalation to attain analgesia. Another effect is greatly reduced analgesic duration, as when an ER opioid normally providing 12 hours of analgesia is effective for only 4 hours [177,203].

Mu Opioid Receptor-1 (OPRM1)

The mu opioid receptor is the primary site of action for opioid analgesics, encoded by the mu opioid receptor-1 (OPRM1) gene. The OPRM1 polymorphism most consistently associated with opioid response is A118G, which results in higher mu opioid receptor binding affinity of beta-endorphins. Studies show a pattern of less analgesia (i.e., higher dose requirements for morphine, tramadol, and fentanyl) and fewer CNS and GI side effects in patients with this polymorphism, reflecting reduced mu opioid receptor sensitivity and higher drug concentrations required to displace beta-endorphin from the mu opioid receptor [202]. A study of genetic influences on oxycodone response also found variations in mu and delta opioid receptor genes that may explain differences in patient responses [207].

Catechol-O-Methyltransferase (COMT)

The COMT enzyme is responsible for inactivating catecholamines. The most widely studied variant is a nucleotide substitution that changes the amino acid from valine to methionine at codon 158 (Val158Met). This alteration reduces the enzymatic activity of COMT, and low COMT activity is associated with increased mu opioid receptor system sensitivity to morphine [193,201].

Cytokines

Cytokines are vital for coordination of immune and inflammatory response and are broadly classed as pro-inflammatory or anti-inflammatory mediators. Polymorphic cytokine gene promoters are associated with greater pain severity and greater morphine dose requirements [193,201].

Clinical Relevance

As discussed, there is patient-to-patient variability in the rate at which opioids are metabolized based on genetic phenotype. Patients who are poor or intermediate metabolizers achieve a therapeutic effect at low doses and are at higher risk of toxicity at usual doses of opioid. Patients who are rapid metabolizers require higher and more frequent opioid dosing in order to achieve and maintain plasma concentrations in the therapeutic range. Importantly, with opioid pro-drugs like codeine and tramadol, phenotypic influence on the pharmacokinetics of the primary analgesic metabolite is reversed [206,208].

Following poor metabolic response to an opioid pro-drug or ultra-rapid metabolic response to a conventional opioid, patients may insist on the need for higher doses due to analgesic failure [204]. Clinicians should avoid assumptions of addiction, abuse, or drug seeking until further investigation clarifies the underlying cause of analgesic failure. This patient behavior may reflect a polymorphic-mediated pseudoaddiction. In patients who rapidly metabolize opioids and who develop physiologic dependence with long-term use, forced or arbitrary opioid reduction can be hazardous—serum opioid concentrations may drop too rapidly to a low or zero level and produce severe opioid withdrawal, pain rebound, and cardiovascular hyperactivity that, in older patients, carries some risk for cardiac arrest or stroke [177].

Codeine

As an inactive pro-drug that requires metabolism by CYP2D6 into morphine for analgesia, poor and intermediate metabolizers gain little to no analgesia from codeine. In contrast, ultra-rapid metabolizers can have dangerously high serum morphine levels with standard-dose codeine, because the codeine-to-morphine conversion progresses more rapidly and a higher overall proportion of codeine is converted to morphine. This can result in severe or life-threatening side effects [206].

Tramadol

Tramadol is also a pro-drug, and clinical response is significantly lower in poor metabolizers, who require at least 30% greater tramadol dosing than patients with normal CYP2D6 activity [148]. Concurrent use of CYP2D6 inhibitors further contributes to metabolic interference. Poor metabolizers show poor pain control and a four-fold need for rescue medication with tramadol, while ultra-rapid metabolizers have shown intoxication, serious adverse effects requiring hospitalization, respiratory depression requiring naloxone, and near-fatal cardiotoxicity [205].

Oxycodone

The biotransformation of oxycodone involves CYP2D6 and CYP3A4; the two isoenzymes are prominently linked by activity and metabolic byproduct [179]. As such, polymorphic CYP2D6 significantly impacts oxycodone analgesia and toxicity. Ultra-rapid metabolizers experience significantly greater analgesic effect and toxicity, while poor metabolizers experience minimal therapeutic or side effects. Concurrent use of CYP3A4 inhibitors dramatically elevates analgesic efficacy and toxicity with oxycodone. This effect is further exaggerated in ultra-rapid metabolizers, who risk serious side effects and potentially fatal respiratory depression; an alternative analgesic should be considered in these patients [179].

Hydrocodone

Poor metabolizers with CYP2D6 polymorphism have a 10- to 20-fold lower rate of hydrocodone clearance and reduced production of the active metabolite hydromorphone [117]. Evidence suggests that there is a heightened risk of side effects and toxicity if these patients concurrently ingest CYP3A4 inhibitors [205].

Methadone

The CYP3A4 and CYP2B6 isoenzymes primarily contribute to methadone metabolism. So, methadone should be used with caution in patients concurrently taking CYP3A4 or CYP2B6 inhibitors [205].

ANTICIPATING FACTORS THAT ALTER PATIENT RESPONSE TO OPIOIDS

Basic guidelines have been established to prevent opioid toxicity and overdose due to factors that alter opioid pharmacokinetics [177,199,208]. Genetic testing to identify polymorphisms relevant to opioid analgesics is not commercially available or affordable. Instead, providers should screen all patients for CYP450 polymorphism before prescribing an opioid by taking a medication history with an emphasis on side effects, therapeutic failure, beneficial effects, drug sensitivity requiring a low dose, and insensitivity requiring a high dose. For example, a history of inadequate response or marked side effects to codeine suggests that selecting an opioid not metabolized by CYP2D6 (e.g., tapentadol, morphine, fentanyl, oxymorphone) is warranted.

With suspected CYP450 polymorphism or in patients requiring several non-opioid medications that interact with CYP2D6, CYP3A4, CYP2C9, or CYP2C19 isoenzymes, prescribers should select an opioid with a metabolic pathway that mostly bypasses the CYP450 system. These include hydromorphone, oxymorphone, levorphanol, and tapentadol. Oxymorphone is perhaps the safest, as it lacks CYP450 metabolism and has no active or toxic metabolites.

All patients prescribed opioid analgesics should receive education on the dangers of co-ingesting benzodiazepines, antidepressants, and agents or drug classes that are known CYP450 enzyme inhibitors.

14. OPIOID SELECTION, INITIATION, AND MANAGEMENT

Analgesic response, safety, and tolerability are highly influenced by the complex interplay of opioid and patient factors. These factors should be considered before selecting an opioid agent and initiating treatment.

OPIOID RESPONSIVENESS

Opioid responsiveness is defined as the "degree of analgesia achieved as the opioid dose is titrated to an endpoint, defined either by intolerable side effects or the occurrence of acceptable analgesia" [209]. Poor pain response to opioids is the result of intolerable side effect(s), inadequate analgesia, or both, despite dose escalation. When poor analgesic response is identified, the clinician should consider using adjuvant analgesics, switching opioids, changing the route of administration, or using NMDA receptor antagonists [105].

RECENT OPIOID EXPOSURE

An essential safety factor in opioid selection is current opioid exposure. Many ER/LA opioid formulations and transmucosal immediate-release fentanyl are explicitly prohibited from use in opioid-naïve patients due to the high risk of severe, potentially fatal respiratory depression [210]. Patients should be identified as opioid-tolerant before considering the use of these particular formulations.

The term "opioid-tolerant" differs from "opioid tolerance." Opioid tolerance is the physiologic adaptation to opioid exposure over time that manifests in reduced drug effect [160,211]. On the other hand, a patient is considered opioid-tolerant after continuous opioid use for at least one week of at least 60 mg/day oral morphine, 25 mcg/hour transdermal fentanyl, 30 mg/day oral oxycodone, 8 mg/day oral hydromorphone, 25 mg/day oral oxymorphone, or an equianalgesic dose of another opioid [190]. ER/LA opioid analgesic products and dose levels restricted to opioid-tolerant patients are shown in Table 6.

Table 6: ER/LA OPIOID ANALGESIC PRODUCTS AND DOSES RESTRICTED TO OPIOID-TOLERANT PATIENTS

Brand Name

Generic Name

Doses Restricted to Opioid-Tolerant Patients

Avinza

Morphine capsules

90 mg, 120 mg

Belbuca

Buprenorphine buccal film

>75 mcg film/day

Butrans

Transdermal buprenorphine

7.5, 10, 15, and 20 mcg/hr

Dolophine, Methadose

Methadone tablets

Refer to full prescribing information

Dilaudid

Hydromorphone tablets

All doses

Hysingla ER

Hydrocodone bitartrate tablets

Single-dose ≥80 mg

MS Contin

Morphine tablets

100 mg, 200 mg

Nucynta ER

Tapentadol tablets

No product-specific concerns

OxyContin

Oxycodone tablets

Single-dose >40 mg, daily dose >80 mg

Targiniq ER

Oxycodone/naloxone tablets

Single-dose >40 mg/20 mg, daily dose >80 mg/40 mg

Xtampza ER

Oxycodone capsules

Single-dose >40 mg, daily dose >80 mg

ER = extended-release.

Source: [190,212,213]

ROUTES OF ADMINISTRATION AND FORMULATIONS

As discussed, opioids are available for many routes of administration, including oral, rectal, SC, IV, transdermal, transmucosal, and intraspinal. The oral route of administration is simple, cost-effective, and preferred, and SA and ER formulations are available for most oral opioids [105]. SA opioids are used to control pain until reaching a steady state.

SC, IV, rectal, transdermal, transmucosal, or intraspinal routes of administration are used when patients cannot take oral medications. IM administration is contraindicated, as it lacks any pharmacokinetic advantage and is painful. SC delivery is relatively easy, effective, and safe. IV is useful when pain is severe or pain levels have acutely increased. Transdermal fentanyl preparations are effective for patients unable to take oral medications who have stable pain control. Transmucosal fentanyl is similar to IV administration in its rapid onset and is used for acute breakthrough pain. The intraspinal route of administration is either epidural or intrathecal. This is the most invasive mode of opioid delivery and requires specialist involvement, but it confers advantages in patients with significant dose-limiting adverse effects, because systemic exposure is circumvented. Intraspinal delivery allows adjuvant medications to be directly administered to the spinal cord [105].

ER/LA Opioid Formulations

Although SA opioids are effective for pain control in many clinical contexts, they are characterized by pharmacokinetic shortcomings that may interfere with achieving sustained analgesia. ER formulations were developed to circumvent these pharmacokinetic shortcomings. Transdermal formulations of fentanyl and buprenorphine avoid the extensive first-pass metabolism that limits bioavailability with oral opioids [1]. ER formulations also lack the acetaminophen or ibuprofen found in many SA codeine, hydrocodone, and oxycodone formulations. These non-opioid analgesics impose a daily dose ceiling because of toxicity risks [140].

Several high-potency oral opioids have been used for decades to treat moderate-to-severe pain, including morphine, oxycodone, hydromorphone, levorphanol, methadone, and oxymorphone [9]. Methadone and levorphanol are inherently long acting, while morphine, oxycodone, hydromorphone, and oxymorphone possess a short analgesic duration and plasma half-life that requires frequent administration to establish and maintain a satisfactory analgesic effect. Before the 1990s, high-potency opioids were primarily used in surgery and inpatient settings, because they required IV or IM administration [157]. Oral ER formulations of these opioids were introduced to fulfill the unmet need of outpatients with chronic or disabling pain who required continuous analgesia not achievable with SA formulations [214,215].

The terminology used to describe delayed-release opioids can be confusing. Opioids formulated with a release-delaying mechanism have been designated as ER, continuous or controlled release (CR), or sustained-release (SR), but these terms lack specific definition. Methadone and levorphanol are termed LA opioids to distinguish their inherently longer analgesic duration from opioids reformulated with an ER mechanism [216]. Likewise, the original strong opioids with relatively brief analgesic duration have been termed immediate-release or IR, but SA is a more accurate designation. IR is better reserved for truly rapid-onset opioids such as transmucosal immediate-release fentanyl.

Absorption, distribution, and metabolism influence the duration and stability of opioid analgesia and are difficult to manipulate with SA opioids. ER formulations modify the kinetic behavior of the opioid without changing the pharmacodynamic characteristics in order to improve analgesia through prolonged plasma concentration, lower maximum and higher minimum concentration, reduced fluctuation in plasma concentration, and delayed time in reaching maximum concentration [217,218]. These ER opioid kinetics are thought to allow pre-emptive pain control instead of attempting to control pain after it becomes established (i.e., "chasing the pain"). This reduces or eliminates gaps in analgesia when plasma levels decline before the next scheduled dosing; decreases sleep interruption, side effects, and early opioid withdrawal symptoms by improving adherence and decreasing dose frequency; and reduces abuse potential by decreasing reward and reinforcement from slower onset of effects [73,157,219].

Fluctuating analgesia levels achieved with SA opioids can result in a need to take the medications more frequently (for comfort). This can cause conditioned passive pill-taking behavior, which can discourage the patient from taking an active role in pain self-care. The enhanced analgesic coverage and adherence with ER opioids may improve assessment of changes in the underlying pain condition or the chronic pain state by reducing the confounding factor of analgesic fluctuation [140].

The theoretical advantages of ER over SA formulations have been difficult to demonstrate in randomized controlled trials. However, there have been some comparison trials that may give some insight into the basis for ER formulations. In one study, a patient adherence advantage was found with ER formulations versus SA opioids, which may translate into improved pain relief [216]. In patients with moderate or greater chronic pain, CR tramadol showed lower pain scores and higher patient and investigator efficacy ratings than SA tramadol [220]. In addition, the daily variations in pain control experienced with twice-daily morphine were not reported with once-daily dosing, and this correlated with stability in serum morphine concentrations [221].

Compared with three-times daily morphine, twice-daily morphine is superior in pain control, sleep quality, and physical and mental impairment. In one study, almost twice as many patients dropped out with three-times daily versus twice-daily morphine, with inadequate pain relief the primary reason [222]. Patients with moderate-to-severe cancer-related pain show significantly greater dropout rates with four-times daily oxycodone than with twice-daily oxycodone due to inadequate pain control and side effects [223]. Another study of patients with cancer pain reported significantly greater tiredness during initial titration with six-times daily morphine versus once-daily morphine [224].

A literature review found that ER formulations of morphine, oxymorphone, oxycodone, and tramadol promoted improvements in ability to fall asleep, sleep quality, sleep duration, and pain-related sleep disturbance compared with SA formulations [216]. Patients with osteoarthritis have shown significantly improved sleep quality scores with ER versus SA oxycodone and with once-daily compared with twice-daily morphine [225,226].

The CDC recommends initiation of opioid therapy with an IR formulation, prescribed at the lowest effective dose [187]. The FDA states that the use of ER/LA opioids is indicated for pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate [190]. To ensure that benefits outweigh risks and to reduce risks while preserving access to opioid analgesics, the FDA has implemented risk evaluation and mitigation strategies (REMS) for ER/LA opioid analgesics. The ER/LA REMS program consists of a core prescriber education component that stresses safe product use, patient safety information, and guidance on patient counseling. This REMS-compliant education is strongly encouraged but not mandatory [190].

Contraindications to ER/LA Opioid Formulations

Class-wide contraindications to ER/LA opioids include [227]:

- Concurrent alcohol use (can cause rapid opioid release and potentially fatal respiratory depression)

- Mild pain, short-term, or acute pain

- Use as pre-emptive analgesia

- Postsurgical pain

- As-needed use for intermittent pain

- Paralytic ileus

- Acute or severe bronchial asthma or hypercapnia

- Significant respiratory depression, unless resuscitative equipment and respiration monitors are available

In addition to contraindications for all ER/LA opioids, there are some agent-specific contraindications. For example, dosages greater than 1,600 mg/day of morphine ER (Avinza) should be avoided due to the risk of severe liver toxicity from the fumaric acid excipient. Oxycodone/naloxone ER (Targiniq) should not be used in patients with moderate or severe hepatic impairment. Tapentadol ER (Nucynta) is contraindicated in the presence of current or past 14-day MAOI use.

With postoperative, acute, or chronic intermittent pain, analgesia often requires frequent titration, and the two- to four-hour analgesic duration with SA hydrocodone, morphine, or oxycodone is more effective than ER formulations. SA opioids are also recommended in patients who are medically unstable or with highly variable pain intensity [19,217,219].

Treatment of moderate-to-severe persistent pain in opioid-naïve patients should be initiated with an SA opioid, with subsequent upward or downward dose adjustment until reaching adequate and tolerable analgesia [19]. When satisfactory analgesia and dose stability are achieved, the patient should be switched to an ER formulation of the initial opioid (assuming patient tolerability) [19,180].

When switching from SA to ER formulations, patients should be advised not to expect the relatively rapid onset of relief they may be used to with the SA opioid. Analgesic benefit will become evident over time, and taking a second tablet to speed the onset of pain relief may lead to delayed toxicity or overdose. These medications should be stored securely, never shared, never chewed or crushed, and properly disposed of when no longer needed, as they contain large amounts of opioid and are potentially lethal if ingested by someone without tolerance or tampered with to cause rapid release of the contents [140].

DOSING

In clinical practice, patients may require more frequent dosing intervals with LA/ER opioids than recommended in product labeling by the manufacturer. For example, the labeling for CR oxycodone recommends every-12-hour dosing, but some studies have found that patients need a dose interval of 7 to 8 hours and that the majority of such patients are prescribed CR oxycodone three to four times daily [228,229]. Other studies of patients with moderate-to-severe pain found the majority used CR morphine three to four times daily [230]. Transdermal fentanyl patch labeling recommends patch replacement every 72 hours, but in one study, close to 50% of patients required patch replacement every 24 or 48 hours [228,230].

This disparity can be explained by how premarket drug evaluation studies obtain pharmacokinetic data used in postmarket product labeling. These data are usually obtained from phase I studies that evaluate kinetic behavior of the drug in younger, healthy volunteers free of medical and psychiatric comorbidity and other medication use. This eliminates most patient factors that alter the pharmacokinetics of the drug. Less often, analgesic pharmacokinetic data are obtained from clinical samples involving subjects with a given pain condition, free of other medical and psychiatric comorbidities and concurrent medication use. These tightly controlled conditions eliminate factors that could later confound postmarking clinical data, but this limits applicability of the results to typical patients in real-world settings. No single opioid dosing protocol can fit the characteristics of all patients to determine analgesic response, tolerability, and required dose frequency [231].

The FDA permits marketing of generic drugs when bioequivalence is shown. This parameter is met when serum levels of the active constituent fall within 80% to 125% of the original branded drug. The allowable variation in serum levels can be problematic in agents with a narrow therapeutic index. An added complexity is that FDA mainly relies on self-reported bioequivalence evaluation by the generic drug makers [231,232].

DOSE TITRATION

Evidence Based Practice Recommendation

The American Society of Interventional Pain Physicians recommends advising patients undergoing dosage titration in a trial of opioid therapy to avoid engaging in dangerous activities, such as driving a motor vehicle or the use of heavy machinery, until a stable dosage is established and it is certain that the opioid dose does not cause sedation, as well as when taking opioids with alcohol, benzodiazepines, or other sedating drugs.

https://painphysicianjournal.com/current/pdf?article=NDIwMg%3D%3D&journal=103

Last Accessed: May 22, 2023

Level of Evidence: Expert Opinion/Consensus Statement

Titration is the process of incremental dose change based on individual patient needs and responses. The dose is increased (escalated) or decreased (tapered) until a reasonable balance is reached between analgesia and tolerability. Gradual titration allows sufficient time to ensure that the patient obtains the fullest degree of analgesia possible at the current dosage before further escalation is considered [233]. Regardless of opioid or dose, titration should be individualized based on health and pain status, treatment goals, and previous opioid response. Side effects such as sedation or nausea can interfere with upward titration.

Opioid titration is slower with ER than SA formulations. When transitioning from SA to ER formulations of the same opioid, the dose is based on the equivalent total daily dose [160].

OPIOID ROTATION OR SWITCHING

Pharmacologists formerly considered opioid analgesics interchangeable, on the basis of shared mu opioid receptor agonism, differing mainly by potency. In contrast, clinicians have long observed subtle but important pharmacologic differences in potency, efficacy, and tolerability [234]. It is now known that individual differences in mu opioid receptor expression and density contribute to this variation.

Opioid rotation exploits these pharmacologic differences and incomplete cross-tolerance among opioids and involves switching the current opioid or route of administration to improve efficiency and safety [124,233]. Opioid rotation can be an effective strategy for overcoming analgesic failure, side effect intolerance, problematic drug interactions, opioid-induced hyperalgesia, change in clinical status, problems related to medication cost and/or availability, need for a different route of administration, and patient preference [124,125,233].

Equianalgesic-Dose Tables

Verbatim use of equianalgesic-dose tables for opioid rotation contributed to opioid analgesic deaths in the 2000s and prompted changes in opioid conversion methods to mitigate risk and improve safety [20]. These tables include calculations derived from single dosing in opioid-naïve patients and permit broad guidance only. To ensure safety, a new opioid should start 50% below the calculated comparable dose to compensate for variable opioid response and incomplete cross-tolerance. The new opioid is titrated using product-specific instructions, with SA opioids used for analgesic rescue in breakthrough pain until reaching up-titration [20,235].

