#91413: Prescription Opioids: Risk Management and Strategies for Safe Use

Inappropriate opioid analgesic prescribing for pain is defined as the nonprescribing, inadequate prescribing, excessive prescribing, or continued prescribing despite evidence of ineffectiveness [10]. Appropriate opioid prescribing is essential to achieve pain control, to minimize societal harms from diversion, and to minimize patient risk of abuse, addiction, and fatal toxicity. The foundation of appropriate opioid prescribing is based on thorough patient assessment, treatment planning, and follow-up and monitoring. Essential for proper patient assessment and treatment planning is comprehension of the clinical concepts of opioid abuse and addiction, their behavioral manifestations in patients with pain, and how these potentially problematic behavioral responses to opioids both resemble and differ from physical dependence and pseudodependence. Prescriber knowledge deficit has been identified as a key obstacle to appropriate opioid prescribing and, along with gaps in policy, treatment, attitudes, and research, contributes to widespread inadequate treatment of pain [7]. A 2013 survey measured primary care physician understanding of opioids and addiction. Of the 200 participants, [11]:

This last point is very important because confusion and conflation of the clinical concepts of dependence and addiction has led to accusations of many nonaddicted patients with chronic pain misusing or abusing prescribed opioids and to failure to detect treatment-emergent opioid problems [12]. Knowledge gaps concerning opioid analgesics, addiction, and pain may be related to attitude gaps, and negative attitudes may interfere with appropriate prescribing of opioid analgesics. For example, when 248 primary care physician survey participants were questioned regarding their prescribing approach in patients with headache pain and either a past or current history of substance abuse, 16% and 42% of physicians, respectively, would not prescribe opioids under any circumstance [13]. Possibly contributing to this knowledge deficit is the extent of educational exposure to concepts central in pain management.

A 2018 systematic review evaluated pain medicine curricula in 383 medical schools in Australia, New Zealand, the United States, Canada, the United Kingdom, and Europe [14]. Pain medicine was primarily incorporated into anesthesia or pharmacology courses, rather than offered as a dedicated pain medicine module. Ninety-six percent of medical schools in the United Kingdom and the United States and nearly 80% of medical schools in Europe had no compulsory dedicated pain medicine education. The median number of hours of pain content in the entire medical school curriculum was 20 in Canada, 20 in Australia and New Zealand, 13 in the United Kingdom, 12 in Europe, and 11 in the United States [14].

The nomenclature related to addiction is often inconsistent, inaccurate, and confusing, partially reflecting the diverse perspectives of those working in the related fields of health care, law enforcement, regulatory agencies, and reimbursement/payer organizations. Changes over time in the fundamental understanding of addiction have also contributed to the persistent misuse of obsolete terminology [15]. The Diagnostic and Statistical Manual of Mental Disorders (DSM), published by the American Psychiatric Association, is perhaps the most influential reference for the diagnosis of addiction and all other psychiatric disorders. Prior to the 2013 release of the DSM-5, previous versions eschewed the term "addiction" in favor of "substance dependence," with a separate diagnostic entity of "substance abuse" representing a lower-grade, less severe version of substance dependence [16]. Also in earlier DSM versions, physiological dependence, manifesting as substance tolerance and withdrawal, was considered a diagnostic criterion of substance dependence. The result was the perpetuation of patient and healthcare professional confusion between physical and psychological dependence and the belief that tolerance and withdrawal meant addiction. This confusion enhanced provider and patient fears over addiction developing from opioid analgesics and contributed to the undertreatment of pain [16]. The DSM-5 has eliminated the categories of substance dependence and substance abuse by combining them into the single diagnostic entity of substance use disorder. The disorder is measured on a continuum from mild to severe [16].

In 2011, the American Society of Addiction Medicine (ASAM) published their latest revision in defining the disease of addiction. Since that time, the public understanding and acceptance of addiction as a chronic brain disease and the possibility of remission and recovery have increased. Additionally, there is growing acknowledgment of the roles of prevention and harm reduction along the spectrum of addiction and recovery. Consequently, ASAM updated its definition of addiction and adopted the following revised definition in 2019 [17]:

According to the ASAM, the five characteristics of addiction are [18]:

This summary of addiction should not be used as diagnostic criteria for addiction because the core symptoms vary substantially among addicted persons, with some features more prominent than others [17].

Many terms used in discussions of opioid use and misuse may have ambiguous meanings (Table 1). The absence of consensus in the terminology and definitions of substance use, substance use disorders, and addiction has led to considerable confusion and misconceptions (Table 2). These misconceptions may be harbored by clinicians, patients, family members, and the public and can negatively impact patient interaction, assessment, treatment, and outcomes. Correction of these erroneous beliefs and attitudes is important, as is the use of nonpejorative and nonstigmatizing language when describing opioid analgesics, the patients who need them, and patients who develop aberrant behaviors or addiction involving opioids (Table 3). Pejorative terminology has a strong negative effect on patients and serves to reinforce their sense of shame and stigma over using opioid analgesics. These terms signal a negative attitude and judgment to patients [15,19].

Opium and its alkaloids have been used for thousands of years as analgesics. From the end of the 19th century into the early 20th century, heroin was sold as a cough suppressant and briefly promoted as more effective and less addictive than morphine. It was legally marketed in pill form and became widely abused for the intense euphoria by crushing the heroin pills into powder for inhalation or injection [1]. Heroin addiction skyrocketed, and Congress banned the drug in 1924. Wariness of prescribing opioids persisted through the 1980s and 1990s [28].

The United States has a long history of pain undertreatment as a standard medical practice. This was a consequence of the long-standing emphasis on treating the underlying primary illness, minimizing the importance of addressing pain, and viewing pain as an endurable consequence [1]. Another primary factor historically responsible for pain undertreatment has been a resistance to prescribing opioids, driven by fears of patient addiction and the threat of prosecution and potential loss of licensure if opioid prescribing was deemed inappropriate by the state medical board. The widespread practice of including non-professional lay members on medical boards intensified physician concerns over prejudicial interpretation by board members, even when legitimate medical necessity merited long-term, high-dose opioid prescribing to patients with severe, chronic noncancer pain [28].

These physician concerns were confirmed by the results of a 1992 survey that captured medical board member perception and opinion of legality and appropriateness in opioid prescribing for different pain conditions. A total of 304 members of 49 state medical boards were surveyed; 85% were physicians (MDs and DOs) and 15% were lay public members [29]. Physician members were asked to rank 12 opioids by their order of recommendation for chronic, moderate-to-severe cancer pain. The top selection was codeine with aspirin/acetaminophen (47%), despite codeine being widely accepted as too weak for chronic moderate-to-severe pain. When asked of the general incidence of psychological dependence (as compulsive nonmedical use) from opioid pain treatment, 39% did not know. When asked to define "addiction" by selecting one or more of several common definitions, 85% chose physical dependence, 71% chose psychological dependence, 41% chose tolerance, 21% chose physical dependence alone, 10% chose psychological dependence alone, and 1% chose tolerance alone [29].

Respondents were also asked for their opinion, as state medical board members, of the legality and medical legitimacy of opioid prescribing longer than three months for several patient scenarios. Approximately 10% of board members described opioid prescribing as illegal under medical practice, controlled substances law, or both, and requiring investigation in patients with cancer pain alone, 26% in cancer pain with patient history of opioid abuse, 59% in chronic noncancer pain alone, and more than 90% in patients with chronic noncancer pain and history of opioid abuse [29]. Underscoring the gravity of these findings was that 80% of respondents stated their medical board was the agency most likely to investigate improper controlled substance prescribing in their state [29].

Against this backdrop, some pain physicians began to re-examine and challenge the intense physician reluctance to prescribe opioids. Observing the extent that suffering was relieved by opioids in cancer patients with severe pain and the apparent lack of euphoria that differed from the responses of opioid abusers, it was suggested that opioids could also be used to relieve suffering in many patients with intense, persistent noncancer pain, with little risk of addiction. This was followed by an effort to destigmatize the use of opioids, with the objective of easing access to opioids by the large number of patients with severe, persistent noncancer pain. While widely viewed as driven by good intentions, this crusade for acceptance of opioid use in noncancer pain was also accompanied by the regular tendency to minimize the inherent potential risks that accompany opioid prescription drug use, despite the absence of valid evidence to support the assumption [30].