Morphine is the reference against which other opioids are compared, and analgesic potency is calculated as dose equivalence to morphine (i.e., MED). Table 7 shows a typical equianalgesic-dose table with figures validated for acute pain in opioid-naïve patients and conversions for opioid-tolerant patients [125].

Table 7: OPIOID ANALGESIC APPROXIMATE DOSE EQUIVALENTS

Opioid Analgesic

Oral Dose

Parenteral Dose

Morphine Equipotency Ratio, Oral

Morphine

30 mg

10 mg

Reference opioid

Codeine

200 mg

100 mg

Not established

Fentanyl (transdermal)

Not applicable

100 mcg

Not applicable

Hydrocodone (Hysingla ER)

30–45 mg

Not applicable

1.5:1

Hydromorphone (Dilaudid)

8 mg

2 mg

4:1

Levorphanol

4 mg

2 mg

Not established

Oxycodone (OxyContin ER)

20–30 mg

10–15 mg

2:1

Source: [125,213]

Breakthrough Pain Management

Breakthrough pain has been defined as a sharply increased pain episode with otherwise stable, well-controlled pain [125]. The incidence of breakthrough pain in patients with chronic cancer and noncancer pain is 50% to 90%, even with pain appropriately managed with around-the-clock opioid analgesic coverage [236,237,238]. Breakthrough pain types include spontaneous, incidental, and end-of-dose failure [125]. It is important to minimize the use of medications to address breakthrough pain in patients with chronic pain by titrating the baseline opioid dose or using adjunctive agents. If necessary, a reasonable dose for breakthrough pain is 10% to 15% of the total daily opioid dose [193]. Transmucosal immediate-release fentanyl products may be considered if prevention and control of breakthrough pain is not achieved.

Pharmacokinetic factors determine the options for breakthrough pain treatment. Analgesics for breakthrough pain are ideally selected according to the time it takes to reach maximum serum concentration. This period depends on the route of administration, usually attained by 1 hour with oral, 30 minutes with SC, and 6 minutes with IV routes [105].

Despite the self-limited duration (mean: 30 to 60 minutes), breakthrough pain is highly distressing to the patient and burdensome to families, caregivers, and healthcare systems. It is linked to decreased functional status, treatment dissatisfaction, and worse medical outcomes. Breakthrough pain may go unrecognized and is often undertreated due to lack of knowledge and undue concern regarding overmedicating [239]. Of patients with breakthrough pain, 60% describe pain intensity as severe but only half take medication to address it [119]. Breakthrough pain has an unpredictable onset and reaches peak pain intensity in 5 to 15 minutes, making SA morphine, hydromorphone, and oxycodone—with onsets of action 30 minutes after oral ingestion—ineffective [146].

IV fentanyl analgesia, with onset of action in 5 to 8 minutes and duration of 30 to 60 minutes, is ideal but not feasible for outpatient breakthrough pain management. Instead, transmucosal immediate-release fentanyl products overcome the limitations of SA opioids to deliver analgesia approaching the rapid onset of IV fentanyl [239]. Available products include [125]:

- Sublingual tablet (Abstral)

- Citrate oral transmucosal lozenge (Actiq)

- Buccal tablet (Fentora)

- Nasal spray (Lazanda)

- Buccal soluble film (Onsolis)

- Sublingual spray (Subsys)

Transmucosal immediate-release fentanyl products have been shown superior in pain reduction to placebo at all time points from 15 to 60 minutes and to SA oral morphine in the initial 45 minutes. Among these products, intranasal fentanyl spray is possibly superior to the buccal tablet and oral transmucosal lozenge in the first 30 minutes of dosing [125,146].

Transmucosal immediate-release fentanyl products are highly potent, rapid-acting opioids, and their use by opioid-naïve persons can be fatal at any dose [125]. To ensure that benefits outweigh risks, the FDA enacted a class-wide REMS that emphasizes appropriate product prescribing and dispensing to opioid-tolerant patients only. It is also important to avoid the inappropriate conversion between one transmucosal immediate-release fentanyl product and another and to safeguard against accidental exposure to children and others. The FDA recommends prescribers, pharmacists, and patients be educated on the safe use and risks of misuse, abuse, addiction, and fatal overdose associated with these products. The diverse routes of administration of transmucosal immediate-release fentanyl products allow greater matching of product with patient preference, often determined by disease and breakthrough pain characteristics [210].

Although often used off-label, transmucosal immediate-release fentanyl medications are only approved for breakthrough pain in adults (18 years of age or older) with cancer who are already receiving, and are tolerant to, regular opioid therapy for underlying persistent cancer pain [146,239]. The exception is Actiq and generic equivalents, which are approved starting at 16 years of age. Even highly opioid-tolerant patients should start at the lowest available dose. Patients may need to switch between formulations to find the best match, but prescribers should never attempt this without guidance from specific product prescribing information, available on the FDA website at https://www.TIRFREMSaccess.com. This website should be consulted for all information regarding transmucosal immediate-release fentanyl products, including new and updated information [210].

Analgesic Failure

Pain control and tolerability in long-term opioid therapy may be hindered by the development of analgesic tolerance, opioid-induced hyperalgesia, oral opioid malabsorption, or HPA-axis dysfunction. One way to gauge the adequacy of pain control is to consider whether the use of added opioids has resulted in improvements in functioning, physical capacity, psychological well-being, family/social interactions, and healthcare resource use, which are weighed against unwanted effects, such as daytime sedation, mental confusion, constipation, and other side effects.

Tolerance

Opioid tolerance and opioid-induced hyperalgesia are both characterized by diminishing pain control. However, tolerance may reflect decreased opioid sensitivity, while opioid-induced hyperalgesia represents increased pain sensitivity [240]. Etiologically, opioid tolerance reflects an adaptation to drug exposure over time that diminishes drug effect, though pain can generally be controlled with dose escalation. Opioid-induced hyperalgesia reflects a paradoxical increase in pain that may worsen with opioid up-titration [241,242].

Tolerance to opioids may develop in several ways. Short-term use inhibits the production and release of endogenous opioids (e.g., beta-endorphins), while long-term use may also inhibit mu-opioid receptor expression. Studies of long-term morphine use have found down-regulation in POMC gene expression and subsequent decrease in endorphin production; decreased mu opioid receptor density on beta-endorphin containing neurons in the hypothalamus; and mu opioid receptor uncoupling from ligand-gated voltage channels with decreased ion channel potency and efficacy [113]. Morphine analgesic tolerance may also result from increased production of the anti-opioid peptides that bind mu receptors to decrease opioid binding and activation of mu opioid receptors. These processes develop over time and correspond with patient requirements for increasing opioid dose to maintain analgesia [113].

Other mechanisms may contribute to the loss of opioid analgesia. Pharmacokinetic changes can accelerate opioid metabolism and elimination from up-regulation of enzymatic activity in the metabolic pathway for the opioid. With enzyme induction, plasma opioid concentration diminishes over time while dosing remains constant [241]. The addition of other medications can induce metabolizing enzymes, with accelerated breakdown and excretion of the opioid leading to loss of analgesia and the need for dose escalation to regain analgesia [243]. Pharmacodynamic processes that include activation of the NMDA receptor/nitric oxide cascade can also result in opioid hypoanalgesia. NMDA receptor or nitric oxide synthase blockade can prevent or reverse opioid tolerance [244,245,246].

Progression of the underlying pain condition can also increase pain intensity and require dose escalation to control the pain. This may be mistaken for pharmacologic tolerance [241]. In general, tolerance can be managed by opioid rotation, dose escalation, or adding a non-opioid analgesic [177].

Opioid-Induced Hyperalgesia

As noted, opioid-induced hyperalgesia is characterized by paradoxical pain amplification. Pain sensitivity is heightened in the absence of a new or exacerbated injury. Opioid-induced hyperalgesia should be suspected in the patient who reports an unusual or unexplained change in pain profile, a diffuse allodynia (i.e., pain from normally non-painful stimuli) not related to the original pain condition, or worsening pain in response to dose escalation [242,247].

Opioid-induced hyperalgesia involves CNS and PNS sensitization that develops through multiple mechanisms, including NMDA receptor activation; increased spinal cord dynorphin levels that activate excitatory pro-nociceptive neuropeptides; and CNS glial cell activation [240,241,242,248]. CNS pain facilitatory mechanisms contribute to hyperesthesia (i.e., exaggerated pain sensitivity) and allodynia. Pain abnormalities with opioid-induced hyperalgesia often reflect exacerbated pre-existing painful conditions, with pain intensity worse than before opioid therapy [240,249]. However, patients often describe the pain as more diffuse, less defined in quality, and typically extending beyond the original painful areas. Many features of pain associated with opioid-induced hyperalgesia resemble the pain experienced during opioid withdrawal, and both share a common neurobiology [240].

The diagnosis of opioid-induced hyperalgesia is often made in association with an increase in the opioid dose. Pain reduction indicates opioid tolerance, while worsening pain indicates opioid-induced hyperalgesia. Conversely, reducing the opioid may alleviate opioid-induced hyperalgesia symptoms, although care should be taken to avoid inducing withdrawal symptoms, which can increase pain and cloud the clinical picture [240].

Opioid-induced hyperalgesia is managed by addressing the underlying mechanisms. Morphine has the highest risk of opioid-induced hyperalgesia and should be replaced, if appropriate, in these patients. Switching to an NMDA antagonist opioid (e.g., methadone, levorphanol) is one approach [125]. Spinal dynorphin is a kappa opioid receptor agonist, and kappa receptor antagonism may reverse opioid-induced hyperalgesia. As such, the kappa receptor antagonist buprenorphine is uniquely helpful as an alternative opioid for opioid-induced hyperalgesia [125,240]. If neuropathic pain is the original condition, it will often preferentially respond to non-opioid analgesics such as amitriptyline or pregabalin, which can enhance analgesia and decrease opioid dosing [125,242].

The NMDA antagonist ketamine has been used successfully in outpatients with opioid-induced hyperalgesia and is perhaps the most effective agent [247]. There is also evidence that concurrent use of the opioid antagonists naltrexone or naloxone at ultra-low doses can prevent opioid-induced hyperalgesia and enhance analgesia [250].

Oral Opioids and GI Malabsorption

Malabsorption may also contribute to analgesic failure. Possible causes of oral opioid failure were studied in 95 patients with intractable pain [15]. Patients were initially screened to assess pain and functional improvement with oral opioids; 21.1% had three or more failed oral opioid trials. Malabsorption symptoms of nausea and steatorrhea were identified in 100%, and undigested medication in the stool detected in 70%. Pain relief from IV hydromorphone was experienced by 75%. The researchers concluded that patients with intractable pain and oral opioid failure may have a GI condition that interferes with absorption. These patients require non-oral routes until the GI dysfunction is resolved [15].

Endocrinopathy

Some patients with severe chronic pain lack analgesic response from lower-dose opioids; their complaints of analgesic failure may be dismissed despite severe impairment and debilitation. It is crucial to consider an underlying endocrinopathy as a possible cause. In one study of 61 patients with refractory chronic pain, 80.3% showed at least one hormone abnormality and 11.5% showed severe pituitary-adrenal-gonadal deficiency [251].

Pain that is uncontrolled, intractable, or severe impacts the endocrine system. Pain is a potent stressor that initially elevates serum pituitary, adrenal, and gonadal hormones. Severe uncontrolled pain depletes serum hormone levels; this serves as a biomarker for endocrinopathies and indicates that enhanced analgesia and hormone replacement may be necessary. Adequate physiologic levels of specific hormones may be required for optimal analgesia, neuroprotection, and neurogenesis. Hormone replacement is not a substitute for opioids but can minimize dose requirements [251].

Patient Nonadherence

Many patients with chronic pain do not take their medication as prescribed or stop altogether. A review of 11 trials involving 2,473 patients found an overall discontinuation rate of 22.9%, including 11.4% with weak opioids and 34.1% with strong opioids [252]. Community-based studies have found that 21% to 38% of patients adhere to their prescribed opioid regimens [253,254].

Treatment adherence is essential for optimal pain control, for quality of life improvement, and to reduce healthcare utilization and associated costs. Inconsistent adherence to strong opioid prescriptions is the most important risk factor for hospitalization in these patients [255]. Poor adherence is also linked to problematic side effects, depression, higher dosing frequency, and negative attitudes of relatives or partners toward the patient's need for opioids. Adherence may be improved by patient education regarding the pain condition, realistic treatment expectations, and perceived benefit from treatment. In addition, primary care providers can modify risk factors for poor adherence by decreasing the dose frequency and addressing treatment expectation and benefit, side effects, depression, and attitudes of relatives and partners [256]. A tailored approach to opioid selection and titration optimizes the balance between pain control and side effects, which often enhances therapy adherence [1].

15. OPIOID ANALGESIC SIDE EFFECTS AND MANAGEMENT

All opioid analgesics have the potential for serious adverse effects when prescribed without careful consideration of patient factors. Even when prescribed with due diligence, patients may experience side effects that, if not anticipated or managed properly, can promote treatment discontinuation or analgesic failure from intolerance of therapeutic dosages. Side effects are generally adverse (with the possible exception of sleep-promoting sedation) and result from specific opioid pharmacology, patient age, comorbidities, genetic polymorphisms, and impaired hepatic or renal function [105].

Upon treatment with opioids, most patients report their pain is less intense, less distressing, or gone entirely, while other sensory perceptions are unchanged. A minority of patients experience euphoria, but it is more common for pain-free volunteers without a history of substance use disorder to describe morphine as unpleasant. Except in cases of acute intoxication, opioids, even highly potent mu agonists, seldom induce the loss of motor coordination or slurred speech characteristic of calming or sedating drugs [106,257].

Evidence Based Practice Recommendation

The American Society of Interventional Pain Physicians recommends monitoring for side effects (e.g., constipation) and managing them appropriately, including discontinuation of opioids when indicated.

https://painphysicianjournal.com/current/pdf?article=NDIwMg%3D%3D&journal=103

Last Accessed: May 22, 2023

Level of Evidence: I (Evidence obtained from multiple relevant high quality randomized controlled trials for effectiveness)

Clinicians should anticipate and monitor common opioid side effects and discuss these effects with patients before opioids are initiated. Many side effects are time-limited and lessen or resolve following stable dosing. Tolerance to opioid effects tends to develop at different rates, ranked below in descending order [177]:

- Euphoria (most rapid)

- Sedation

- Nausea

- Analgesia

- Constipation (late, if ever)

SEDATION

Sedation is a dose-dependent and often time-limited side effect. Anticholinergic activity of some opioids may contribute to sedation and drowsiness, but alleviation of pain can itself promote relaxation and sleep. Excessive sedation can occur with higher-dose initiation or rapid dose escalation and may result in nonadherence or reduced quality of life [112].

Management approaches for opioid-induced sedation include reduction or elimination of nonessential sedating medication (e.g., benzodiazepines, antihistamines, some TCAs, muscle relaxants), opioid dose reduction, and/or opioid rotation [112].

PRURITUS

Opioid analgesics can cause pruritus, which may be severe and difficult to manage, highly distressing to the patient, and among the top reasons for discontinuation. Pruritus is often misdiagnosed as an opioid allergic reaction, but true allergic and anaphylactic reaction to opioids is rare (<1%) and results from activation of central mu opioid, dopamine, serotonin, prostaglandin, and histamine receptors. Reactions related to histamine activation have been reported, most often with morphine. These reactions include urticaria, bronchospasm, and hypotension. When pruritus does occur, it typically involves the face, nose, and torso, and intrathecal administration is most associated with intense itching. Histamine release is most common with morphine [106,258].

The goal of treating opioid-associated pruritus is to ameliorate the symptom without reversing analgesia with opioid antagonists. Options include anti-histamines (e.g., diphenhydramine, hydroxyzine) or H2 blockers (e.g., ranitidine, cimetidine). Naloxone infusion may be considered if other treatments fail and itching is severe. Opioid rotation to a different synthesis class (natural, semisynthetic, or synthetic) may also be successful. Epidural kappa opioid receptor agonists nalbuphine or butorphanol can reverse pruritus from mu agonists while maintaining analgesia [112,258,259]. If a true opioid allergy is identified, the offending opioid should be replaced by an opioid from a different chemical class to avoid antibody recognition [130].

OPIOID-INDUCED CONSTIPATION AND BOWEL DYSFUNCTION

GI symptoms are among the most common side effects reported with opioid use. Providers should be alert to the character and extent of patient distress resulting from these effects and the potential for non-adherence to therapy. Opioid-induced bowel dysfunction takes various forms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation. Opioid activation of mu and kappa receptors in the neuronal plexus of the gut wall increases intestinal wall and sphincter resting tone and reduces biliary, pancreatic, and intestinal secretions. This results in dysrhythmic, non-propulsive contractions (bowel spasm), delayed passage and increased viscosity of intestinal contents, and the onset of constipation. Spasm and colic can also result from increased biliary tract tone [107,109].

Up to 91% of patients taking opioids experience constipation, the most common opioid-induced bowel dysfunction symptom. Opioid-induced constipation, often in combination with chronic nausea, can cause considerable distress, greatly diminished quality of life, and opioid discontinuation by as many as 33% of patients [260]. Most patients require constipation management for the duration of opioid therapy because complete tolerance rarely develops [125].

In order to prevent opioid-induced constipation, a laxative bowel regimen and bowel management education should be provided to all patients prescribed an opioid. In the event of laxative or stool softener nonresponse, patients may try [125,174]:

- Mild osmotic agents (70% sorbitol solution, lactulose, milk of magnesia)

- Polyethylene glycol

- Bulk-forming laxatives (psyllium) with proper liquid intake

- Mild cathartic laxatives (senna, bisacodyl)

Saline or tap water enemas may be necessary to avoid fecal impaction.

Opioid switching from a hydrophilic agent (e.g., morphine, oxycodone, hydromorphone) to a lipophilic opioid (e.g., fentanyl, buprenorphine, methadone) may be helpful, as there is greater GI opioid receptor activity with hydrophilic opioids. Peripherally acting mu opioid receptor antagonists are indicated when other opioid-induced constipation treatments fail, including methylnaltrexone (50% to 60% efficacy in severe refractory opioid-induced constipation) or subcutaneous naloxegol injections [174].

NAUSEA AND VOMITING

Roughly 33% to 66% of patients receiving opioids experience nausea and vomiting, usually during initiation and titration. This often resolves by the first week of treatment but can recur later with a significant dose increase. Nausea and vomiting results from reduced GI motility and constipation, delayed gastric emptying, and activation of opioid receptors, dopamine tracts, and other transmitters in the chemoreceptor trigger zone [125]. Some patients report a sharp exacerbation of nausea upon movement, suggesting a component of opioid-induced vestibular dysfunction [107].

Nausea and vomiting during opioid initiation should be controlled with antiemetics, and these agents should be available as needed after dosing is stabilized. Metoclopramide and domperidone are first-line options due to a mechanism that improves GI motility. Around-the-clock and/or transdermal prescribing may be considered, with extra doses for rescue. Extrapyramidal symptoms may occur, but are considered infrequent [125].

Antihistamines block histamine receptors in the vomiting center and on vestibular afferents. They may be used when [125]:

- Vestibular sensitivity mimics motion-induced nausea

- GI prokinetic agents are contraindicated due to bowel obstruction

Ondansetron and other serotonin receptor antagonists are also effective in treating nausea and vomiting. Chlorpromazine is likely to produce significant sedation; prochlorperazine has greater antiemetic potency. However, potential extrapyramidal symptoms and anticholinergic side effects limit the clinical use of these agents [125].

RESPIRATORY DEPRESSION

Therapeutic doses of morphine depress all phases of respiratory activity, including the breathing rate, minute volume, and tidal exchange. Respiratory depression results from decreased brainstem sensitivity to carbon dioxide build-up and is the primary lethal side effect of opioids [122]. Patients are most vulnerable to respiratory depression in the first five days of opioid initiation, especially the first 24 hours. Risk factors include obesity, sleep apnea, and pre-existing respiratory disorders (e.g., acute asthma, respiratory infection). Respiratory depression is antagonized by pain, and patients with substantial pain relief following uncontrolled pain are also at risk. Coingestion of any CNS respiratory depressant, including benzodiazepines or alcohol, elevates the risk of pronounced respiratory depression and fatality [106,261].

Opioid use at appropriate prescribed doses seldom results in significant respiratory depression, even in patients with end-stage chronic obstructive pulmonary disease or dyspnea from advanced-stage cancer [262]. Patients on stable-dose, long-term opioid therapy have low risk of respiratory depression, although concerns remain prevalent among clinicians and patients [125]. It is important to note that respiratory depression may occur with a change in opioid analgesic, rapid dose escalation, development of renal failure or a serious pulmonary condition, or a single, large, inappropriate dose [261].

Sedation always precedes respiratory depression. With fatal respiratory depression, the process begins with sedation followed by reduction and finally cessation of breathing over the course of 5 to 15 minutes. Respiratory depression is characterized by rising peripheral carbon dioxide pressure, falling peripheral oxygen, and decreasing respiratory rate [262]. While these laboratory markers directly measure ventilation and ventilatory drive, they are often only available in an inpatient setting. In the outpatient setting, breathing rate and/or oxygen saturation are surrogate measures of ventilatory drive. In these cases, severe respiratory depression is defined by a respiratory rate less than 8 to 10 breaths per minute and oxygen saturation of <85% for more than six minutes per hour [122].