Results from a 1986 chart review study of 38 patients with chronic noncancer pain receiving long-term opioid therapy were cited to support the assertion that long-term opioid use in patients with intractable nonmalignant pain was effective and safe with little risk of addiction. Of the 38 patients in the study, the 2 who developed opioid problems had histories of drug abuse [31]. This paper was followed by several other publications on opioids for chronic noncancer pain [32,33,34,35]. Each paper cited the prevalence rates of iatrogenic opioid addiction reported by three earlier pain studies [36,37,38]:

These iatrogenic addiction figures were disseminated through communications to specialists, general practitioners, other providers, administrators, regulators, and the lay public. "Less than 1%" became the message that opioids posed little risk of addiction in patient with pain without substance abuse histories. Substantial support for compassion-based efforts to broaden opioid use for pain control also came from the 1990 opinion paper by the co-author of the landmark paper describing gate control theory that revolutionized the concept of pain [39]. In 1988, the Federation of State Medical Boards (FSMB) released a policy explicitly reassuring physicians they would not face regulatory action for prescribing even large amounts of opioids, assuming it was medically warranted [30]. Physician awareness of the new FSMB policy was promoted by widely circulated publications. For example, the Joint Commission published a guide, supported by Purdue Pharma, stating, "Some clinicians have inaccurate and exaggerated concerns about addiction, tolerance, and risk of death," and "This attitude prevails despite the fact there is no evidence that addiction is a significant issue when persons are given opioids for pain control" [30].

During the 1990s, the American Pain Foundation endorsed more aggressive treatment of chronic pain, while the American Pain Society (APS) promoted the position that pain should be considered a fifth vital sign. The APS and the American Academy of Pain Medicine (AAPM) published a landmark consensus statement in 1997 that stated long-term opioid analgesic use for chronic noncancer pain posed minimal risk of overdose or addiction [30,40]. The pharmaceutical industry was also instrumental in the movement toward loosening opioid prescribing constraints and broadening the indications for opioid use in managing chronic pain [30,41]. Professional pain societies wrote consensus statements claiming little risk of addiction or overdose in patients with pain and that long-term opioids were easy to discontinue. In 1997, Congress passed SB402, also known as The Pain Patient's Bill of Rights [42]. In 2001, the Joint Commission issued new standards requiring hospitals to make pain assessment routine and pain treatment a priority. The now familiar pain scale was introduced, with patients asked to rate their pain from 1 to 10 and circle a smiling or frowning face, and pain became the fifth vital sign [43]. Immediately following the release of the new standards, concern was raised that the standards would lead to the inappropriate use of opioids. By 2002, pain as a "fifth vital sign" in the standards was changed to "pain used to be considered the fifth vital sign," and by 2004, this phrase no longer appeared in the Joint Commission's Accreditation Standards manual [44]. The standard that pain be assessed in all patients also remained controversial for two reasons: It seemed inappropriate for some patients due to the nature of their medical condition; and no similar standard existed requiring the universal assessment of other symptoms [44]. Thus, in early 2016, the Joint Commission began revising its pain assessment and management standards, with a focus on acute pain in the hospital setting. Draft standards were published in 2017, implemented in 2018, and revised in 2019 [45,46].

The financial support supplied to professional societies by drug companies helped influence members to change prescribing practices. Patient advocacy groups, often guided by physicians who felt constrained by the prohibition of opioid prescribing and pain specialist organization consensus that chronic pain had been previously undertreated, worked to elevate awareness that pain was untreated and unrecognized [28,40]. During this time, opioid prescribing for chronic noncancer pain dramatically increased across the country. The movement for more aggressive pain treatment culminated in 2000, when Congress proclaimed 2000–2010 as the Decade of Pain Control and Research [47]. Shifting demographics also contributed to the changing attitudes toward opioid prescribing. With painful chronic illness rates increasing with the overall population age, there came growing awareness of the importance in providing effective pain relief [43].