Naloxone can reverse respiratory depression caused by most opioids (though it is ineffective with meperidine). The extent and duration of naloxone reversal is determined by the specific opioid and dose, route of administration, concurrent medication(s), underlying disease, pain and state of arousal, and genetic factors [122].

When indicated for reversal of opioid-induced respiratory depression, naloxone (1:10 dilution) titrated in small increments or given by infusion should be administered to improve respiratory function without reversing analgesia [262]. The patient should be monitored carefully until the respiratory depression episode resolves [125].

Naloxone should be administered cautiously by slow IV infusion in opioid-dependent patients because it can abruptly induce acute opioid withdrawal syndrome and precipitate severe uncontrollable pain. Given this potential for abrupt, overwhelming physiologic and emotional stress with naloxone intervention, its use in respiratory depression should be strictly limited to patients unresponsive to physical or verbal stimulation or patients with shallow respirations, respiratory rate less than seven breaths per minute, or pinpoint pupils [122]. The 30- to 81-minute duration of naloxone is less than most mu opioid agonists, and re-administration is usually required.

The unique properties of nalbuphine make it effective in reversing opioid-induced respiratory depression or pruritus while maintaining analgesia. Nalbuphine can be a good analgesic option for patients susceptible to severe respiratory depression, pruritus, or nausea and vomiting with standard opioids [112].

SEROTONIN SYNDROME

Serotonin syndrome results from overactivation of central and peripheral serotonin receptors, usually from concurrent use of multiple serotonergic agents. Serotonin syndrome can result from drugs that influence the reuptake, metabolism, synthesis, or release of serotonin; influence serotonin receptor activity; or interfere with CYP2D6 or CYP3A4 metabolism. The most commonly implicated agents are SSRIs, but other medications that may affect serotonin levels include serotonin-norepinephrine reuptake inhibitors, MAOIs, antipsychotics, analgesics, antiemetics, cough suppressants, and dietary supplements. In more severe cases, patients develop hyperthermia, autonomic instability, delirium, and muscle rigidity, with complications including seizure, rhabdomyolysis, arrhythmias, and respiratory arrest. Suspicion of serotonin syndrome requires urgent emergency management [263,264].

Tramadol is the only opioid analgesic associated with serotonin syndrome. SSRIs inhibit CYP2D6, which decreases tramadol analgesic efficacy. Concurrent use of tramadol and paroxetine or venlafaxine has been reported to cause serotonin syndrome [263,264]. Genetic susceptibility to serotonin syndrome has been identified and is influenced by a patient's ability to produce different ratios of positive and negative tramadol enantiomers [264].

NEONATAL ABSTINENCE SYNDROME

Teratogenic effects from opioid exposure during pregnancy have not been identified. However, chronic opioid use during pregnancy can result in physical dependence in utero and potentially life-threatening opioid withdrawal in the neonate at birth and for up to 12 days after [106].

If signs of neonatal abstinence syndrome are present, the neonate should be taken to intensive care for observation and further assessment. Opioid replacement may be necessary to stabilize the patient, reverse the syndrome, and reduce complications of withdrawal. Additional medications may be necessary to control seizures and other symptoms.

MORPHINE AND CARDIAC RISK

Morphine is commonly used for chest pain in patients with a suspected acute coronary syndrome, but data suggest morphine use in patients with unstable angina and non-ST segment elevation myocardial infarction may increase mortality. It should be used with great caution or avoided entirely in this patient group [265].

NEUROPSYCHIATRIC EFFECTS

Hallucinations are more strongly associated with mixed agonist/antagonist opioids and rarely occur with mu opioid agonists, with few exceptions. In fact, a review concluded that mu receptor agonist opioids were not only free of psychoses risk, but probably possesses antipsychotic activity yet to be characterized [266].

Other adverse CNS effects, including cognitive impairment, delirium, and generalized myoclonus, are associated with meperidine, morphine, or hydromorphone use in patients with renal impairment. In these patients, opioid metabolites accumulate to neurotoxic levels. The metabolites have anticholinergic activity, which can result in cognitive changes and delirium [125].

There is little research that sufficiently addresses brain response to chronic opioid therapy. Positron emission tomography and magnetic resonance imaging studies show changes in brain response to long-term opioid therapy in patients with chronic pain. However, it is unclear whether these neuroimaging findings are the result of the chronic pain or the opioid medication use [267].

Differential diagnosis is necessary in patients with suspected opioid-induced delirium to rule out dehydration, other CNS medications, sepsis, and hypercalcemia. Tactile hallucinations and myoclonus suggest opioid toxicity. Immediate delirium management consists of neuroleptics to control agitation and perceptual or delusional disturbances. Haloperidol is the first-line option; methotrimeprazine and chlorpromazine are alternative options, especially when sedation is beneficial. For resistant delirium, midazolam is preferred; lorazepam is used for comorbid anxiety. In cases of cognitive impairment in the absence of delirium, methylphenidate or modafinil may be used. These agents are not recommended with evidence of perceptual or delusional disturbances [125].

Opioid toxicity from accumulating neurotoxic metabolites may present with generalized myoclonus, sedation, confusion, or chronic nausea. This is generally resolved by opioid switching [125].

IMMUNOLOGIC CHANGES

The traditional view of opioids as immunosuppressive has been challenged by evidence showing a more complex role of opioid receptors in immune function. Different opioids or routes of administration act through different mechanisms to produce immunosuppressive, immunostimulatory, or dual immune effects. The impact of specific opioids on immune function probably result from a combination of direct effects on immunocytes and indirect effects on centrally mediated mechanisms, systemic production, and release of immunomodulatory mediators [268].

The interaction between opioids and the immune system is complex. Trauma and severe pain alone are immunosuppressive, which is reversible by sufficient pain control [269]. Exogenous opioid drugs can induce immunosuppression, while endogenous opioids appear to promote immunoactivation.

Opioid therapy has been shown to inhibit humoral and cellular immune responses, including antibody production, lymphocyte activity, cytokine expression, and phagocytic activity. Potential underlying mechanisms include HPA modulation, sympathetic nervous system stimulation, and activation of mu opioid receptor on immune cells [270,271]. Opioids vary by immune system interaction. Compared with morphine, tramadol produces greater enhancement in natural killer cell activity, lymphocyte proliferation, and interleukin-2 release, while buprenorphine produces a negligible effect on immune response [257].

ENDOCRINE EFFECTS

Opioid therapy can result in HPA suppression and hypopituitarism, clinically expressed as hypogonadism, impotence, infertility, and/or osteoporosis [272]. Opioid-induced hormone dysfunction has been observed in men and women with oral, transdermal, IV, and intrathecal administration [257].

Opioids appear to differ in degree of adverse effect on hormonal function. In one study, men receiving buprenorphine maintenance therapy for opioid addiction showed significantly higher plasma testosterone levels and less sexual dysfunction than those receiving methadone [273]. Although long-term opioid therapy produces a dose-dependent decrease in total and free testosterone level, serum hormone levels return to normal in both sexes shortly after opioid cessation. Not all men experience androgenic suppression with long-term opioid therapy; body mass index and smoking status are thought to increase the risk of opioid-induced hormonal dysfunction [257].

If a patient on opioid therapy complains of changes in libido or sexual dysfunction, treatment is empirical, with knowledge that multiple factors may be involved in the pathogenesis of sexual dysfunction. In these cases, non-opioid analgesics should be added to reduce or, if possible, discontinue the opioid. In men, testosterone replacement is indicated if serum testosterone is low and not contraindicated. Sildenafil or another phosphodiesterase type 5 inhibitor may be used for men experiencing sexual side effects [125,274].

For women taking opioids with complaints of sexual side effects, dehydroepiandrosterone is the first-line option. This is because adrenal gland suppression is a greater contributor to female androgen deficiency. In younger women, oral contraceptives with a relatively androgenic progestin component may be used [125,274].

ACETAMINOPHEN TOXICITY

Several codeine, hydrocodone, and oxycodone formulations include acetaminophen. In the United States, acetaminophen toxicity has replaced viral hepatitis as the most common cause of acute liver failure and is the second most common cause of liver failure requiring transplantation [275]. In 2009, the FDA imposed a daily dose ceiling for acetaminophen of 4,000 mg; however, doses less than 4,000 mg per day can produce subclinical liver toxicity. Concurrent alcohol use also increases the risk, and chronic alcohol use is a high risk factor for fatal acetaminophen toxicity [232,276]. It is crucial to use caution when prescribing any opioid preparation containing acetaminophen to older patients or patients with hepatic or renal disease.

OPIOID USE DISORDERS

There is no adequately validated instrument to differentiate pain patients who are at risk of dependence from those who are not. Research suggests that patients, even alcoholics, with no history of opioid dependence are not at heightened risk of becoming addicted with short-term opioid exposure. However, those with a positive history of dependence would benefit from active recovery efforts while receiving such medications.

Despite the rise in prescription opioid analgesic use and misuse, definitive data on the rate of dependence among patients administered opioids for acute pain does not yet exist. There is, however, agreement on how to minimize the risk of iatrogenic dependence. These steps include screening for risk potential based on a family history of substance abuse and the exploration of different delivery systems that adequately treat pain but minimize abuse potential. Although a pattern of aberrant behavior may be grounds for caution, a history of opioid misuse does not necessarily preclude a patient from successful treatment with an opioid. Screening for psychological disorders is also advisable, including psychosomatic causes of pain.

16. CONCLUSION

Safety is the foundation of effective pain control with opioid prescribing. Safety risks are mitigated by understanding that most opioid analgesic overdoses involve co-ingested CNS sedatives or alcohol, with side effects, tolerability and analgesic response largely determined by comorbidities, drug interactions, and genetic variation.

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249. Ossipov MH, Lai J, King T, Vanderah TW, Porreca F. Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Biopolymers. 2005;80(2-3):319-324.

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Evidence-Based Practice Recommendations Citations

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95074 • Antibiotics Review

Donna Coffman, MD

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

Choosing an antibacterial agent can be challenging, given the wide array of drugs available. Learning the important properties and uses of these drugs is made easier by the fact that they are grouped in classes based on their biochemical structure. Members of a drug class share characteristics such as clearance, mechanism of action, absorption, and side effects; knowing these shared properties makes it easier to choose the appropriate agent for a particular patient. In addition, it is easier to quickly grasp the strengths and weaknesses of a newly marketed antibiotic if you understand the general pharmacology of its class. A good grasp of the use of specific agents to target specific bacteria leads to improved clinical response to treatment and a decrease in the likelihood of the development of microbial resistance. This course is intended as an overview of the general characteristics of the major antibiotic classes, with a brief discussion of the individual agents and indications, giving greater perspective to the actions and characteristics of antibiotics. Due to the large number of antibiotics available, this course focuses on eight major classes of antibiotics: the penicillins, cephalosporins, other beta-lactams, aminoglycosides, macrolides, quinolones, sulfonamides, and tetracyclines. A brief discussion of vancomycin and the newer glycopeptide analogues is also included.

Table of Contents

95074 • Antibiotics Review

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. GENERAL CHARACTERISTICS OF ANTIBIOTICS

3. ANTIBIOTIC RESISTANCE

4. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

5. PENICILLINS

MECHANISM OF ACTION

PHARMACOKINETICS

ABSORPTION/ELIMINATION

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

6. CEPHALOSPORINS

MECHANISM OF ACTION

PHARMACOKINETICS

ABSORPTION/ELIMINATION

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

7. CARBAPENEMS

MECHANISM OF ACTION

PHARMACOKINETICS

ABSORPTION/ELIMINATION

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

8. MONOBACTAMS

MECHANISM OF ACTION

PHARMACOKINETICS

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

9. AMINOGLYCOSIDES

MECHANISM OF ACTION

PHARMACOKINETICS

TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

10. MACROLIDES

MECHANISM OF ACTION

PHARMACOKINETICS

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

11. QUINOLONES

MECHANISM OF ACTION

PHARMACOKINETICS

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

12. SULFONAMIDES

MECHANISM OF ACTION

PHARMACOKINETICS

ABSORPTION/ELIMINATION

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

13. TETRACYCLINES

MECHANISMS OF ACTION AND PHARMACOKINETICS

ABSORPTION/ELIMINATION

SIDE EFFECTS/TOXICITY

DRUG INTERACTIONS

SPECIAL POPULATIONS

14. VANCOMYCIN

MECHANISMS OF ACTION AND PHARMACOKINETICS

ABSORPTION/ELIMINATION

SIDE EFFECTS/TOXICITY

15. ANTIMICROBIAL PEPTIDES

DAPTOMYCIN

LYPOGLYCOPEPTIDES

16. PLEUROMUTILINS

17. INVESTIGATIONAL ANTIBIOTICS FOR DRUG-RESISTANT MICRO-ORGANISMS

18. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95074 • Antibiotics Review

Education Category. Pharmacology

Release Date. 02/01/2024

Expiration Date. 01/31/2027

Course Overview

Choosing an antibacterial agent can be challenging, given the wide array of drugs available. Learning the important properties and uses of these drugs is made easier by the fact that they are grouped in classes based on their biochemical structure. Members of a drug class share characteristics such as clearance, mechanism of action, absorption, and side effects; knowing these shared properties makes it easier to choose the appropriate agent for a particular patient. In addition, it is easier to quickly grasp the strengths and weaknesses of a newly marketed antibiotic if you understand the general pharmacology of its class. A good grasp of the use of specific agents to target specific bacteria leads to improved clinical response to treatment and a decrease in the likelihood of the development of microbial resistance. This course is intended as an overview of the general characteristics of the major antibiotic classes, with a brief discussion of the individual agents and indications, giving greater perspective to the actions and characteristics of antibiotics. Due to the large number of antibiotics available, this course focuses on eight major classes of antibiotics: the penicillins, cephalosporins, other beta-lactams, aminoglycosides, macrolides, quinolones, sulfonamides, and tetracyclines. A brief discussion of vancomycin and the newer glycopeptide analogues is also included.

Audience

This course is designed for healthcare providers who prescribe and administer antibiotics to patients, including physicians, physician assistants, pharmacists, pharmacy technicians, nurses, nurse practitioners, and surgical technologists and assistants.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is approved by the California Nursing Home Administrator Program as a provider of continuing education. Provider number 1622. NetCE is approved to offer continuing education through the Florida Board of Nursing Home Administrators, Provider #50-2405.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 5 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 5 ANCC contact hour(s). NetCE designates this continuing education activity for 5 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 6 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 5 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. NetCE designates this activity for 5 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-24-006-H01-P. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the activity with individual assessments of the participant and feedback to the participant, enables the participant to earn 5 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. This continuing education activity is approved for 8.5 CE credits by the Association, and Associate members of AST of Surgical Technologists, Inc., for continuing education for the Certified Surgical Technologist, Certified Surgical First Assistant, and Associate members of AST. This recognition does not imply that AST approves or endorses any product or products that are included in the enduring materials. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. This home study course is approved by the Florida Board of Nursing Home Administrators for 5 credit hour(s). This course is approved by the California Nursing Home Administrator Program for 5 hour(s) of continuing education credit - NHAP#1622005‐8952/P. California NHAs may only obtain a maximum of 10 hours per course. AACN Synergy CERP Category A.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through July 29, 2025); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to provide a review of the major classes of antibiotics and their characteristics as well as an overview of selected individual agents within each class that are most useful for today's clinical practitioner.

Learning Objectives

Upon completion of this course, you should be able to:

1. Describe the general characteristics and mode of action of antibiotics commonly in use.

2. Employ best practice principles for limiting the emergence and transmission of antimicrobial-resistant strains within the healthcare environment, including in surgical practices.

3. Discuss the mechanism of action, pharmacokinetics, and spectrum of activity of natural and extended-spectrum penicillins.

4. Select the most appropriate, cost-effective cephalosporin based on "generational" characteristics and spectrum of activity.

5. Describe the role of carbapenems and monobactams.

6. Discuss the characteristics, expected toxicities, and indications for the use of aminoglycosides, macrolides, and sulfonamides.

7. Outline the mechanism of action, pharmacokinetics, and advantages inherent to quinolones and the tetracyclines.

Faculty

Donna Coffman, MD, attended medical school at the University of Louisville and completed her residency in Family Practice at St. John's Mercy Medical Center in St. Louis, Missouri. She is board-certified in Family Medicine and currently on staff at John Cochran VAMC in St. Louis.

Faculty Disclosure

Contributing faculty, Donna Coffman, MD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Ronald Runciman, MD

Mary Franks, MSN, APRN, FNP-C

Randall L. Allen, PharmD

Shannon E. Smith, MHSC, CST, CSFA

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

The number of antibiotic agents available is remarkable, and new agents are added regularly. This course is intended as an overview of the general characteristics of the major antibiotic classes, emphasizing mechanism of action, pharmacokinetics, and potential toxicities, with a brief discussion of the individual member agents and their clinical indications. The purpose of this course is to enlarge clinical perspective and enhance the understanding and confidence required for the selection of appropriate therapy of bacterial infections. The goal is to improve efficacy and safety while limiting the risk for selection and transmission of antimicrobial-resistant pathogens.

Given the large array of available antimicrobial agents, the scope of this course is confined to the eight major classes of antibiotics commonly employed for acute bacterial infection: the penicillins, cephalosporins, carbapenems, aminoglycosides, quinolones, macrolides, sulfonamides, and tetracyclines. A brief discussion of vancomycin, daptomycin, and newer glycopeptide analogues available for treatment of multi-resistant Staphylococcus aureus (MRSA) and enterococcal species is included.

For the purposes of the course, it is impractical to list or describe all the possible adverse effects, recommended uses, and off-label uses of the antibiotics discussed. Before using any antimicrobial, it is important to review the manufacturer's package insert and dosing recommendations for the drug.

2. GENERAL CHARACTERISTICS OF ANTIBIOTICS

Evidence Based Practice Recommendation

According to the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America, the infusion of bezlotoxumab should be performed while a patient is receiving standard-of-care antibiotics and has been shown to be effective in preventing recurrent C. difficile infection if administered at any time before ending antibacterial treatment

https://academic.oup.com/cid/article/73/5/e1029/6298219

Last Accessed: January 11, 2024

Strength of Recommendation: Expert Opinion/Consensus Statement

There are some characteristics that all antibiotics share. All antibiotics can elicit allergic responses, although some are more allergenic than others. Allergic reactions can range from mild, annoying rashes to life-threatening reactions such as anaphylaxis and the Stevens-Johnson syndrome. In some cases, there is a cross-sensitivity between agents in different classes. In addition, all antibiotics exert some impact on normal body flora as well as pathogens, in some cases leading to the emergence of Candida species and pathogenic bacteria such as Clostridioides difficile. Overgrowth of C. difficile within intestinal flora is often a serious complication of antimicrobial therapy that can produce symptoms ranging from mild diarrhea to severe, life-threatening pseudomembranous colitis [1]. Most cases resolve with supportive care and discontinuation of the offending antibiotic, but many require treatment. Furthermore, C. difficile colitis can develop days or weeks after the primary antimicrobial has been discontinued. A high degree of suspicion and judicious use of laboratory testing are the keys to recognizing and managing these complications.

3. ANTIBIOTIC RESISTANCE

Repeated exposure to an antibiotic may lead to the emergence of selective subpopulations of the same or related bacteria now resistant to the therapeutic agent. The Centers for Disease Control and Prevention (CDC) note that approximately 2.8 million people become infected with bacteria that are resistant to antibiotics, and approximately 35,000 people die annually because of these infections [2]. When C. difficile colitis, not typically resistant but associated with antimicrobial use, is added to these, the U.S. toll of all threats exceeds 3 million infections and 48,000 deaths [2]. Mechanisms of microbial resistance include altered cellular permeability (leading to greatly diminished intracellular concentration of the drug), increased efflux of the antibiotic from the cell, and elaboration of deactivating enzymes that alter the antibiotic's interaction at binding sites within the cell wall or cytoplasm [3].

Decreased cell membrane permeability is an important mechanism of bacterial resistance to beta-lactams, quinolones, and vancomycin. Microbial resistance to tetracyclines and quinolones is often mediated by increased efflux of the antibiotic from the cell. Enzymatic deactivation by beta-lactamases is the common mechanism of resistance to penicillins and cephalosporins. Resistance to aminoglycosides may result from altered cytoplasmic membrane transport (influx) or from intracellular enzymes (e.g., phosphotransferases and acetyltransferases) that deactivate the drug.

There are various mechanisms by which the interaction of an antibiotic with its binding site may be altered or bypassed, resulting in loss of antimicrobial activity. One such example, affecting the target site for quinolone activity, is an acquired structural alteration of deoxyribonucleic acid (DNA) gyrase, an enzyme essential for bacterial DNA synthesis. As a result, quinolones are no longer able to bind to the enzyme and the drug loses its antimicrobial effect. Another example is the methylation of ribosomal ribonucleic acid (rRNA) that prevents the binding of macrolides. The effectiveness of trimethoprim/sulfamethoxazole, which acts through disruption of folate synthesis by the cell, may become diminished by the adaptive ability of some bacteria to utilize an alternate metabolic pathway, thereby avoiding the effects of trimethoprim [4].

These resistance mechanisms may be acquired through mutations in the genes that encode for the target or affected transport proteins. As the bacterial cells without the adaptive mutations succumb to the action of the antibiotic, the subpopulation that has the adaptive mutation continues to replicate, replacing the original population with a resistant one.

Bacterial resistance can be transferred from one bacterium to another, or from one bacterial species to related group, by means of plasmids or transposons that gain entry to the cell. These agents are small segments of DNA that are readily exchanged between bacteria. A plasmid that contains a gene for an adaptive mutation can be shared with many nearby bacteria, which may or may not be the same species. In this manner, resistance can quickly spread from species to species [5].

Evidence Based Practice Recommendation

A meta-analysis published by the Cochrane Database of Systematic Reviews found high-certainty evidence that any professional or structural interventions are effective in increasing compliance with antibiotic policy and reducing duration of antibiotic treatment in the hospital setting.

https://www.cochrane.org/CD003543/EPOC_improving-how-physicians-working-hospital-settings-prescribe-antibiotics

Last Accessed: January 11, 2024

Level of Evidence: Meta-analysis

Many strategies have been used to circumvent the multiple mechanisms of resistance encountered in bacteria. Among these are addition of beta-lactamase inhibitors to extended-spectrum penicillins, alteration of cephalosporin side chains to produce new generations of the drug with broader activity, and combining drugs to enhance the antimicrobial effect (e.g., sulfamethoxazole with trimethoprim). In 2021, in response to perceived overuse of antibiotics, the American College of Physicians recommended limiting antibiotic courses to five to seven days for the some of the most common bacterial infections, including durations of antibiotic therapy in patients with common bacterial infections, such as acute bronchitis, community-acquired pneumonia, urinary tract infection, and cellulitis [172].

In addition, new categories of antibiotics are being created to stay ahead of the rapid evolution of bacterial resistance. Linezolid and tedizolid, the only two FDA-approved drugs in the oxazolidinone category, are examples of this, with linezolid being the first of the two to be developed. Oxazolidinones are a unique category of drugs that prevent formation of the 70S protein synthesis complex in bacteria and may be useful in the treatment of vancomycin-resistant enterococci and MRSA [6,7]. Nonetheless, development of resistance in bacteria is relentless.

Considering the efficient means by which bacteria develop resistance, clinicians should avoid, where possible, practice patterns that contribute to the process. In 2002, the CDC issued a position paper outlining recommendations for minimizing nosocomial infection and the emergence of resistant organisms [8]. In this paper, the CDC recommended a multistep approach that included: preventing infection (by paying careful attention to the proper use of invasive medical devices); tailoring medical treatment to fit the infection (by avoiding broad-spectrum antibiotics and prolonged treatment when possible); and preventing the transmission of resistant bacteria between patients (by emphasizing hand washing and implementing hospital infection control programs) [8]. Since issuance of the CDC's position paper, the agency has taken many additional steps and implemented coordinated, strategic action plans to change the course of antibiotic resistance. This includes publication of The National Action Plan for Combating Antibiotic-Resistant Bacteria (CARB), 2020–2025 [9]. The CARB builds on the first National Action Plan, released in 2015, and prioritizes infection prevention and control to slow the spread of resistant infections and reduce the need for antibiotic use. The CARB also integrates a "one health" approach, which recognizes the relationships between the health of humans, animals, plants, and the environment [9]. It has also been hypothesized that the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and associated COVID-19 illness might increase use of antibiotics and other antimicrobial medicines (both appropriate and inappropriate) to address primary or secondary infections, with the potential to further accelerate the emergence of antibiotic resistance despite the rate of the development of new antibiotics [9].

In 2022, the CARB Task Force issued a Year 5 Progress Report on combating antimicrobial-resistant bacteria, summarizing accomplishments achieved between 2015 and 2020. This report showed that substantial progress had been achieved for the following targeted bacteria: health care-associated C. difficile infection decreased by 36%; hospital-onset multidrug-resistant Pseudomonas aeruginosa decreased by 41%; and hospital-onset MRSA bloodstream infections decreased approximately 31.5% [173].

4. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

Obtaining a detailed patient history is a vital aspect of the appropriate prescription of antibiotics, particularly in empirical treatment. Furthermore, communication with patients regarding treatment regimens and compliance depends on clear communication between the patient and clinician. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. The interpreter should be considered an active agent in the diagnosis and/or treatment processes, negotiating between two cultures and assisting in promoting culturally competent communication and practice [10].

5. PENICILLINS

Alexander Fleming discovered penicillin in 1928. After observing that Penicillium colonies inhibited the growth of staphylococci on agar plates, Fleming made an extract from the mold and proved that it inhibited bacterial growth. Penicillin became available for general use in the 1940s [11].

MECHANISM OF ACTION

Penicillin is bactericidal, killing susceptible bacteria by interrupting cell wall synthesis. The drug exerts its effect by preventing cross-binding of the peptidoglycan polymers necessary for cell wall formation and by binding with carboxypeptidases, endopeptidases, and transpeptidase ("penicillin-binding proteins" [PBPs]) that participate in cell wall synthesis [12]. Although the exact mechanisms involved are not known, the result is that the cell wall is structurally weakened and lyses, leading to cell death.

The basic form of penicillin is structured around the beta-lactam ring (a thiazolidine ring) and can be altered by substituting side chains. By doing so, the antimicrobial spectrum, absorption characteristics, and resistance to beta-lactamase deactivation can be favorably modified.

Bacterial resistance to penicillins may take different forms. The most significant is the bacterial production of beta-lactamases, which can destroy the beta-lactam ring by means of hydrolysis, effectively preventing antimicrobial activity by the agent [13]. In addition, some bacteria are able to prevent binding to the PBPs by various means, including altered binding sites for the penicillins [14].

Various strategies have been employed to circumvent these microbial adaptations. Altering the structure of the penicillin molecule to produce agents that are more resistant to the hydrolysis from the beta-lactamases has resulted in the development of the extended-spectrum penicillins.

Another strategy has been to combine penicillins with other agents that block bacterial beta-lactamases [6]. Examples include amoxicillin plus clavulanic acid, ampicillin plus sulbactam, piperacillin plus tazobactam, and ticarcillin plus clavulanic acid. Clavulanic acid is produced by Streptomyces clavuligerus. Sulbactam and tazobactam are derived from the basic penicillin ring. These agents have little intrinsic antimicrobial activity, but they bind irreversibly to many beta-lactamases, preventing hydrolytic activity against the beta-lactam ring.

PHARMACOKINETICS

Penicillins can be separated into groups based on their pharmacokinetics and spectrum of antibacterial activity. These groups are the natural penicillins, the aminopenicillins, the penicillinase-resistant penicillins, and the antipseudomonal penicillins [15].

Table 1: THE PENICILLINS

Agent

Adult Dosing Range

Pediatric Dosing Range

Route

Common Side Effects

Comments

Natural Penicillins

Penicillin G benzathine

1.2–2.4 MU

50,000 U/kg in one dose

Max: 2.4 MU divided between 2 injection sites

IM

Rash, GI upset

Indicated for syphilis and group A strep infections.

Note: Do not administer IV (except parenteral/aqueous preparation) or IM near nerve or artery. Cardiopulmonary arrest and death have occurred from accidental IV administration.

Penicillin G benzathine or penicillin G procaine

2.4 MU in one dose

<14 kg: O.6 MU

14 to 27 kg: 1.2 MU in one dose

IM

Rash, GI upset

Penicillin G (parenteral/aqueous)

2–30 MU per day

100,000–400,000 U/kg/day in divided doses every 4 to 6 hours

Max: 24 MU/day

IM, IV

Rash, GI upset

Penicillin V potassium

125–500 mg every 6 to 8 hours

Pneumonia (off label): 50–75 mg/kg/day in 3 to 4 divided doses

Pharyngitis: 250 mg 2 to 3 times per day

PO

Rash, GI upset

––

Aminopenicillins

Amoxicillin

250–500 mg every 8 hrs, or 500–875 mg twice daily

Manufacturer recommendation: >3 months and <40 kg: 20–100 mg/kg/day in divided doses every 8 to 12 hrs

≤3 months: 20–30 mg/kg/day divided every 12 hrs

AAP recommendation:

All infants and children <40 kg: 25–50 mg/kg/day in divided doses every 8 hrs

PO

Rash, diarrhea

Not to be confused with amoxicillin/clavulanate ES formulation.

Extended-release tablet 775 mg once daily for adults and children ≥12 years of age

Amoxicillin/clavulanate

250–500 mg every 8 hrs, or 875 mg every 12 hrs

15–40 mg/kg/day divided every 8 hrs, or 25–45 mg/kg/day divided every 12 hrs

Max: 4g/day

<3 mos: 30 mg/kg/day every 12 hrs (125 mg/5 mL suspension only)

PO

Rash, diarrhea

Dosing for amoxicillin/clavulanate is based on the amoxicillin component; the ES formulation of amoxicillin/clavulanate is not interchangeable with the regular suspension and requires product specific dosing.

Ampicillin

250–500 mg every 6 hrs

PO: 50–100 mg/kg/day in 4 divided doses

Max:2–4 g/day

IV, IM: 25–200 mg/kg/day every 3 to 4 hrs

Max: 12 g/day

PO, IV, IM

Rash, GI symptoms (very common)

The IV form can be given in divided doses or in a continuous infusion.

Ampicillin/sulbactam

1.5–3 g every 6 hrs IV

≥1 year: IV: 100–400 mg/kg/day every 6 hrs

Max: 8 g/day

IV, IM

Rash, diarrhea, local pain at injection or infusion site (very common with IM use)

Dosing for ampicillin/sulbactam is based on the ampicillin component.

Penicillinase-Resistant Penicillins

Dicloxacillin

125–500 mg every 6 hrs

<40 kg: 12.5–100 mg/kg/day in 4 doses divided every 6 hrs

>40 kg: 125–250 mg every 6 hrs

PO

Rash, diarrhea

Use with caution in neonates, as elimination of drug is slow.

Nafcillin

IV: 0.5–2 g every 4 to 6 hrs IM: 0.5 g every 4 to 6 hrs

Neonates: 50 mg/kg/day in 4 divided doses Children: IV: 50–200 mg/kg/day in 4 divided doses

IM: 25 mg/kg every 12 hrs

IV, IM

Phlebitis at IV site, neutropenia, rash

Tissue necrosis can occur with IV extravasation.

Oxacillin

0.25–2 g every 4 to 6 hrs

<40 kg: 50–100 mg/kg/day in divided doses every 6 hrs

>40 kg: 250–1,000 mg every 4 to 6 hrs

IV, IM

Phlebitis at IV site, hepatitis, rash

Drug-induced hepatitis is usually reversible if drug is discontinued. Neonatal dosing may require the use of alternate container system/dosage forms.

May contain a significant amount of sodium.

Antipseudomonal Penicillins

Piperacillin

IV, IM:3–4 g every 4 to 6 hrs

Max: 24 g/day

Neonates: IV, IM: 100 mg/kg every 12 hrs

Infants/children: IV, IM: 200–300 mg/kg/day divided every 4 to 6 hrs

IV, IM

Rash, GI upset, phlebitis at infusion site

—

Piperacillin/tazobactam

IV: 3.375–4.5 every 6 to 8 hrs

Max: 18 g/day

Infants 2 to 9 months: 80 mg piperacillin/kg/dose every 8 hrs

Infants and children >9 months: 100 mg piperacillin/kg/dose

IV

Rash, GI upset

Dosing for adults and pediatrics based on traditional infusion method (IV infusion over 30 minutes).

Dosage in pediatric patients based on piperacillin component.

Pediatric dose is mg/kg/dose, not mg/kg/day.

Ticarcillin or ticarcillin/clavulanate potassium

<60 kg: 200–300 mg/kg/day divided every 4 to 6 hrs

>60 kg: 3.1 g every 4 to 6 hrs

Max: 18 g/day

Use adult dosing by weight

IV

Rash, GI upset

Potential warfarin interaction. Ticarcillin/clavulanate doses are based on the ticarcillin component.

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

AAP = American Academy of Pediatrics; MU = million units; ES = extra strength.

Source: [6,16]

The Natural Penicillins

The natural penicillins include various penicillin G preparations and penicillin V potassium. Penicillin G is very unstable in stomach acid and must be given parenterally. Penicillin V potassium is more acid-stable and is the appropriate form for oral administration.

The natural penicillins are active against gram-positive organisms such as streptococci, Enterococcus faecalis, and Listeria monocytogenes. However, most S. aureus isolates are now resistant. The natural penicillins are also active against anaerobic species, such as Bacteroides species and Fusobacterium species. At serum levels achieved by parenteral administration, the natural penicillins are effective against some gram-negative bacteria, such as Escherichia coli, H. influenzae, Neisseria gonorrhoeae, and Treponema pallidum. For the treatment of moderate-to-severe infections in which resistant organisms are considered a possibility, reliance upon penicillin alone should be avoided unless the identity and sensitivity of the infecting organism have been confirmed. Labeled uses include treatments for infections of the upper and lower respiratory tract, throat, skin, and genitourinary tract and prophylaxis of recurrent rheumatic fever and pneumococcal infections [6].

The Aminopenicillins

The aminopenicillins have about the same activity as the natural penicillins against susceptible gram-positive organisms, plus improved coverage of selected gram-negative bacilli, including Enterobacteriaceae. Amoxicillin/clavulanic acid and ampicillin/sulbactam have better coverage against H. influenzae and Klebsiella species than the natural penicillins and the aminopenicillins alone.

The aminopenicillins include ampicillin and amoxicillin. Ampicillin can be given parenterally or orally. These agents are useful for the management of sinusitis/bronchitis, endocarditis, meningitis, susceptible urinary tract infection, and salmonellosis [6]. Amoxicillin is the best absorbed of the oral penicillins. It is acid-stable and its absorption, unlike ampicillin, is not much affected by food. Improved absorption is also thought to provide an advantage over ampicillin in reducing the risk of antibiotic-associated diarrhea. Labeled uses include endocarditis prophylaxis and as a component of a multidrug H. pylori eradication regimen [6].

The Penicillinase-Resistant Penicillins

The penicillinase-resistant penicillins were developed in response to the emergence of penicillinase-producing S. aureus. These penicillins are resistant to hydrolysis by the lactamase produced by the staphylococci, and they include nafcillin and oxacillin, which are parenteral formulations, and dicloxacillin, which is given orally. Methicillin and cloxacillin are no longer available in the United States [6].

Although penicillinase-resistant penicillins have the same spectrum of activity against many of the same gram-positive pathogens as the natural penicillins, they lack significant activity against gram-negative or anaerobic organisms. They are, however, notable for their usefulness against penicillin-resistant (methicillin-sensitive) Staphylococcus species.

The Antipseudomonal Penicillins

The antipseudomonal penicillins are often also referred to as extended-spectrum penicillins; these include ticarcillin and piperacillin (both of which are parenteral). Mezlocillin, which was also parenteral, and carbenicillin, which could be administered orally, are no longer available in the United States [6,17].

The extended-spectrum penicillins retain their activity against gram-positive bacteria and anaerobic gram-negative pathogens such as Bacteroides fragilis. However, these agents were developed because of their excellent activity against Pseudomonas aeruginosa and other multidrug-resistant gram-negative pathogens, including Klebsiella species and Serratia species. The antipseudomonal penicillins are effective for treatment of H. influenzae as well.

The Addition of Beta-Lactamase Inhibitors

The addition of clavulanic acid, sulbactam, or tazobactam increases the spectrum of activity of the penicillin derivative with which they are combined. They are generally active against the beta-lactamases produced by H. influenzae, Moraxella catarrhalis, and S. aureus. However, their activity is variable against some of the gram-negative bacteria, such as some species of Pseudomonas, Enterobacter, E. coli, Klebsiella, and Serratia, due to resistance to these beta-lactamase inhibitors [18].

ABSORPTION/ELIMINATION

While most penicillins can be absorbed via the oral route, the bioavailability varies considerably, and food may interfere with absorption. Penicillin V, amoxicillin, ampicillin, and dicloxacillin can be given orally; the remaining penicillins are either too unstable in the acidic environment of the stomach or must be given intravenously in order to achieve sustained therapeutic levels. Amoxicillin is the best absorbed of the oral penicillins and the least affected by a recent meal.

Following oral administration and GI absorption, these agents are widely distributed throughout the body. Therapeutic concentrations of penicillins are readily achieved in tissues and secretions (e.g., joint fluid, pleural fluid, pericardial fluid, and bile). Low concentrations are found in prostatic secretions, brain tissue, intraocular fluid, and phagocytes. Cerebrospinal fluid (CSF) concentrations vary but are less than 1% of serum concentration when the meninges are normal. When the meninges are inflamed, CSF concentrations may rise to 5% and can be increased by co-administration of probenecid (500 mg 4 times daily) [6,19]. Concentration in urine is high due to renal clearance mechanisms.

Penicillins are excreted in the kidney by means of glomerular filtration and renal tubular secretion. Probenecid markedly reduces the tubular secretion of the penicillins and decreases the apparent volume of distribution, resulting in higher serum levels. All the penicillins are excreted to some degree in the bile, but biliary excretion is most important for antipseudomonal penicillins and nafcillin [20].

In patients with mild renal insufficiency, dosage adjustment is not needed, except with the use of ticarcillin [21]. If the creatinine clearance is less than 50 mL/min, then dosage adjustments of parenteral penicillins should be made to avoid excess serum levels. Nafcillin undergoes extensive hepatic metabolism, and the dosage must be adjusted for severe renal and hepatic insufficiency.

SIDE EFFECTS/TOXICITY

These drugs are usually well tolerated. However, gastrointestinal (GI) disturbances may occur with all oral penicillins.

Allergy to any of the penicillins is the only absolute contraindication to use of a penicillin agent. However, studies have found that penicillin allergy is less common than previously thought [22,23,24,25]. Traditionally, allergic reactions were believed to occur in up to 10% of patients; however, more recent studies have found the rate to be much lower. While penicillin-induced anaphylaxis death rate estimates are similar to previous statistics (i.e., approximately 0.002% among the general population), the percentage of individuals with a true penicillin allergy as defined by immunoglobulin E (IgE)-mediated reaction is generally less than 10%, with some studies showing a true penicillin allergy rate of only 0.7% [22,23,24,26]. It is also important to note that approximately 90% of patients previously diagnosed with a penicillin allergy will show no reactivity if not exposed to the antibiotic for 10 years or more, due to the absence of a true allergy or loss of allergy over time [22,24,25]. Allergy skin testing is the most reliable way to determine true penicillin allergy and may allow for previously avoided antibiotics to be used as indicated.

Reactions commonly misdiagnosed as true allergic responses vary and can include a mild rash (the most common) and urticaria. Rarely, serum sickness, exfoliative dermatitis, and Stevens-Johnson syndrome may develop [6,20]. These responses were originally thought to develop in response to the beta-lactam ring and its derivatives and, therefore, there is a common misperception that penicillins are cross-reactive with other antibiotics with the same beta-lactam structure (e.g., cephalosporins) [6]. However, the major determinant in the immunologic reaction is now recognized to be the similarity in the side chain of first-generation cephalosporins and penicillins (not the beta-lactam structure), with the reaction nearing 0% in third-generation cephalosporins [22,23,24].

Rarely, penicillins may cause hematologic reactions with neutropenia due to reversible bone marrow suppression. Abnormal platelet aggregation may occur, particularly with ticarcillin [27]. Other rare reactions include hepatitis, seizures, interstitial nephritis, and hypokalemia due to local effects in the renal tubules.

DRUG INTERACTIONS

The penicillins should not be given concurrently with tetracycline or other bacteriostatic agents. Penicillin works in cells that are actively synthesizing cell wall components, and if metabolism is prevented, then the activity of penicillin is diminished. The antipseudomonal penicillins also may affect warfarin metabolism. Therefore, the prothrombin time, using the international normalized ratio (INR), should be monitored [6,28].

SPECIAL POPULATIONS

The penicillins are pregnancy category B, indicating no adverse events noted in animal studies [6,29]. These agents are secreted in breast milk, and breastfeeding should be avoided if the infant is allergic to any of the penicillins [30]. Use while breastfeeding may cause modifications of normal intestinal flora and allergic sensitization in the infant [6].

6. CEPHALOSPORINS

Giuseppe Brotzu discovered the first cephalosporin in 1948, observing that the fungus Cephalosporium acremonium produced a substance that inhibited the growth of S. aureus and other bacteria. The initial substance was identified and modified to create the cephalosporins that are now used. The cephamycins were created by adding a methoxy group on the beta-lactam ring of the original compound, based on the structure of cefoxitin, produced by Streptomyces lactamdurans. By altering the chemical groups substituted on the basic molecule, greater antimicrobial activity and longer half-lives have been obtained [31].

MECHANISM OF ACTION

Like penicillins, the cephalosporins are beta-lactams in which the beta-lactam ring is joined to a dihydrothiazine ring. Their antimicrobial effect is based on the same mechanism of action as that for the penicillins. The cephalosporins inhibit bacterial cell wall synthesis by blocking the transpeptidases and other PBPs involved in the synthesis and cross-linking of peptidoglycan [32,33].