Pharmaceutical companies began introducing new opioid formulations, and existing opioid products became more widely prescribed (Table 5). The theme of minimal abuse liability was widely used in the marketing materials distributed to prescribers and pharmacists [48]. When the escalating rates of addiction, diversion, and fatal overdose involving prescribed opioids became apparent, the same pain specialists and organizations, pain advocacy groups, drug companies, and media reinforced the perception of opioid legitimacy by primarily attributing the growing individual and public health hazard to improper Internet availability, illicit diversion, and the prevalence of societal drug addiction tendencies [49].

The story of extended-release oxycodone, marketed as OxyContin, is informative and unique. Although the United States has experienced several waves of widespread prescription drug abuse over the past 150 years, the rapid ascent of OxyContin from market entry to miracle drug for chronic pain to a demonized substance of abuse and diversion on a vast scale is without precedent. Multiple factors facilitated this phenomenon. OxyContin contains a larger amount of high-potency opioid than short-acting opioid formulations. The delayed-release mechanism was easy to circumvent by chewing and swallowing or by crushing the pill and then injecting or snorting the powder. This produced a rapid, powerful opioid effect on par with heroin. Large profits were also possible from illicit sales of OxyContin, which generally commanded a black-market value of $1 per milligram (with higher prices in more rural areas) [51]. In addition, the original product labeling warned against crushing the tablets because rapid release of a potentially toxic amount of oxycodone would ensue, alerting abusers on how to best achieve maximum drug effect. The original labeling also included the FDA-condoned statement that the extended-release (ER) mechanism of OxyContin presented a lower abuse potential than other oxycodone products. Perhaps most importantly, its release coincided with the growing acceptance of opioids in pain treatment and the aggressive sale and marketing tactics of its producer, Purdue Pharma [43].

The timing of product launch was fortuitous. Until the 1990s, Schedule II opioids were primarily limited to use in operating rooms and inpatient settings because they required intravenous or intramuscular administration. This posed a serious obstacle to patients with chronic pain who required high-potency opioids. In response to the increasingly permissive climate and by genuine unmet patient need, several high-dose ER formulations of pre-existing opioids were introduced to market. MS Contin, an ER version of morphine sulfate, was introduced in 1985 but was primarily limited to use in cancer pain, partially a result of the stigma surrounding morphine. OxyContin was introduced in late 1995, at the point in time when prescriber attitudes were shifting from fearing iatrogenic addiction to developing a sense of security with prescribing opioid analgesics [43].

To help ensure product success, innovative approaches were employed to elevate visibility and encourage OxyContin prescribing, as well as highly aggressive marketing and sales tactics. The amount of money spent in promotion, marketing, and sales was unprecedented for an opioid, exceeding $200 million in 2001 alone [52]. Marketing and promotion efforts and the timing of the product launch resulted in a tenfold increase in OxyContin prescribing and sales revenue in just three years' time (Table 6).

In addition to the usual doctor-directed ads in medical journals, a novel indirect marketing campaign involving "nonbranded education" was implemented. Direct-to-consumer advertising of opioid drugs was prohibited, so the concept of pain relief from opioids was promoted to consumers without explicit mention of OxyContin. The public-education program Partners Against Pain (PAP) was launched, with videos, patient pain journals, and an elaborate website that marketed (to prescribers and patients) the message that pain was widespread and treatable with opioid analgesics [43,53]. The FDA later stated that the PAP website did provide information about OxyContin specifically and also contained a "Find a Doctor" feature to link consumers to physicians in their geographic area known to be willing to prescribe OxyContin [43].