Because each bacterial species has a unique chemical structure in its cell wall, the cephalosporins may have different mechanisms of action by which they inhibit cell wall synthesis.

As with penicillins, resistance to cephalosporins results from mutations in the penicillin-binding proteins (preventing the cephalosporins from binding to them) and from the production of extended-spectrum beta-lactamases that deactivate the drug [34]. An additional source of resistance in gram-negative bacteria is alteration in the cell-membrane porins that normally allow passage of the cephalosporins into the cell [35].

Of these mechanisms, the production of beta-lactamase is the most clinically significant. This form of resistance may occur through mutations or may be carried on plasmids [36].

PHARMACOKINETICS

The cephalosporins have been classified in different ways, based on chemical structure and pharmacologic activities. The conventional classification for clinical purposes groups cephalosporins into "generations" based on when they were developed and similarities in antimicrobial coverage.

Table 2: THE CEPHALOSPORINS

Agent

Adult Dosing Range

Pediatric Dosing Range

Route

Common Side Effects

Comments

First Generation

Cefadroxil

1–2 g/day in 2 divided doses

30 mg/kg/day in 2 divided doses

Max: 2 g/day

PO

Rash, diarrhea

Can interfere with some urine glucose tests.

Cefazolin

1–2 g every 8 hrs

Max: 12 g/day

>1 mo: 25–100 mg/kg/day divided every 6 to 8 hrs

Max: 6 g/day

IV, IM

Phlebitis at infusion site, seizure,rash, diarrhea

Can interfere with some urine glucose tests.

Cephalexin

250–1,000 mg every 6 to 12 hrs

Max: 4 g/day

>1 yr to <15 yrs: 25–100 mg/kg/day in 3 to 4 divided doses

Max: 4 g/day

PO

GI upset, rash

Can interfere with some urine glucose tests.

Second Generation

Cefaclor

250–500 mg every 8 hrs

>1 mo: 20–40 mg/kg/day in 2 to 3 divided doses

Max: 1 g/day

PO

Rash, GI upset

Can interfere with some urine glucose tests.

Cefotetan

1–2 g every 12 hrs

Max: 4–6 g/day

AAP recommendation: 30–50 mg/kg/dose every 12 hrs

Max: 4,000 mg/day

IV, IM

Phlebitis at infusion site, rash, GI upset

Disulfiram-like reaction with alcohol. Can interfere with some urine glucose tests.

Not recommended for treatment of community-acquired intra-abdominal infections.

Cefoxitin

1–2 g every 6 to 8 hrs

Max: 12 g/day

>3 mos: 80–160 mg/kg/day in 4 to 6 divided doses

Max: 12 g/day

IV, IM

Phlebitis at infusion site, rash

IM injection is painful. Can interfere with some urine glucose tests.

In pediatrics, for group A beta-hemolytic streptococcal infections, antimicrobial therapy should be given for at least 10 days to guard against the risk of rheumatic fever or glomerulonephritis.

Cefprozil

250–500 mg every 12 to 24 hrs

>6 mos: 7.5–20 mg/kg every 12 hrs

>2 yrs: 7.5–15 mg/kg/day in 2 divided doses, or 20 mg/kg every 24 hrs

Max: 1 g/day

PO

Rash, GI upset, elevated liver enzymes

Avoid use in phenylketonuria. Can interfere with some urine glucose tests.

Cefuroxime

PO: 250–500 mg every 12 hrs for 10 days

IV, IM: 0.5–1.5 g every 6 to 8 hrs

Max: 6 g/day

PO: 20–30 mg/kg/day in 2 divided doses

IV, IM: 75–150 mg/kg/day in 3 divided doses

Max: 6 g/day

PO, IV, IM

Phlebitis at infusion site, rash, GI upset

Tablets and oral suspension forms require different dose. Oral doses noted here are for tablet formulation.

Higher doses can be used for severe infection.

Third Generation

Cefdinir

300 mg every 12 hrs, or 600 mg every 24 hrs for 10 days

7 mg/kg/dose twice daily or 14 mg/kg/dose for 10 days

Max: 600 mg/day

PO

Rash, diarrhea

Iron and antacids can reduce absorption. Can interfere with some urine glucose tests.

Cefditoren

200–400 mg every 12 hrs for 10 to 14 days

Not studied for patients <12 yrs

PO

GI upset, headache

Interaction with proton-pump inhibitors, H2 blockers, antacids. Contraindicated with milk protein allergy.

Cefixime

400 mg/day in 1 or 2 doses

>6 mos and <45 kg:8–20 mg/kg/day every 12 to 24 hrs

Max: 400 mg/day

>12 yrs or >50 kg: Use adult dosing

PO

Diarrhea, rash

Can interfere with some urine glucose tests.

Cefotaxime

1–2 g every 4 to 12 hrs

1 mo to 12 yrs and <50 kg: 50–225 mg/kg/day in 3 to 4 divided doses

IV, IM

Phlebitis at infusion site, rash, GI upset

Single dose can be given for GC. Transient arrhythmias have developed after administration of this agent through central venous catheter.

Cefpodoxime

100–400 mg every 12 hrs for 7 to 14 days

10 mg/kg/day in 2 divided doses

PO

Diarrhea, nausea, vomiting

Decreased absorption with antacids and H2 blockers. Can be given as a single dose for GC.

Ceftazidime

500–1,000 mg every 8 hrs

IV: 30–50 mg/kg every 8 hrs

Max: 6 g/day

AAP recommendation for IV: 90–200 mg/kg/day every 8 hours

Max: 6 g/day

IV, IM

Phlebitis at infusion site, rash, GI upset

Can interfere with some urine glucose tests. The L-arginine formulation should not be used in children.

Ceftibuten

400 mg every 24 hrs for 10 days

9 mg/kg/day

Max: 400 mg/day for 10 days

PO

Rash, GI upset, headache

Can interfere with some urine glucose tests.

Ceftriaxone

IV, IM: 1–2 g every 12 to 24 hrs

50–100 mg/kg/day in 1 to 2 divided doses

Max: 4 g/day

IV, IM

Phlebitis at infusion site, rash

Avoid in neonates with hyperbilirubinemia. Higher doses are used for meningitis. A ceftriaxone-calcium salt can precipitate in the gallbladder, causing sonographically detectable abnormalities.

Fourth Generation

Cefepime

IV:1–2 g every 8 to 12 hrs

IM: 0.5–1 g every 12 hrs

IV, IM: 50 mg/kg every 8 to 12 hrs

Not to exceed adult dosing

IV, IM

Phlebitis at infusion site, GI upset

Can interfere with some urine glucose tests.

Cefiderocol

2 g every 8 hours for 7 to 10 days

—

IV

Phlebitis at infusion site, rash, GI upset

Can interfere with some urine glucose tests.

Fifth Generation

Ceftaroline fosamil

600 mg every 12 hours for 5 to 14 days

>2 mos to <2 yrs: 8 mg/kg/dose every 8 hrs for 5 to 14 days

>2 yrs to <18 yrs and <33 kg: 12 mg/kg/dose every 8 hrs for 5 to 14 days

>2 yrs to <18 yrs and >33 kg: 400–600 mg every 8 to 12 hrs for 5 to 14 days

IV

Phlebitis at infusion site, GI upset, headache

Slow IV infusion over 60 minutes. Can interfere with some urine glucose tests.

Ceftobiprole

500 mg every 8 hours

—

IV

Hyponatremia, phlebitis at infusion site, headache, nausea/vomiting

Approved for use in Canada but not the United States.

Not for use in patients with ventilator-associated pneumonia.

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

GC = gonococcal infection.

Source: [6,16]

First-Generation Cephalosporins

The first-generation cephalosporins are most active against aerobic gram-positive cocci. These agents include cefazolin, cephalexin, and cefadroxil, and they are often used for skin infections caused by S. aureus and Streptococcus and for susceptible urinary tract infections. They have activity against E. coli and some activity against H. influenzae and Klebsiella species, but because of the limited gram-negative coverage, they are not first-line agents for infections that are likely to be caused by gram-negative bacteria.

Second-Generation Cephalosporins

The second-generation cephalosporins are more active against gram-negative organisms, such as Moraxella, Neisseria, Salmonella, and Shigella. Cefoxitin and cefotetan, which are included in this group under this classification system although they are technically cephamycins, also have more coverage against anaerobic bacteria. The true cephalosporins that are also part of this class are cefprozil, cefuroxime, cefaclor, cefoxitin, and cefotetan. These drugs are used primarily for respiratory tract infections because they are better against some strains of beta-lactamase producing H. influenzae.

Third-Generation Cephalosporins

The third-generation cephalosporins have enhanced activity and a broader spectrum against gram-negative organisms, including Neisseria species, M. catarrhalis, Klebsiella, and other Enterobacteriaceae. Of these agents, ceftriaxone has the best activity against gram-positive cocci, specifically S. pneumoniae and methicillin-sensitive S. aureus. Ceftazidime is active against P. aeruginosa. Other cephalosporins in this class include cefdinir, cefditoren, cefixime, cefotaxime, cefpodoxime, ceftibuten, and ceftriaxone. These drugs are useful for more severe community-acquired respiratory, intraabdominal, and urinary tract infections and for nosocomial infections (because of the high incidence of resistant organisms) [37].

Fourth-Generation Cephalosporins

Cefepime is classed as a fourth-generation cephalosporin because it has good activity against both gram-positive and gram-negative bacteria, including P. aeruginosa and many Enterobacteriaceae. The gram-negative and anaerobic coverage makes cefepime useful for intra-abdominal infections, respiratory tract infections, and skin infections.

Fifth-Generation Cephalosporins

Ceftaroline fosamil is a novel advanced-generation cephalosporin approved by the U.S. Food and Drug Administration (FDA) in 2010, for the treatment of community-acquired bacterial pneumonia and bacterial skin and soft-tissue infections [6]. As with other beta-lactams, ceftaroline exerts its antimicrobial affect by binding to PCP and inhibiting cell wall synthesis. This agent is unique in that it also has a high affinity for PBP2a, which is associated with resistance to methicillin. Consequently, ceftaroline is highly active against methicillin-sensitive and resistant strains of S. aureus and against multidrug-resistant S. pneumoniae[38]. It is ineffective for P. aeruginosa, and its activity against Enterobacteriaceae is variable. Beta-lactamase-producing Enterobacteriaceae and AmpC mutants are resistant. Prospective clinical trials have shown that the efficacy of ceftaroline is comparable to vancomycin plus aztreonam for the treatment of bacterial skin and soft-tissue infection (including methicillin-resistant S. aureus [MRSA]) and to ceftriaxone for the treatment of community-acquired bacterial pneumonia [39]. Among cases of pneumonia caused by S. pneumoniae, clinical cure rates were higher with ceftaroline (83.3%) than with ceftriaxone (70%) in a phase III clinical trial, and the agent was well tolerated [40].

Ceftobiprole is a fifth-generation cephalosporin with a broad spectrum of antimicrobial activity, including drug-resistant pneumococci, P. aeruginosa, and methicillin-resistant S. aureus (MRSA). The drug is approved for the treatment of community- and hospital-acquired pneumonia in Canada and parts of Europe, The results of a pivotal clinical trial of patients hospitalized with community-acquired pneumonia treated with ceftobiprole showed a high rate of clinical cure [41,42,43].

ABSORPTION/ELIMINATION

The orally administered cephalosporins include cefaclor, cefadroxil, cephalexin, cefprozil, cefuroxime axetil, cefixime, cefpodoxime proxetil, ceftibuten, and cefdinir. In general, the orally administered cephalosporins are absorbed rapidly. Cephalexin, cefadroxil, cefaclor, cefixime, ceftibuten, and cefdinir are nonesterified and are absorbed from the GI tract by active transport in the small intestine. Other agents, such as cefuroxime axetil and cefpodoxime proxetil, are prodrug esters and are passively absorbed. Once absorbed into the cells lining the small intestine, these agents are hydrolyzed and then excreted into the blood stream as active cephalosporins [44].

The presence of food or antacids may increase or decrease the absorption, depending on the drug. Cefuroxime axetil and cefpodoxime proxetil have increased absorption when taken with food. Cefaclor, cefadroxil, and cephalexin have slowed absorption when food is in the stomach. Cefixime, cefprozil, and ceftibuten are not affected by the presence of food. Cefpodoxime is the only cephalosporin whose absorption is decreased by the presence of antacids or H2 antagonists [45].

There is extensive distribution of the cephalosporins into body tissues and fluids. They readily cross the placenta and are also found in synovial fluid. Concentrations in bile and urine are high. Most cephalosporins do not cross into the CSF in sufficient concentration to be recommended for the treatment of meningitis, but there are some exceptions. Cefuroxime, cefotaxime, ceftriaxone, cefepime, and ceftaroline all have good penetration into the CSF [38,46].

Most cephalosporins are eliminated by the kidney. The exception in the oral cephalosporins is cefixime, half of which is excreted in the urine [6]. The remaining half is metabolized in the liver to inactive metabolites and partly excreted in the bile. Cefotaxime is deacetylated by the liver to a bioactive metabolite and inactive forms. The deacetylated metabolites are excreted by the kidney. Cefditoren is excreted predominantly in the bile.

In severe hepatic insufficiency, compensatory changes in renal excretion of the hepatically metabolized drugs may occur [47]. In the presence of severe renal and/or hepatic insufficiency, dosage adjustment of cefotaxime is necessary.

SIDE EFFECTS/TOXICITY

As a group, cephalosporins are relatively well tolerated [48]. The most common complaints are GI upset, resulting in nausea, vomiting, or diarrhea. Thrombophlebitis can occur with intravenous (IV) administration. One to three percent of patients develop an allergic reaction. Rash, fever, eosinophilia, and urticaria can develop. Anaphylaxis is rare. Infrequently, there is some cross-sensitivity with true penicillin allergy (estimated nearly 0%to 10% of cases); this occurs mostly with first-generation cephalosporins [21,22,23,24]. If a patient develops urticaria, anaphylaxis, or angioedema with penicillins or a cephalosporin, avoid using any of the other cephalosporins.

Although uncommon, nephrotoxicity has been reported [49]. Cephalosporins that contain the methylthiotetrazole (MTT) side chain (cefotetan) may induce a disulfiram-like reaction with alcohol ingestion (e.g., flushing, tachycardia, nausea and vomiting, diaphoresis, dyspnea, hypotension, and confusion). This is due to increased circulating acetaldehyde.

Ceftriaxone has been associated with cholelithiasis and cholestatic hepatitis due to precipitation in bile [50,51]. Rare reactions include hematologic toxicity with resultant eosinophilia, thrombocytopenia, and leukopenia, all of which resolve after stopping treatment [52]. Rarely, hemolytic anemia develops [53]. Hypoprothrombinemia may occur with cephalosporins with the MTT side chain as a result of interference by the MTT moiety with the synthesis of vitamin-K-dependent clotting factors [54]. For patients at high risk of bleeding, exogenous vitamin K may help alleviate this side effect. False-positive glucosuria testing with a copper reduction test (Clinitest) may occur with many cephalosporins [6,55].

DRUG INTERACTIONS

The serum levels of all the cephalosporins are increased with co-administration of probenecid. The effects of warfarin may be enhanced by co-administration of cefotetan, cefazolin, cefoxitin, and ceftriaxone [6].

SPECIAL POPULATIONS

Cephalosporins are generally considered safe to use in pregnancy and are designated as category B. They are excreted in breast milk in low concentrations, and the American Academy of Pediatrics (AAP) considers this compatible with breastfeeding [6,56,57].

7. CARBAPENEMS

Meropenem, imipenem/cilastatin, doripenem, and ertapenem are parenteral synthetic beta-lactams derived from thienamycin, an antibiotic produced by Streptomyces cattleya [58]. They have a lactam ring, like the penicillins and cephalosporins, but have a methylene moiety in the ring. The newest carbapenem is combination imipenem/cilastatin/relebactam [6].

MECHANISM OF ACTION

Like other beta-lactams, the carbapenems inhibit mucopeptide synthesis in the bacterial cell wall by binding to PBPs, leading to lysis and cell death. Bacterial resistance may occur due to a specific beta-lactamase that affects carbapenems. Another significant source of resistance is a mutation that results in the absence of the outer membrane porin, thus not allowing transport of the drug into the cell [59]. Cross-resistance may occur between the carbapenems.

PHARMACOKINETICS

Imipenem and ertapenem have a wide antimicrobial spectrum with excellent activity against enteric gram-negative bacilli and pseudomonas as well as anaerobic bacteria, including Bacteroides species. They also cover many gram-positive cocci, such as Enterococcus and Streptococcus [60]. Meropenem has somewhat greater activity against gram-negative bacteria, which are not affected by most beta-lactamases. Doripenem has good activity against Pseudomonas aeruginosa. Imipenem and ertapenem are approved by the FDA for use in urinary tract infections, pneumonia, intra-abdominal infections, and skin and soft-tissue infections [6]. Meropenem is approved by the FDA for treatment of intra-abdominal infections, skin and skin structure infections, and meningitis in patients older than 3 months of age [6]. Combination meropenem/vaborbactam is approved for the treatment of complicated urinary tract infections caused by susceptible micro-organisms [6,61]. The combination imipenem/cilastatin/relebactam was approved by the FDA in 2019 for the treatment of complicated urinary tract infections and complicated intra-abdominal infections [6,62].

ABSORPTION/ELIMINATION

Imipenem/cilastatin, imipenem/cilastatin/relebactam, meropenem, and ertapenem are given parenterally, as they are unstable in stomach acid. Imipenem is combined with cilastatin, which inhibits dehydropeptidase I in the proximal renal tubular cells. Dehydropeptidase I inactivates imipenem by hydrolysing the beta-lactam ring, so adding the cilastatin allows increased levels of imipenem in the urine and also prevents the production of the nephrotoxic metabolites of imipenem [63]. The addition of relebactam to imipenem protects imipenem from degradation by certain serine beta-lactamases [6]. Meropenem, doripenem, and ertapenem do not require a dehydropeptidase I inhibitor.

Following administration, meropenem penetrates well into body tissues and fluids, including the CSF. Imipenem/cilastatin/relebactam and ertapenem are distributed throughout body tissues, but with only low concentrations in the CSF [64].

Most of the imipenem/cilastatin and imipenem/cilastatin/relebactam doses are excreted in the urine [6]. The remaining 20% to 25% of the dose is excreted through an unknown mechanism. Meropenem is excreted unchanged into the urine by means of glomerular filtration and tubular secretion [65]. Ertapenem is metabolized by hydrolysis of the beta-lactam ring, and then both the metabolite and parent drug are excreted in the urine.

The carbapenems require dosage adjustment in patients with renal insufficiency. No changes in dosage are necessary for patients with hepatic insufficiency.

SIDE EFFECTS/TOXICITY

The carbapenems are generally well tolerated. Occasional reactions include nausea and vomiting, phlebitis at the infusion site, elevation of liver enzymes, and leukopenia. Seizures may occur. The risk is higher in patients with underlying central nervous system (CNS) disease and in patients with renal disease, which results in high serum levels of the drug [66]. Hypersensitivity reactions may occur, and while there is a degree of cross-sensitivity with penicillins, this risk is lower than previously believed [22,23,24]. Carbapenems should be used with caution in patients allergic to the carbapenems or penicillins [6].

DRUG INTERACTIONS

There are few drug interactions associated with the carbapenems, but probenecid may increase the serum levels of meropenem, ertapenem, imipenem/cilastatin, and imipenem/cilastatin/relebactam and should be avoided. Ertapenem cannot be infused with dextrose or other medications. Meropenem may reduce levels of valproic acid [67].

SPECIAL POPULATIONS

Meropenem, doripenem, and ertapenem are pregnancy category B, with animal studies showing no adverse reactions [68]. Imipenem/cilastatin is pregnancy category C, based on studies in monkeys that showed increased embryonic loss and side effects in the mother [69]. No pregnancy category has been assigned to imipenem/cilastatin/relebactam [6,70]. No data are available regarding breastfeeding and carbapenem administration.

The safety of doripenem use has not been studied in children. Meropenem has been used in children and is indicated by the FDA for the treatment of pediatric meningitis but has not been studied in infants younger than 3 months of age [6,71]. Ertapenem can be used in infants older than 3 months of age, and imipenem can be used from birth; these agents are useful for treating complicated infections in pediatric patients (e.g., complicated urinary tract infections).

8. MONOBACTAMS

Monobactams have a single beta-lactam core, distinguishing them from the other beta-lactam drugs [72]. Aztreonam is the only available example of this class of drugs. Aztreonam was originally extracted from Chromobacterium violaceum. It is now manufactured as a synthetic antibiotic.

Table 3: THE OTHER BETA-LACTAMS

Agent

Adult Dosing Range

Pediatric Dosing Range

Route

Common Side Effects

Comments

Carbapenems

Doripenem

500 mg every 8 hours for 5 to 14 days

Not studied for pediatric use

IV

Headache, rash, nausea, vomiting, diarrhea, phlebitis

Dosage adjustment necessary for renal impairment. Cannot be used in patients with known serious hypersensitivity or history of anaphylaxis to any beta-lactam antibiotic. Seizure risk in patients with CNS disorders.

Ertapenem

1 g/day for 3 to 14 days

15 mg/kg every 12 hrs

Max: 1 g/day for 3 to 14 days

IV, IM

Diarrhea, nausea, phlebitis at infusion site

Seizure risk in patients with CNS disorders.

IV therapy may be administered for up to 14 days; IM for up to 7 days.

Imipenem/cilastatin

500–1,000 mg every 6 to 8 hrs

Max: 4 g/day

>3 mos: 15–25 mg/kg every 6 hrs

Max: 4 g/day

IV

Phlebitis at infusion site, rash

Documentation of cross-allergy with penicillin allergy is limited. Seizure risk in patients with CNS disorders.

Adults <70 kg may require decreased dosing.

Imipenem/cilastatin/relebactam

1.25 g every 6 hours for a 5-14 days

N/A

IV

Anemia

Documentation of cross-allergy with penicillin allergy is limited. Seizure risk in patients with CNS disorders.

Meropenem

1.5–6 g/day in 3 divided doses

Infants <3 mos (IV):

Gestational age <32 weeks AND postnatal age <14 days: 20 mg/kg/dose every 12 hrs

Postnatal age ≥14 days: 20 mg/kg/dose every 8 hrs

Gestational age ≥32 weeks AND postnatal age <14 days: 20 mg/kg/dose every 8 hrs

Postnatal age ≥14 days: 30 mg/kg/dose every 8 hrs

3 mos and <50 kg: 30–120 mg/kg/day in 3 divided doses

Max: 6 g/day

50 kg: Same as adult dosing

IV

Diarrhea, nausea, inflammation at the injection site, headache

Can cause elevated LFTs. Seizure risk in patients with CNS disorders.

Meropenem/vaborbactam

4 g every 8 hrs for <14 days

Not studied in pediatric patients

IV

Headache, GI symptoms, phlebitis at infusion site

Dosage adjustment necessary for renal impairment.

Monobactams

Aztreonam

IV:1–2 g every 8 to 12 hrs

Nebulizer: 75 mg 3 times/day at least 4 hours apart for 28 days; do not repeat for 28 days after completion.

>9 mos: 30–50 mg/kg/dose every 6 to 8 hrs

Max: 120 mg/kg/day

>7 years of age (nebulizer): Same as adult dosing

IV, IM, oral inhalation

Rash, nausea, vomiting, phlebitis at infusion site

Rare cross-sensitivity with allergy to other beta-lactams.

For oral inhalation, pretreatment with a bronchodilator is recommended.

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

CNS = central nervous system; LFTs = liver function tests (liver enzymes).

Source: [6,16]

MECHANISM OF ACTION

As with other beta-lactams, aztreonam inhibits mucopeptide synthesis in the bacterial cell wall by binding to the penicillin-binding proteins of gram-negative bacteria, leading to cell lysis and death. Aztreonam is resistant to most beta-lactamases. Treatment in combination with an aminoglycoside appears to be synergistic against Pseudomonas.

PHARMACOKINETICS

Aztreonam does not have significant activity against gram-positive or anaerobic bacteria and is primarily used as an alternative therapy for gram-negative bacterial infections, including P. aeruginosa and Klebsiella, that are resistant to the first-line beta-lactams or carbapenems. It is indicated for use in pneumonia, soft-tissue infections, urinary tract infections, and intra-abdominal and pelvic infections that are caused by gram-negative aerobic bacteria.

There is no oral form of aztreonam, and intravenous is the preferred mode of parenteral administration. It is distributed widely in body tissues and fluids, including inflamed meningeal tissue [6,73]. Aztreonam is mainly excreted in the urine as an unchanged drug, although there is also minimal hepatic metabolism [6,74]. Doses must be adjusted for renal insufficiency based on glomerular filtration rate [6,75].

SIDE EFFECTS/TOXICITY

Frequent adverse reactions include elevations of liver enzymes and transient eosinophilia. Less common reactions include phlebitis at the infusion site, rash, diarrhea, and nausea [6,76].

There have been a few reports of cross-allergy reactions in patients who are allergic to ceftazidime, but patients with penicillin and cephalosporin allergy can usually tolerate aztreonam [77]. Aztreonam is contraindicated in patients with prior allergic reactions to it or to any component of the formulation.

DRUG INTERACTIONS

No drug interactions have been reported with aztreonam [6,78].

SPECIAL POPULATIONS

Aztreonam is pregnancy category B, based on animal studies that have shown no ill effects of the drug. There are no human data available [6].

Aztreonam is secreted in breast milk in low concentrations; breastfeeding is not recommended because the effects of the drug have not been studied in young infants [78].

Aztreonam has not been studied for use in children younger than 1 month of age but appears safe in children older than 1 month of age, although it should be noted that manufacturer recommendations are for children older than 9 months of age [6,78]. It has been shown to be very useful in children with respiratory symptoms of cystic fibrosis [79].

9. AMINOGLYCOSIDES

The first aminoglycoside, streptomycin, was derived from Streptomyces griseus during the 1940s. Actinomycetes were studied for possible antimicrobial byproducts, and it was found that Micromonospora and Streptomyces produced useful agents. As newer, safer, and more effective aminoglycosides have been developed, the use of streptomycin is now confined primarily to certain management strategies for the treatment of tuberculosis.

Table 4: THE AMINOGLYCOSIDES

Agent

Adult Dosing Range

Pediatric Dosing Range

Route

Common Side Effects

Comments

Amikacin

5mg/kg every 8 hrs or 7.5 mg/kg every 12 hrs

15–22.5 mg/kg/day every 8 hrs OR 15–20 mg/kg/dose every 24 hours

IV, IM

Renal failure, vestibular nerve damage, auditory nerve damage

Predisposition to auditory/vestibular nerve damage may be genetic; check family history. Check serum levels. Doses are based on lean body mass; maintenance dose is based on calculation with creatinine clearance. Additional dose adjustments are needed in renal failure.

Gentamicin

3–5 mg/kg/day in divided doses every 8 to 12 hrs, or5–7 mg/kg once daily

Infants:2–2.5 mg/kg/dose every 6 to 8 hrs

IV, IM, topical

Neomycin

4–12 g/day in 4 to 6 divided doses for 5 to 6 days, or 4 g/day for an indefinite period

50–100 mg/kg/day in 3 to 4 divided doses

PO, topical

Systemic absorption is possible, resulting in the same side effects as amikacin.

Used as a bowel prep for surgery. Is also formulated in some topical eye, ear, and skin preparations.

Plazomicin

15 mg/kg once daily for 4-7 days

N/A

IV

Renal failure

Boxed warning: Risk factors for nephrotoxicity include pre-existing renal impairment, elderly patients, concomitant. May cause ototoxicity; symptoms may be irreversible and may not become evident until after therapy is complete.

Streptomycin

15–30 mg/kg/day or 1–2 g daily

20–40 mg/kg/day every 6 to 12 hrs in divided doses

Max: 1 g/dose or 2 g/day

IM

Renal failure, vestibular nerve damage, auditory nerve damage

This is the most ototoxic of aminoglycosides; levels must be monitored closely.

Can cause neuromuscular blockade and respiratory paralysis, especially when given soon after muscle relaxants or anesthesia.

Tobramycin

1–2.5 mg/kg every 8 to 12 hrs. or4–7 mg/kg once daily dose

<5 yrs: 2.5 mg/kg every 8 hrs

>5 yrs:2–2.5 mg/kg every 8 hrs

IV, IM inhalation solution, ophthalmic ointment or solution

Renal failure, vestibular nerve damage, auditory nerve damage

Effects of nondepolarizing muscle relaxants can be increased.

Total body weight (as opposed to ideal body weight) should be used for underweight patients.

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

Source: [6,16]

MECHANISM OF ACTION

The basic structure of the aminoglycosides is an aminocyclitol ring. Different members of the family have different glycosidic linkages and side groups.

The aminoglycosides have at least two effects on the bacterial cell that ultimately result in cell death. These agents bind negative charges in the outer phospholipid membrane, displacing the cations that link the phospholipids together. This leads to disruption in the wall and leakage of cell contents. In addition, they inhibit protein synthesis by binding to the 30S subunit of the ribosome, causing miscoding and termination [80].

Although resistance to aminoglycosides is less common than with many other antibiotics, it can develop as a result of three known mechanisms. The most common pattern of resistance involves modification of the aminoglycoside molecule itself by enzymes produced by some bacteria. After the aminoglycoside is altered, it cannot bind as well to the ribosomes. The genes that encode for these enzymes are carried on plasmids, allowing rapid transfer of resistance between bacteria. Of note, amikacin has an S-4 amino 2-hydroxybutyryl (AHB) side chain that protects it against deactivation by many bacterial enzymes and is therefore less susceptible to this bacterial defense mechanism [81].

The binding site for aminoglycosides on the rRNA of the ribosome may also be altered, reducing binding. In addition, mutations that cause reduced uptake of aminoglycosides have been documented [81].

To combat resistances and overcome the relative natural resistance of enterococcus, other agents that target the cell wall are often used in conjunction with the aminoglycosides. Damage to the cell wall from the additional agents may be bactericidal in some cases and makes the cell wall more permeable to the aminoglycosides [82].

PHARMACOKINETICS

The aminoglycosides are effective for the treatment of aerobic gram-negative bacilli, such as Klebsiella species, Enterobacter, and P. aeruginosa. There is very little activity against anaerobes and gram-positive organisms, so combination therapy with a beta-lactam, vancomycin, or other agents active against gram-positive organisms and anaerobes is commonly used. The aminoglycosides are indicated for infections caused by susceptible organisms of the urinary tract, respiratory tract, skin and soft tissues, and sepsis due to gram-negative aerobic bacilli.

The aminoglycosides commonly used at present for treatment of systemic bacterial infection include gentamicin, tobramycin, and amikacin. Kanamycin is discontinued [17]. Aminoglycosides have negligible oral absorption and thus require parenteral administration. They also can be administered directly into body cavities and have a role in the management of pleural and peritoneal infection. Tobramycin is particularly useful for treatment of recurrent Pseudomonas infection in patients with cystic fibrosis and can be administered by aerosolized inhalation to facilitate optimal local antimicrobial effect [79]. In a large randomized, placebo-controlled clinical trial involving critically ill adults who had undergone invasive mechanical ventilation, a three-day prophylactic regimen of inhaled amikacin reduced the subsequent incidence of ventilator-associated pneumonia [174]. Neomycin is often used orally as part of a pre-operative bowel decontamination protocol.

The aminoglycosides are widely distributed in extracellular fluid, including pleural fluid, synovial fluid, abscesses, and peritoneal fluid. They are relatively insoluble in lipid, so the volume of distribution is lower in obese patients. They have poor distribution in bile, aqueous humor, bronchial secretions, sputum, and the CSF [15].

Aminoglycosides are excreted unchanged by the kidneys [6]. There is no reduction of dosage necessary in liver failure, as there is no hepatic metabolism of these agents. In renal failure, the dosage must be carefully adjusted based on glomerular filtration rate and measured serum levels. Serum levels should be monitored in all patients with reduced renal function [83].

TOXICITY

The most common adverse effect associated with aminoglycoside usage is nephrotoxicity, occurring in 10% to 25% of therapeutic courses [84]. Aminoglycosides are freely filtered by the glomeruli and quickly taken up by the proximal tubular epithelial cells, where they exert their main toxic effect by altering phospholipid metabolism. Aminoglycosides also cause renal vasoconstriction [85]. Critical factors in the development of acute kidney injury secondary to aminoglycoside nephrotoxicity are dosing and duration of therapy. A single daily large dose is preferable to more frequent dosing, as it appears to cause less accumulation in the tubular cells once the saturation point is reached [84]. Additionally, extending the dose interval to more than 24 hours in patients with renal impairment has been found to be effective, with irreversible nephrotoxicity reported in only 1% of patients studied [86].

Vestibular and auditory toxicity may also complicate treatment with aminoglycosides, though this is less common now as clinical awareness and careful dosage adjustment in relation to renal function has improved. These effects are usually reversible, and because there is some data suggesting that there is a genetic predisposition to ototoxicity, this drug class should be avoided in patients who have a family history of ototoxicity with aminoglycosides [87]. When aminoglycoside therapy is expected to exceed five to seven days, baseline testing of auditory function should be performed and monitored weekly for the duration of treatment.

Neuromuscular blockage has also been observed as a side effect. Aminoglycosides may aggravate muscle weakness in patients with neuromuscular disorders, such as myasthenia gravis and Parkinson disease, due to a curare-like effect on neuromuscular function [88].

Hypersensitivity reactions are not common with aminoglycosides, but rash, fever, urticaria, angioneurotic edema, and eosinophilia may occur. Very rare reactions include optic nerve dysfunction, peripheral neuritis, arachnoiditis, encephalopathy, pancytopenia, exfoliative dermatitis, and amblyopia. Bronchospasm and hoarseness have been known to occur with tobramycin inhalation solution [89].

The aminoglycosides are contraindicated in patients with hypersensitivity to the drug. Cross-sensitivity between aminoglycosides does occur. Streptomycin also contains metabisulfite and should be avoided if the patient is allergic to sulfites (more common in asthmatics) [6,90].

DRUG INTERACTIONS

There are numerous drug interactions that should be taken into consideration when using the aminoglycosides. The risk of nephrotoxicity may be increased with co-administration of other drugs that are nephrotoxic or in patients receiving loop diuretics (e.g., furosemide). Respiratory depression may occur if aminoglycosides are given with nondepolarizing muscle relaxants. Neomycin may affect digoxin levels by altering the bowel flora responsible for the metabolism of digoxin in the GI tract. Gentamicin may also cause increased serum digoxin levels [6,91].

In vitro deactivation of penicillins due to acylation has been observed, so the drugs should not be mixed in vitro. Tobramycin inhalation solution cannot be mixed in the nebulizer with dornase alfa [6].

SPECIAL POPULATIONS

Amikacin, gentamicin, neomycin, and streptomycin are pregnancy category D due to eighth cranial nerve toxicity that has occurred in the fetus with some aminoglycosides [6]. Plazomicin and tobramycin carry a boxed warning that states pregnant patients should be apprised of potential harm to the fetus with their administration [6].

Traces of amikacin, gentamicin, streptomycin, and tobramycin are excreted in breast milk, but they are compatible with breastfeeding because they are very poorly absorbed from the GI tract [6]. However, they may cause alterations in the normal bowel flora of the infant [6]. It is not known if neomycin or plazomicin are present in breast milk [6].

Half-life alterations occur in patients at extremes of age. The half-life in neonates and low-birth-weight infants may be considerably prolonged. The elderly may also have a longer aminoglycoside half-life due to an age-related decrease in renal function [92]. Geriatric dosing should be based on ideal body weight estimates [6].

10. MACROLIDES

The original macrolide, erythromycin, was discovered in 1952 by J.M. McGuire. It is produced by Saccharopolyspora erythraea (formerly known as Streptomyces erythreus). Semisynthetic derivatives (clarithromycin, azithromycin) have been produced from the original erythromycin, with modifications that improve acid stability, antibacterial spectrum, and tissue penetration.

Table 5: THE MACROLIDES

Agent

Adult Dosing Range

Pediatric Dosing Range

Route

Common Side Effects

Comments

Azithromycin

PO: 250–600 mg/day, or1–2 g/day

IV: 250–500 mg/day

PO:5–12 mg/kg/day

Max: 500 mg/day

Otitis media: 30 mg/kg as single dose (not to exceed 1,500 mg)

PO, IV, ophthalmic drops

GI upset

One dose of 1 g given PO can be used for non-GC urethritis/cervicitis. Interaction with pimozide/cyclosporine.

Clarithromycin

250–500 mg every 12 hrs, or 1 g/day extended-release formulation for 7 to 14 days

>6 mos of age: 7.5 mg/kg every 12 hrs

PO

GI upset, metallic taste

Inhibits liver CYP 450 enzyme 3A4, resulting in multiple significant drug interactions. Special dosing combined with omeprazole and amoxicillin or lansoprazole and amoxicillin is one regimen used for H. pylori treatment.

Erythromycin

Base: 250–500 mg PO every 6 to 12 hrs

Max: 4 g/day

Ethylsuccinate: 400–800 mg PO every 6 to 12 hrs

Max: 4 g/day

Lactobionate: 15–20 mg/kg/day IV in 4 divided doses, or 0.5–1 g IV every 6 hrs, or continuous infusion over 24 hrs (Max: 4 g/day)

Base: 30–50 mg/kg/day PO in 2 to 4 divided doses

Max: 2 g/day

Ethylsuccinate: 30–50 mg/kg/day PO in 2 to 4 divided doses Max: 4 g/day

Stearate: 30–50 mg/kg/day PO in 2 to 4 divided doses

Max: 2 g/day

Lactobionate: 15–50 mg/kg/day IV in 4 divided doses

Max: 4 g/day

PO, IV, ophthalmic solution, topical ointment, gel, or pad

GI intolerance (common), phlebitis at IV infusion site

Inhibits liver CYP 450 enzymes 3A4 and 1A2, resulting in multiple significant drug interactions.

Fidaxomicin

200 mg twice daily for 10 days

Not studied in pediatric patients

PO

Nausea, abdominal pain

Used for treatment of diarrhea due to C. difficile

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

Non-GC = nongonococcal infection.

Source: [6,16]

MECHANISM OF ACTION

The macrolides are bacteriostatic, inhibiting protein synthesis by binding at the 50S ribosomal unit and by blocking transpeptidation and translocation. At high concentrations or with rapid bacterial growth, the effects may be bactericidal [93]. Data challenge the view of macrolides as global inhibitors of protein synthesis. Evidence demonstrates that these agents selectively inhibit the translation of a subset of cellular proteins, that they impact protein synthesis in a context-specific manner, and that they manifest site specificity of action [94,95,96,97,98].

Many bacteria that are resistant to the penicillins are also resistant to erythromycin. Bacterial resistance may result from decreased permeability of the cell membrane; in addition, an increase in active efflux of the drug may occur by incorporating a transporter protein into the cell wall [98,99,100].

The gene for this mechanism is transferred on plasmids between bacteria. Mutations of the 50S ribosomal receptor site may also develop, preventing binding of the erythromycin [101]. Lastly, bacterial enzymes have been described that may deactivate erythromycin [102]. It is likely that this form of resistance is also transferred on plasmids.

Many strains of H. influenzae are resistant to erythromycin alone but are susceptible to a combination with a sulfonamide [103]. Erythromycin ethylsuccinate and sulfisoxazole are manufactured as suspensions for use in treating acute otitis media in children older than 2 months of age [6]. They are useful for targeting H. influenzae, one of the common pathogens in otitis media in this age group.

PHARMACOKINETICS

Erythromycin has a wide spectrum of activity. Gram-positive bacteria that are usually susceptible to erythromycin include the Streptococcus species. Erythromycin is a second-line agent for gram-negative bacteria, such as H. influenzae (when used concomitantly with sulfonamides) and M. catarrhalis. Macrolides are particularly useful for their coverage of atypical bacteria, such as Mycoplasma and Chlamydia. Some spirochetes and mycobacteria are also susceptible to the macrolides. These drugs are indicated for upper respiratory tract infections, such as sinusitis, otitis media, pharyngitis, and bronchitis. They are also useful in the treatment of pertussis, Legionnaires disease, and diphtheria.

Macrolides are relatively poorly absorbed orally. Fidaxomicin is minimally absorbed and active only locally in the gastrointestinal tract. Food increases absorption of extended-release clarithromycin but has little or no effect on the immediate-release preparation of the drug. Food causes decreased absorption of both azithromycin capsules and erythromycin (including base and stearate formulations) [104]. Erythromycin may also be given intravenously.

All the macrolides have extensive tissue distribution, with less than adequate penetration into the brain tissue and the CSF [104]. Erythromycin is primarily excreted in feces and urine, with 2% to 15% unchanged [6]. Azithromycin is primarily excreted unchanged into the bile. Clarithromycin is excreted in the urine, both unchanged and as the hydroxy metabolite.

It may be necessary to adjust the doses of the macrolides in the presence of severe hepatic insufficiency. Azithromycin should be used with caution in adults with hepatic impairment; no dosage adjustments are recommended for renal impairment [6]. A dosage adjustment of clarithromycin may be appropriate in patients with hepatic impairment and concomitant severe renal impairment; clarithromycin doses may have to be reduced in severe renal failure [6].

SIDE EFFECTS/TOXICITY

While serious side effects with the macrolides are rare, milder side effects are common. Erythromycin stimulates motility in the GI tract, and this may cause abdominal cramping, diarrhea, nausea, and vomiting. Hepatic dysfunction with or without jaundice has occasionally been reported with erythromycin estolate. There have also been some reports of reversible hearing loss in patients treated with erythromycin in high doses or in the presence of renal insufficiency. With IV erythromycin, prolongation of the QT interval and ventricular tachycardia may occur [104].

Clarithromycin may cause nausea, diarrhea, abnormal taste, dyspepsia, and headache. There have been reports of tooth discoloration that is reversible with professional cleaning. Transient CNS changes with anxiety and behavioral changes, which resolve when the drug is discontinued, have also been reported [105].

Allergic reactions to macrolides are rare but may include rash and eosinophilia. Very rarely, severe reactions such as Stevens-Johnson syndrome have occurred. The drugs are contraindicated in patients with known hypersensitivity to the macrolides.

DRUG INTERACTIONS

Drug interactions are extensive. Erythromycin and clarithromycin are inhibitors and substrate for the 3A isoform subfamily of the cytochrome P450 enzyme system (CYP3A4). If they are given with a drug that is primarily metabolized by CYP3A, the drug serum levels may be increased and/or prolonged [6]. Erythromycin is contraindicated with concurrent use of cisapride, pimozide, dihydroergotamine, ergotamine, lovastatin, simvastatin, astemizole, or terfenadine. Clarithromycin is contraindicated with concurrent use of cisapride, pimozide, ergot alkaloids (e.g., ergotamine), or lomitapide [6]. Serum levels of theophylline, cyclosporine, ergotamine, carbamazepine, benzodiazepines, warfarin, amiodarone, and tacrolimus may also be affected by concurrent administration with erythromycin and clarithromycin. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors levels may also be elevated, with increased risk for rhabdomyolysis [6,106].

Azithromycin is not likely to interact with drugs metabolized by CYP3A4. However, azithromycin interacts with pimozide, potentially resulting in QT interval prolongation and arrhythmia [107]. Co-administration with pimozide is therefore contraindicated. Levels of cyclosporine could potentially be increased and therefore should be monitored closely [6,108].

SPECIAL POPULATIONS

Erythromycin is pregnancy category B, with an erythromycin estolate preparation as the preferred form because it is less likely to cause hepatotoxicity. Surveillance studies have not shown any increase in adverse outcomes. Azithromycin is also category B [6]. The CDC recommends the use of azithromycin for the treatment of Chlamydia during pregnancy. Treatment with erythromycin is an approved alternative regimen [109].

Clarithromycin is pregnancy category C, based on the finding that it causes growth retardation in monkeys and adverse effects on other mammals, including fetal loss. A postmarketing surveillance study did not find any evidence of teratogenicity, but a Danish study found a doubling in the frequency of miscarriages among women treated with clarithromycin [110,111]. The manufacturer recommends that clarithromycin not be used in pregnant women unless there are no alternative therapies [6].

Erythromycin is excreted in breast milk, but the AAP considers it usually compatible with breastfeeding [57]. Clarithromycin is excreted in breast milk, but breastfeeding is considered acceptable when the relative infant dose is less than 10% [112]. One systematic review and meta-analysis demonstrated a significant association between post-natal use of erythromycin and infantile hypertrophic pyloric stenosis [113].

11. QUINOLONES

The first quinolone, nalidixic acid, was introduced in 1962. It was developed as a result of chloroquine synthesis. Later, derivatives with broader spectrum antimicrobial coverage were produced, leading to the current class of quinolone drugs (fluoroquinolones). As with other classes of synthetic and semisynthetic antimicrobials, alterations of side chains affect antimicrobial activity and pharmacokinetics [114].

Table 6: THE QUINOLONES

Agent

Adult Dosing Range

Pediatric Dosing Range

Route

Common Side Effects

Comments

Besifloxacin

1 drop 3 times daily (4 to 12 hrs apart) for 7 days

Same as adult dosing

Ophthalmic drops

Headache

Contact lenses should not be worn during treatment

Ciprofloxacin

PO: 250–750 mg every 12 hrs

IV: 200–400 mg every 12 hrs

PO: 20–30 mg/kg/day in 2 divided doses

Max: 1.5 g/day

IV: 20–30 mg/kg/day in 2 divided doses

Max: 800 mg/day

PO, IV, topical, otic, ophthalmic solution or ointment

GI upset, headache

Photosensitivity can occur. Antacids decrease absorption. Can prolong QT interval.

Quinolones may cause tendon inflammation and rupture and may exacerbate myasthenia gravis associated muscle weakness.

Delafloxacin

PO: 450 mg every 12 hrs for 5 to 14 days

IV: 300 mg every 12 hrs for 5 to 14 days

Not studied in pediatric patients

PO, IV

GI upset, increased serum transaminases

Gatifloxacin

Days 1 and 2: 1 drop every 2 hrs while awake

Max: 8/day

Days 3–7: 1 drop 2 to 4 times/day

>1 yr: same as adult dosing

Ophthalmic drops

Headache, GI upset, conjunctival irritation, keratitis

Levofloxacin

250–750 mg/day for 5 to 14 days

N/A

PO, IV, ophthmalmic drops, inhalation

GI upset, headache, phototoxicity

Moxifloxacin

400 mg/day for 5 to 14 days

N/A

PO, IV, ophthalmic drops

GI upset, headache

Ofloxacin

200–400 mg every 12 hrs

N/A

PO, otic, ophthalmic drops

GI upset, headache

Ozenoxacin

Apply thin layer to affected area (up to 100 cm^2) twice/day for 5 days

Infants >2 mos to 12 yrs: Same as adult dosing, except treated area may only be up to 2% of total body surface area (Max: 100 cm^2)

>12 yrs: same as adult dosing

Topical

<1% experience rosacea-like face eruption, seborrheic dermatitis

Novel drug for treatment of impetigo caused by Staphylococcus aureus or Streptococcus pyogenes

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

Source: [6,16]

MECHANISM OF ACTION

Quinolones inhibit DNA gyrase and DNA topoisomerase, enzymes that mediate DNA supercoiling, transcription, and repair [6,115]. Quinolones convert these enzymes into cellular toxins, inhibit replication of bacterial DNA by blocking and/or inhibiting the enzymes, relax DNA supercoils, and enable DNA replication and repair. The interference with replication and transcription processes can lead to permanent chromosomal breaks. If the breaks overwhelm the SOS response and other DNA repair pathways, cell death can occur [116,117].

Bacterial resistance develops as a result of spontaneous mutations that change the binding sites for quinolones on the DNA gyrase and the DNA topoisomerase [116]. Mutations that decrease the ability of quinolones to cross the cell membrane also occur. Plasmids that carry quinolone resistance genes have been identified as an emerging clinical problem [117,118].

PHARMACOKINETICS

The quinolones are active against many gram-positive cocci, gram-negative bacilli, and atypical bacteria (e.g., Legionella, Mycoplasma). Older quinolones have poor activity against streptococci and anaerobes, at achievable serum levels, is relatively poor, although newer agents, such as moxifloxacin, have better coverage against streptococci (including S. pneumoniae with reduced penicillin sensitivity) and some anaerobes [119]. Gram-negative coverage includes Campylobacter, Enterobacter, E. coli, H. influenzae, Klebsiella, Salmonella typhi, Shigella, and Vibrio cholerae[119]. Indications for the use of quinolones include urinary tract infections, non-gonococcal infections of the urethra and cervix, pneumonia, sinusitis, soft-tissue infections, and prostatitis. Ciprofloxacin is indicated for post-exposure prophylaxis for anthrax, and levofloxacin has an indication for the treatment of inhalation anthrax infection [6]. The quinolones are absorbed well after oral administration, and peak serum levels in the elderly and those with reduced renal function approximate those achieved with intravenous usage. Food may delay the time to reach peak serum concentration but does not decrease total absorption. Oral absorption is diminished by coadministration of aluminum, magnesium, calcium, zinc, and/or iron preparations [119]. The drugs are distributed well throughout all tissues, including the prostate, although the levels in the CSF and prostatic fluid are lower than serum levels [6].

Most quinolones are metabolized in the liver and excreted in the urine, reaching high levels in urine. Moxifloxacin is mainly excreted nonrenally. It is metabolized, via glucuronide and sulfate conjugation in the liver, to an inactive metabolite [6,119,120]. Ciprofloxacin has a mixed route of elimination. As much as 35% to 70% of the ciprofloxacin dose is excreted renally [6].

In renal insufficiency, the quinolones that are primarily excreted renally and those with mixed routes of elimination require dosage adjustments [6]. Moxifloxacin doses do not have to be adjusted for mild hepatic insufficiency [6].

SIDE EFFECTS/TOXICITY

The most common side effect with the use of quinolones is GI upset. Less common side effects include headache, insomnia, dizziness, peripheral neuropathy, tendon rupture, elevated liver enzymes, and interstitial nephritis [6,121,122]. Rarely, hematologic toxicities have occurred, resulting in hemolytic anemia (more likely to occur in patients with glucose-6-phosphate dehydrogenase [G6PD] deficiency), aplastic anemia, and agranulocytosis [123]. Very rarely, hepatic necrosis and hepatic failure have been reported [6; 124].

Although allergic reactions are not common, they may occur and range from a rash to severe reactions, such as Stevens-Johnson syndrome. Very rare cases of severe fatal hypoglycemia have been reported with concurrent treatment with glyburide and ciprofloxacin [125]. Use quinolones with caution in patients with medical problems that predispose the patient to seizures. Quinolones should not be used in patients with CNS disorders [119].

There is also a risk of disabling peripheral neuropathy associated with the use of oral or injectable fluoroquinolones [126]. The onset can be rapid, and patients should be advised to contact their healthcare provider if any signs or symptoms develop. In these cases, the fluoroquinolone should be stopped and an alternative non-fluoroquinolone drug used, unless the benefit of continued treatment outweighs the risk [119,126].

In 2018, the FDA strengthened the warnings about the risks of mental health side effects (e.g., disorientation, agitation, delirium) and serious blood sugar disturbances (including hypoglycemia coma) associated with fluoroquinolones [127].

DRUG INTERACTIONS

Drug interactions are common and vary among the quinolones. Antacids may decrease the absorption of these agents. Iron supplements and other supplements with divalent and trivalent cations cause quinolone-cation complexes and impair absorption [119,128]. Concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) appears to increase the risk of seizures [6,129].

Theophylline, phenytoin, and warfarin levels may be elevated in patients concurrently treated with ciprofloxacin. Serum levels or prothrombin time should be monitored, and the doses of these drugs should be altered as appropriate [6]. Dosage adjustments are not typically needed with other quinolones [119].

SPECIAL POPULATIONS

Quinolones should be used in pregnancy only if clinical benefit exceeds risk and a safer alternative is not available [119]. Because quinolones enter breast milk, their use during breastfeeding should be avoided if alternative agents are available [119].

Quinolones are not routinely used as first-line therapy for pediatric patients but may be considered a reasonable alternative in situations where no safe and effective substitute is available (e.g., multi-drug resistance) [6].

12. SULFONAMIDES

Sulfonamides, the first true antibiotics, are derived from azo dyes. The first agent was sulfachrysoidine, used in 1935, which released sulfanilamide in vivo [130]. Modifications were made to the sulfanilamide to reduce side effects, resulting in the development of the modern sulfonamides. Many of the sulfonamides are no longer used as parenteral agents, but they continue to be used as topical agents or for treatment in specific conditions (e.g., prophylaxis for drug-resistant malaria). Some of these agents are no longer available in the United States but are still commonly used in other countries.

MECHANISM OF ACTION

The sulfonamides are bacteriostatic, exerting their effect as competitive antagonists of para-aminobenzoic acid (PABA). They inhibit dihydropteroate synthase from using PABA to synthesize dihydropteroic acid, a precursor of folic acid. The lack of folic acid intermediates ultimately results in impaired synthesis of nucleotides. Bacteria that use pre-formed folate are not susceptible to the bacteriostatic action. Silver sulfadiazine is one exception, as it exerts its effects on the cell membrane and cell wall and is bactericidal.

Unfortunately, bacterial resistance to sulfonamides is common, with cross-resistance between agents frequently occurring [131]. Mutations that result in additional production of PABA or changes in the enzyme binding sites for sulfonamides are responsible for the resistance [132,133]. Genes for these resistant mutations may be carried on plasmids, allowing rapid transfer to other similar bacteria and resulting in more rapid development of resistance patterns than through random mutation alone [133,134].

One method for improving bacterial activity against potentially resistant strains is the addition of trimethoprim [135]. Trimethoprim is a competitive inhibitor of dihydrofolate reductase, another enzyme active in the synthesis of folate [6]. Trimethoprim resistance is also common [136].

PHARMACOKINETICS

The sulfonamides can be divided into groups based on absorption and excretion characteristics. They are classified as short-to medium-acting agents, agents limited to activity in the GI tract, and topical agents.

Table 7: THE SULFONAMIDES

Agent

Adult Dosing Range

Pediatric Dosing Range

Route

Common Side Effects

Comments

Short- to Medium-Acting

Sulfadiazine

2–4 g/day in 3 to 6 divided doses

>2 mos (initial): 75–150 mg/kg/day in 4 to 6 divided doses

>2 mos (maintenance): 150 mg/kg/day in 4 to 6 divided doses

Max: 6 g/day

PO

Rash, pruritus

Multiple drug interactions.

Contraindicated in infants <2 mos of age.

Sulfamethoxazole/trimethoprim (TMP/SMX)

PO: 1–2 DS tablets every 12 to 24 hrs

IV: 8–20 mg TMP/kg/day in 2 to 4 divided doses

>2 mos PO:6–20 mg TMP/kg/day in 2 divided doses

IV: 6–20 mg TMP/kg/day every 12 to 24 hours

Max single dose: 160 mg TMP/dose

PO, IV

Rash, pruritus

Multiple drug interactions.

Weight-based dosing recommendations based on trimethoprim content.

Limited to GI Tract

Sulfasalazine

RA: Initial: 0.5–1 g every 6 to 8 hrs Maintenance: 2 g/day in divided doses

UC: Initial: 3–4 g in evenly divided doses every 8 hours

Titrate to 4–6 g in 4 divided doses

>2 yrs: 40–60 mg/kg/day in 3 to 6 divided doses

PO

Anorexia, headache, GI upset

Contraindicated with hypersensitivity to salicylates, sulfasalazine, sulfonamides, or mesalamine.

Topical

Mafenide

Cream: Apply 1.6 mm thick layer to burn area every 12 or 24 hrs

Solution: Wet dressing gauze every 4 hrs or as needed

Use adult dosing

Cream, powder for solution

Burning at application site, rash, allergic reaction

Used for treatment of second- and third-degree burns to prevent infection.

Burn area should be covered with cream/wet at all times.

Apply with sterile gloved hand.

Silver sulfadiazine

Apply 1.6-mm layer to burn area once or twice daily

Use adult dosing

Cream

Rash, allergic reaction

Sulfacetamide

Dosage varies with the preparation.

Use adult dosing

Prepared in complex with other topical medications as a solution or ointment

Rash, local irritation

Combinations with fluorometholone, prednisolone, and phenylephrine are available, each with differing dosing, indications, and contraindications. Common for ophthalmic and topical use.

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

DS = double strength; RA = rheumatoid arthritis; TMP = trimethoprim; UC = ulcerative colitis.

Source: [6,16]

The Short- to Medium-Acting Sulfonamides

This group of agents includes sulfadiazine and sulfamethoxazole. Sulfadiazine is readily diffused into CSF and excreted largely in urine, 15% to 40% as metabolites and 43% to 60% as unchanged drug [6]. It is indicated for use in treating chancroid, trachoma, inclusion conjunctivitis, nocardiosis, UTIs, toxoplasmosis encephalitis, and malaria and for prophylaxis of rheumatic fever [6]. Sulfamethoxazole is combined with trimethoprim and is indicated for Pneumocystis jiroveci prophylaxis and treatment, upper respiratory tract infections, and urinary tract infections [6].

Sulfonamides Limited to Gastrointestinal Tract Activity

The agents limited to the GI tract are very poorly absorbed and have been used for reducing bacterial flora in the bowel before surgery. The only available agent in this class is sulfasalazine, which is used in the treatment of ulcerative colitis and for juvenile and rheumatoid arthritis in patients who have responded inadequately to salicylates or other NSAIDs [6]. Although absorption of sulfasalazine from the intact intestine is very low, inflammation in the bowel may result in significant absorption of the metabolite sulfapyridine [6].

Topical Sulfonamides

The topical sulfonamides include mafenide acetate and silver sulfadiazine, which are used in the treatment of burns. Mafenide is used less often because it may cause a metabolic acidosis as a result of carbonic anhydrase inhibition. An additional topical agent is sulfacetamide, which is used in ophthalmic and lotion formulations. Topical sulfonamides may be absorbed systemically, and if large burn areas are treated, absorption may be significant [6].

ABSORPTION/ELIMINATION

The sulfonamides are quickly absorbed after administration unless they have been altered to stay in the lumen of the intestine (e.g., sulfasalazine). After absorption, they are acetylated in the liver into a toxic but inactive form. The acetylated form is mostly excreted in the urine, with a small amount excreted in bile. These drugs are widely distributed throughout body tissue and fluids, including the CSF and peritoneal fluid [137].

The sulfonamides undergo acetylation and glucuronidation in the liver. Both the unchanged and metabolized forms are excreted in the urine through glomerular filtration and renal tubular secretion.

Mafenide may be used in renal failure, but monitoring of acid-base balance is recommended. Dosage and frequency of administration of other sulfonamides must be adjusted in renal failure based on serum levels. No data is available on dosing in hepatic insufficiency.

SIDE EFFECTS/TOXICITY

Allergic reactions with rash and itching are relatively common. Nausea, vomiting, diarrhea, headache, and photosensitivity may occur. Rare but severe hypersensitivity reactions, including vasculitis, anaphylaxis, serum sickness, and Stevens-Johnson syndrome, may occur [131]. Sulfacetamide lotion also contains metabisulfite, which may cause an allergic reaction in patients allergic to sulfites [6].

Sulfonamide ophthalmic preparations may cause local irritation. The topical mafenide may cause pain or burning locally. Systemic reactions may develop during treatment with ophthalmic and topical preparations of sulfonamides due to systemic absorption.

Less common reactions include metabolic acidosis that may occur with absorption of mafenide due to a byproduct, (rho) carboxybenzenesulfonamide, that inhibits carbonic anhydrase. Very rare reactions with sulfonamides include blood dyscrasias (agranulocytosis, aplastic anemia, thrombocytopenia, hemolytic anemia), hepatitis and hepatocellular necrosis, and toxic nephrosis due to crystalluria. Hemolysis is more likely to develop in patients with G6PD deficiency [131].

Sulfonamides are contraindicated in patients who are known to be allergic to sulfa drugs and in cases where there have been previous adverse effects to sulfonamides [6].

DRUG INTERACTIONS

Warfarin, phenytoin, and sulfonylureas may all be potentiated due to displacement of the drugs from serum albumin by the sulfonamides [6]. Cyclosporine levels may be decreased, and levels should be monitored [6]. Administration of PABA may antagonize the effects of sulfa drugs.

SPECIAL POPULATIONS

Sulfa drugs should be avoided in pregnancy near term due to the increased potential for kernicterus in the newborn [131]. Animal studies with sulfamethoxazole show bone abnormalities and a higher incidence of cleft palate. Adequate studies have not been done in pregnant women [131].

Mafenide, sulfacetamide ophthalmic drops, and sulfadiazine are pregnancy category C. Sulfacetamide lotion has not been studied in pregnancy. Adverse events were not observed in animal reproduction studies of silver sulfadiazine; nevertheless, it is contraindicated for use near term in pregnant women [6].

Sulfonamides are excreted in breast milk. Sulfamethoxazole and sulfisoxazole are considered compatible with breastfeeding by the AAP, although they should be avoided if hyperbilirubinemia or G6PD deficiency is present [57]. Sulfacetamide lotion and silver sulfadiazine have not been studied in breastfeeding but would presumably also be excreted in breast milk; use with caution in breastfeeding women [6]. The manufacturer considers the use of sulfadiazine to be contraindicated in breastfeeding women [6].

Because of the risk of neonatal kernicterus, use of sulfonamides should be avoided in the newborn. Sulfacetamide eye drops have not been studied in children younger than 2 months of age [6].

13. TETRACYCLINES

Chlortetracycline, the first tetracycline, was developed in 1948 as a product of Streptomyces aureofaciens. Chlortetracycline was altered to produce tetracycline. Doxycycline and minocycline are semisynthetic derivatives.

Tetracyclines bind to the 30S ribosomal subunit (and possibly the 50S ribosomal subunits of susceptible bacteria), blocking the binding of aminoacyl transfer-RNA [6,138]. This results in inhibition of protein synthesis, with bacteriostatic effects.

Bacterial resistance is typically the result of mutations that either prevent entrance of tetracyclines into the cell or increase the export of tetracycline out of the cell [139]. The resistance may be transmitted by plasmids [140].

MECHANISMS OF ACTION AND PHARMACOKINETICS

The tetracyclines have a broad spectrum of activity that includes aerobic gram-positive and gram-negative bacilli, atypical bacteria (such as Chlamydia trachomatis, Chlamydia psittaci, and Mycoplasma pneumoniae), and spirochetes (such as Borrelia burgdorferi). Tetracycline is also a second-line agent for T. pallidum. It is approved by the FDA for treatment of rickettsial infections, typhus, Rocky Mountain spotted fever, trachoma, nongonococcal urethritis, and lymphogranuloma venereum [6].

As a result of decades of clinical and agricultural use, the prevalence of resistance to tetracyclines is now high among common gram-positive and gram-negative pathogens. For this reason, and because they are bacteriostatic, the role of tetracyclines is limited for treatment of most pyogenic infections. Primary indications for this class are atypical infections (e.g. mycoplasma and chlamydia) and zoonoses (e.g. tularemia and brucellosis).

The tetracyclines may be divided into three groups based on their pharmacokinetic traits. These groups are the short-acting group, intermediate-acting group, and long-acting group. The varying half-lives are the result of different rates of renal excretion [6].

Table 8: THE TETRACYCLINES

Agent

Adult Dosing Range

Pediatric Dosing Rangea

Route

Common Side Effects

Comments

Short-Acting

Tetracycline

250–500 mg every 6 to 12 hrs

25–50 mg/kg/day in 4 divided doses

PO

Photosensitivity, tooth enamel deformities in children <8 yrs of age

Polyvalent cations decrease absorption.

Intermediate-Acting

Demeclocycline

150 mg every 6 hrs or 300 mg every 12 hrs

≥8 years:8–12 mg/kg/day in 2 to 4 divided doses

PO

GI upset, tooth enamel deformities in children <8 yrs of age

Polyvalent cations decrease absorption. Use caution if used with warfarin.

Long-Acting

Doxycycline

PO: 100–200 mg/day in 1 to 2 divided doses

IV: 100 mg every 12 hrs

<45 kg: 2–5 mg/kg/day in 1 to 2 divided doses

Max: 200 mg/day

>45 mg: Same as adult dosing

PO, IV

Phlebitis at IV site, photosensitivity, tooth enamel deformities in children <8 yrs of age

Polyvalent cations decrease absorption. Use caution if used with warfarin.

Minocycline

Initial: (IV, PO): 200 mg Maintenance: (IV): 100 mg every 12 hrs

Max: 400 mg/day

Maintenance (PO): 100 mg every 12 hrs, OR 100–200 mg initially, followed by 50 mg 4 times daily

Initial: (IV, PO): 4 mg/kg/dose

Maintenance: 2 mg/kg/dose every 12 hrs

Max: 400 mg/day

PO, IV

GI upset, tooth enamel deformities in children <8 yrs of age

Prescribing information is given for comparison purposes only. The higher dosage ranges reflect dosages for more severe infections. Please consult the manufacturer's package insert for the antibiotic for complete prescribing information, maximum dosages, and indications.

SIADH: syndrome of inappropriate antidiuretic hormone hypersecretion.

aAll pediatric doses are for children older than 8 years of age.

Source: [6,16]

Short-Acting Tetracyclines

The short-acting tetracyclines include tetracycline, the namesake of the class. Frequent dosing is needed because of the very short half-life of these agents. The class previously included oxytetracycline, but the agent is no longer available in the United States [6]. Tetracycline is inexpensive but requires dosing every six hours for most indications. A less frequent dosage protocol is commonly used for the treatment and prevention of acne [6].

Intermediate-Acting Tetracyclines

The only intermediate-acting agent available in the United States is demeclocycline. Demeclocycline is no longer used as an antibiotic but rather has been used as an off-label drug to treat the syndrome of inappropriate antidiuretic hormone (SIADH) [6,141]. However, studies have suggested that there is limited high-quality evidence to suggest that demeclocycline is effective in managing this condition, and European clinical practice guidelines recommend against the use of demeclocycline for the management of hyponatremia in patients with SIADH [6,142].

Long-Acting Tetracyclines

The long-acting tetracycline agents include doxycycline and minocycline. The main difference between these and the short-acting agents is that these may be dosed less frequently (once or twice daily), which is an advantage in ensuring compliance [6]. The spectrum of bacterial coverage is essentially the same and the indications are the same, with the additional indication for the treatment of inhalation anthrax as part of a multidrug regimen.

ABSORPTION/ELIMINATION

Tetracycline is well absorbed after an oral dose taken in the fasting state. Doxycycline and minocycline are well absorbed after an oral dose and may be given with or without food.

The tetracyclines are well distributed throughout body tissues and fluids; distribution in the CSF is adequate for the treatment of some infections [6,143,144]. The excellent tissue penetration results in the ability of the drug to cross into the dentin, where the tetracycline permanently chelates with the calcium [145].

Most of the tetracycline dose is excreted unchanged into the urine by glomerular filtration, although there is some biliary excretion as well. Nonrenal, possibly hepatic, mechanisms account in large part for excretion of doxycycline and minocycline. Approximately 23% to 40% of doxycycline and 5% to 12% of minocycline is excreted in the urine [6].

Tetracycline should be used with caution in the presence of renal insufficiency, because it accumulates rapidly in the serum in the presence of decreased renal function [6]. Doxycycline may be used in renal failure, as it will be excreted into the bile [6,146]. Hepatotoxicity has been rarely reported [6].

SIDE EFFECTS/TOXICITY

Tetracyclines commonly cause GI upset, including nausea, vomiting, and diarrhea. There is conflicting evidence of staining and deformity of the teeth in children younger than 8 years of age. Photosensitivity, idiopathic intracranial hypertension, esophageal ulceration, and hepatotoxicity occur rarely [6].

Minocycline is often associated with vertigo, nausea, and vomiting, and it may increase azotemia in renal failure. In addition, prolonged use of minocycline may cause reversible discoloration of the fingernails, the sclera, and the skin [6]. Minocycline has been associated with a lupus-like reaction [6].

Allergic reactions to tetracyclines are not common but may range from mild rashes to anaphylaxis. Tetracyclines are contraindicated in patients who have shown hypersensitivity to any tetracyclines.

DRUG INTERACTIONS

Several types of drug interactions result in alterations in serum levels of tetracyclines. Agents that alkalinize the urine will increase excretion of the tetracyclines. Polyvalent metal cations (calcium, aluminum, zinc, magnesium, and iron) and bismuth decrease absorption [6,147]. Drugs that induce hepatic enzymes may decrease the half-life of doxycycline.

Interactions that affect the efficacy of other drugs also occur. The bactericidal effect of penicillins may be decreased by co-administration with tetracyclines. Concurrent use of oral contraceptives may make the contraceptive less effective [6,148,149]. The effects of warfarin are increased, probably because tetracyclines depress warfarin metabolism and plasma prothrombin activity, resulting in a synergistic effect [6,150]. Digoxin effects may be increased because of changes in the bowel flora that are responsible for digoxin metabolism [151].

SPECIAL POPULATIONS

Evidence Based Practice Recommendation

The Infectious Diseases Society of America asserts that tetracyclines should not be used in children younger than 8 years of age.

https://academic.oup.com/cid/article/52/3/e18/306145

Last Accessed: January 11, 2024

Level of Evidence: A-II (Good evidence from >1 well-designed clinical trial, without randomization; cohort or case-controlled analytic studies; multiple time-series; or dramatic results from uncontrolled experiments)

Tetracycline is pregnancy category D because of impaired bone development in the fetus. Hypoplasia of the enamel and discoloration of fetal teeth may occur, and maternal hepatic toxicity has been reported as well [6,152,153].

Tetracyclines are excreted into the breast milk in small amounts. Most exposed infants have very low blood levels of the drug and probably are not at risk [6]. In the past, tetracyclines were contraindicated in children younger than 8 years of age because of the risk for tooth deformity. However, doxycycline is the current first-line therapy for Rocky Mountain spotted fever in children of all ages, including those younger than 8 years of age [154]. Limited studies indicate that short courses of the medication were not associated with dental side effects in this population [155].

14. VANCOMYCIN

Vancomycin is the oldest member of the glycopeptide antibiotics class, a group of large molecules that inhibit bacterial cell wall synthesis. Glycopeptides have a high binding affinity for peptides found only in bacterial cell walls. This interaction disrupts peptidoglycan polymerization, the late-stage reaction that imparts rigidity to the cell wall [6,156]. Gram-positive organisms, both cocci and bacilli, are highly susceptible to glycopeptides.

Vancomycin was developed more than 50 years ago as an alternative intravenous therapy for serious staphylococcal and streptococcal infections in patients allergic to beta-lactams. In this early period, vancomycin usage was associated with a high incidence of vestibular and renal toxicity. The cause was attributed in large part to impurities in the formulation, a problem solved in subsequent years. At present, the major role for vancomycin is in the treatment of serious infections caused by MRSA, methicillin-resistant S. epidermidis (MRSE), and ampicillin-resistant enterococci [157]. An oral formulation is available for the treatment of C. difficile-associated diarrhea/colitis.

MECHANISMS OF ACTION AND PHARMACOKINETICS

Vancomycin is not absorbed by the intestinal tract and must be administered by intravenous infusion, except for the formulation for the treatment of C. difficile-associated diarrhea/colitis [6]. The determination of a safe, effective dosage regimen, and decisions regarding monitoring of therapy, are complex matters that require consideration of multiple factors, including the site and severity of infection, the patient's weight and renal function, the susceptibility of the infecting organism, and the anticipated duration of therapy [158]. The usual adult dose is 15–20 mg/kg/dose every 12 hours. The rate of infusion should be no more than 500 mg/hour, as rapid infusion causes an uncomfortable generalized erythroderma ("red man" syndrome) [6]. The red man syndrome is a histamine-mediated flushing that occurs during or immediately following infusion and does not mandate discontinuation unless slowing the infusion rate fails to mitigate the reaction.

ABSORPTION/ELIMINATION

Vancomycin is cleared almost entirely by the kidneys. Prolonged usage at excessively high therapeutic serum levels has been associated with nephrotoxicity and ototoxicity [6]. In treating patients with invasive staphylococcal infection and MRSA, it is considered important to use the maximum dosage (target trough serum vancomycin level of 15–20 mcg/mL) in order to assure optimal therapeutic effect [158]. The serum creatinine and trough vancomycin level (target <20 mcg/mL) should be monitored once or twice weekly in such cases, as well as in all patients who are elderly or have impaired renal function.

SIDE EFFECTS/TOXICITY

Apart from the (avoidable) red man syndrome, vancomycin administration is well tolerated and side effects are uncommon. As with beta-lactams and sulfonamides, vancomycin is a good sensitizing agent; allergic manifestations such as fixed drug eruptions and drug fever are relatively common. Vancomycin nephrotoxicity does occur. The incidence is low, the exact mechanism is poorly understood, and the impact is usually reversible upon discontinuation of the drug. Risk factors for nephrotoxicity include total daily dose in excess of 3–4 grams, trough serum vancomycin levels >20 mcg/mL, pre-existing renal disease, concomitant use of other nephrotoxic drugs (e.g. aminoglycosides), and duration of therapy longer than one week [159].

In 2017, the FDA published a safety review that indicated that use of intraocular vancomycin prophylactically during cataract surgery, alone or in a compound formula, should be avoided because of the risk of hemorrhagic occlusive retinal vasculitis [6,160].

Reversible neutropenia, presumably from bone marrow toxicity, is sometimes seen in patients receiving prolonged vancomycin therapy (e.g., for endocarditis and osteomyelitis). Oral vancomycin is not absorbed and thus imposes no risk of nephrotoxicity or ototoxicity.

15. ANTIMICROBIAL PEPTIDES

The increasing prevalence of antimicrobial resistance among clinical isolates of staphylococci and streptococci severely limits therapeutics for serious infections caused by these common pathogens. Thus, there is ongoing research on alternative antimicrobial mechanisms and development of novel therapies needed for treatment of multidrug-resistant bacterial infection. Antimicrobial peptides are naturally occurring molecules and semisynthetic derivatives that have bactericidal activity against micro-organisms. Naturally occurring peptides with antimicrobial activity are produced by a variety of organisms (e.g., plants, insects, marine life) and serve to protect the host from pathogenic micro-organisms. Antimicrobial peptides exert their effects via multiple mechanisms: cell-membrane attachment, disruption, and leakage of cell contents; inhibition of intracellular protein and nucleic acid synthesis; attenuation of protein folding; and prevention of cell wall biosynthesis [175].

DAPTOMYCIN

Daptomycin is a cyclic lipopeptide produced by Streptomyces roseosporus having bactericidal activity against a wide range of gram-positive cocci. The spectrum of activity includes human pathogens such as methicillin-sensitive Staphylococcus aureus, MRSA, and Enterococcus. The exact mechanism of action is unclear; it targets the bacterial cell membrane where interactions lead to rapid depolarization due to potassium efflux, leakage of cell contents, and disruption of the architecture of the cell membrane [175]. Following clinical trials to assess efficacy and the parameters of safe dosage, daptomycin was approved by the FDA in 2006 for parenteral treatment (4 mg once daily) of complicated bacterial skin and soft tissue infections. Subsequent experience and formal clinical trials have demonstrated that daptomycin efficacy is comparable to standard therapy for treatment of MRSA bacteremia and endocarditis, especially when administered at the higher dose of 6–10 mg daily. Daptomycin is an option for salvage and first-line treatment of bacteremia, endocarditis, and osteomyelitis caused by MRSA and Enterococcus isolates showing resistance to vancomycin (minimal inhibitory concentration >2 mg/L) [176].

Adverse effects of daptomycin are rare with once daily dosing. Skeletal myopathy has been reported, mostly prior to 2006 when daptomycin was administered in multiple daily doses. When high dosage or prolonged daptomycin regimens are employed, coadministration with other drugs associated with myopathy, such as hydroxymethylglutaryl CoA reductase inhibitors (statins), should be avoided, and patients should be monitored for muscle pain or weakness [177]. Eosinophilic pneumonia has been reported in association with prolonged treatment of osteomyelitis. In a cohort study involving 1,021 patients who received daptomycin for bone and joint infections, 17 (1.7%) were diagnosed with daptomycin-induced eosinophilic pneumonia [178]. All patients recovered upon discontinuation of daptomycin.

LYPOGLYCOPEPTIDES

Lipoglycopeptides are semisynthetic derivatives of glycopeptides, akin to vancomycin and developed for treatment of multidrug-resistant staphylococcal and enterococcal infections. These newer agents have enhanced activity and favorable pharmacokinetics—in some cases, permitting administered at weekly intervals. In comparison to vancomycin, lipoglycopeptides have greater potency against gram-positive bacteria, including vancomycin-resistant strains, and appear less likely to lead to emergence of resistant organisms [161,162,179]. As with vancomycin, lipoglycopeptides must be administered intravenously. The lipophilic side chain prolongs plasma half-life and helps anchor these agents to the outer structure of the bacterial cell, inhibiting cell wall synthesis and disrupting cell membrane integrity [163]. In animal studies, lipoglycopeptides have proven effective in treating a variety of serious gram-positive infections, including bacteremia, pneumonia, and endocarditis [161,162]. Clinical studies of efficacy in humans have been limited to date.

At present, three lipoglycopeptides, telavancin, dalbavancin, and oritavancin, are approved by the FDA for the treatment of acute bacterial skin and soft-tissue infection. Clinical trials show equivalent or superior efficacy against MRSA skin infection when compared with vancomycin [7,162,164]. Telavancin is also approved for treatment of hospital-acquired and ventilator-associated S. aureus pneumonia. A phase III clinical trial is ongoing to assess telavancin efficacy and safety for treatment of complicated S. aureus bacteremia and right-sided endocarditis [179]. The side effect profile of these agents is mild and comparable to other effective regimens. Reported adverse effects include headache, nausea, pruritus, pain at injection site, and fever. Taste disturbance (i.e., metallic taste), nausea and vomiting, and foamy urine have been reported with telavancin [6,163].

Of note, a risk/benefit analysis should be conducted when using telavancin in patients with pre-existing moderate-to-severe renal impairment treated for hospital-acquired or ventilator-associated bacterial pneumonia, as mortality is increased compared with administration of vancomycin [6].

Dalbavancin has the advantage of a prolonged plasma half-life (6 to 10 days), allowing for weekly administration and perhaps obviating the need for an indwelling central line. In adults and children 12 to 17 years of age, the best-studied treatment protocol is 1 g IV, followed by 500 mg weekly [164,165]. In a randomized trial comparing dalbavancin (1 g IV on days 1 and 8) with vancomycin (IV for 3 days followed by the option of oral linezolid to complete 10 to 14 days) for treatment of skin infection, the clinical response outcomes were similar in both treatment arms. For patients with S. aureus infection, including MRSA, clinical success was observed in 90.6% of patients treated with dalbavancin and 93.8% of those who received vancomycin-linezolid [164].

The lipoglycopeptides have had some adverse effects on fetal development in animals; safety data in pregnant women are limited. These agents should be used during pregnancy only when the benefit outweighs the risk [163].

16. PLEUROMUTILINS

Pleuromutilins were discovered as natural-product antibiotics in 1950. However, their use was limited to veterinary medicine until 2007, when the first agent (retapamulin) was approved for use in humans [166]. Retapamulin was only approved for topical application. In 2019, lefamulin was approved for human use via oral and intravenous delivery [6]. Pleuromutilin derivatives are designed primarily through modifications at the C(14) side chain [166].

These agents inhibit bacterial protein synthesis through interactions (hydrogen bonds, hydrophobic interactions, and Van der Waals forces) with the A- and P-sites of the peptidyl transferase center in domain V of the 23s ribosomal RNA of the 50S subunit [6]. The binding pocket of the bacterial ribosome closes around the mutilin core for an induced fit that prevents correct positioning of transfer RNA [6].

Retapamulin is used for the topical treatment of impetigo. A small amount is applied to the affected area twice per day for five days [6]. Possible side effects include eczema, application site reactions, diarrhea, headache, and nasopharyngitis.

Lefamulin is approved for the treatment of community-acquired bacterial pneumonia [6,167]. The usual dose is 600 mg every 12 hours for oral administration or 150 mg every 12 hours for IV use [6]. Treatment is generally at least five days; patients should be afebrile for ≥48 hours and clinically stable prior to discontinuation. The most common adverse reactions include diarrhea, nausea, injection site reactions, elevated liver enzymes, and vomiting [167]. It is contraindicated in patients with certain arrhythmias or who are prescribed drugs to prolong QT intervals.

17. INVESTIGATIONAL ANTIBIOTICS FOR DRUG-RESISTANT MICRO-ORGANISMS

Researchers continue to explore new methods and the search for drugs to aid in the prevention of antibiotic resistance. Progress has been made in recent years, with two new antibiotics void of cross-resistance with existing antibiotics being discovered through soil sample screening: teixobactin and pseudouridimycin.

Teixobactin, a cyclic depsipeptide antibiotic, works by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid), inhibiting bacterial cell wall biosynthesis [168,169]. Teixobactin has been shown effective at treating an array of gram-positive pathogens, including MRSA, vancomycin-resistant Enterococcus, and Mycobacterium tuberculosis, with no known cross-resistance to other antibiotics [168,169]. With reports in 2016 of efficient syntheses of two teixobactin analogues, this class of drugs may be part of the solution to bacteria resistant to currently available antibiotics [168,169].

Pseudouridimycin, a nucleoside-analog inhibitor, acts by inhibiting bacterial RNA polymerase, an enzyme responsible for bacterial RNA synthesis, through a binding site. The structure is similar to rifampin, an antitubercular agent that inhibits the enzyme; however, the mechanism of action does differ so as not to cause a cross-reaction with rifampin [170,171]. Pseudouridimycin has been shown effective for a broad spectrum of drug-sensitive and drug-resistant bacteria.

Researchers are currently attempting to conduct synthesis of these two new classes of drugs with varying, but promising, success. Although it may take several years for these or other new antibiotics with no cross-resistance to be developed, promising progress is continuing, and researchers estimate that, once approved, resistance to these novel drugs could take decades, rather than years, to develop [168,169,170,171].

18. CONCLUSION

Antibiotics are commonly used drugs that have diverse actions, side effects, and toxicities. The large number of antibiotics available makes it challenging to understand the important characteristics of each antimicrobial class, including clinical indications, spectrum of activity, dosage, and toxicities. Knowing the general characteristics by antibiotic class and having experience with one or two key agents within each class improves recall and facilitates the selection of the most appropriate antibiotic for a given bacterial infection.

An understanding of the mode of action, spectrum of activity, and potential toxicity enables the practitioner to tailor a therapeutic regimen specific to the infectious etiology and of appropriate duration. This in turn lessens the likelihood developing microbial resistances and reduces risk of adverse effects.

It is important to remember that the indications given by the FDA are guidelines. Many antibiotics are used for off-label purposes, and occasionally in doses that differ from those recommended for the usual indications. This may be necessary when faced with managing severe and life-threatening infections or for special populations, such as premature infants, neonates, and the elderly. Before using a specific agent, one should always consider carefully reviewing the detailed information (package insert) provided by the manufacturer.

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Evidence-Based Practice Recommendations Citations

1. Johnson S, Lavergne V, Skinner AM, et al. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults. Clin Infect Dis. 2021;73(5):e1029-e1044. Available at https://academic.oup.com/cid/article/73/5/e1029/6298219. Last accessed January 11, 2024.

2. Davey P, Marwick CA, Scott CL, et al. Improving how physicians working in hospital settings prescribe antibiotics. Cochrane Database System Rev. 2017;(4):CD003543. Available at https://www.cochrane.org/CD003543/EPOC_improving-how-physicians-working-hospital-settings-prescribe-antibiotics. Last accessed January 11, 2024.

3. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52(3):e18-e55. Available at https://academic.oup.com/cid/article/52/3/e18/306145. Last accessed January 11, 2024.