More than 40 national pain-management and speaker-training conferences were conducted between 1996 and 2001. Thousands of prescribers attended the all-expenses-paid symposia held in resort locations [52]. From 1996 to July 2002, more than 20,000 pain-related educational programs and continuing medical education offerings for prescribers were funded by pharmaceutical sponsorship or financial contribution. This included a program that educated hospital physicians and staff on hospital and postoperative pain treatment compliance with Joint Commission pain standards. Pharmaceutical funding was used to underwrite the cost of the Joint Commission pain management educational programs, including the distribution of educational videos and a book on pain management (sold on the Joint Commission's website) [52]. Pharmaceutical funding has also paid for websites that provided free continuing medical educational on pain management; numerous pain management websites; groups such as the American Chronic Pain Association, the AAPM, and the APS; and a youth-focused website [43].

In 1999, pharmaceutical sales representatives were reportedly given 14,000 copies of a promotional video for physician distribution. Physicians were instructed to encourage patient viewing in their waiting rooms or as a "check-out" item and to use the video as an educational tool for office or hospital staff. The FDA later stated they were not provided the video before distribution for detection of inaccurate or unfounded claims, of which they later found several examples [43]. A patient starter coupon program was initiated that provided patients with a free limited-time prescription. Roughly 34,000 coupons had been redeemed when the program ended in 2001 [43,52].

Between 1996 and 2000, the internal sales force of the pharmaceutical firm that produces OxyContin grew from 318 representatives to 671, and a bonus system was implemented to encourage OxyContin sales [52]. The company is said to have maintained an active database containing nationwide profiles of individual physicians and their prescribing patterns, allowing for the identification of high-end and low-end OxyContin prescribers by zip code, county, and state; practices with large numbers of patients with chronic pain; and high prescribers of the company's older product MS Contin [52]. Sales representatives were reportedly directed to high opioid prescribers in their sales territories, with the goal of expanding the primary care OxyContin prescribing base. Sales representatives were also directed to call on oncology nurses, consultant pharmacists, hospices, hospitals, and nursing homes [43].

In 1996, the majority of ER opioid prescriptions went to cancer patients, but by 2000, only 3% of OxyContin prescriptions came from oncologists [54,55]. Opioid medications, and OxyContin in particular, had been successfully promoted as the first-line therapy for an increasingly wide range of moderate-to-severe pain conditions. Family practice physicians became the largest group of OxyContin prescribers, accounting for 21% of prescriptions in 2000 and close to 50% in 2003 [52,53]. This was followed by the growing concern that, in a managed care system, time constraints imposed on primary care physicians did not allow sufficient time to evaluate and follow patients with complex chronic pain [52].

The most critical issue and source of greatest prescriber concern was the risk of iatrogenic addiction. To help counter this perception, promotion and marketing to healthcare professionals and patients alike emphasized that OxyContin prescribing carried little risk of addiction. Misrepresenting this risk proved costly. In 2007, the pharmaceutical company paid $634 million in fines following guilty pleas from three of its executives to criminal charges for promoting false claims that OxyContin was less addictive and less subject to abuse and diversion than other opioids [52].

The escalating rates of OxyContin misuse were integral to the growing nationwide problem of prescription opioid abuse, diversion, addiction, and overdose. By 2004, OxyContin had become the most prevalent prescription opioid abused in the United States. Predictably, this public health epidemic created a backlash from regulatory and law enforcement agencies [56].

By the mid-2000s, professional and law enforcement efforts had emerged to curtail OxyContin abuse, including the pain management movement and creation of the pain management subspecialty. However, these efforts had some unintended negative consequences. Pharmacists were tasked with evaluating legal prescription appropriateness through a "drug use review." Encouraged by drug enforcement authorities, some became adversaries of physicians and patients by reporting any out-of-the-ordinary prescribing to the police [56].

Legitimate OxyContin use was also tarnished by negative media coverage suggesting that drug diversion was the result of irresponsible prescribing practices. A 2011 study of OxyContin coverage content in lay media and professional publications found that abuse, addiction, crime, and death were emphasized, typically from law enforcement and the criminal justice system perspectives. The majority of patients with legitimate medical need who benefited from the drug were rarely mentioned. An unfortunate outcome is the stigma sometimes experienced by patients who require OxyContin for long-term pain control [57].

A decision to prescribe opioids is based on clinician knowledge and judgment and also on patient preference, availability of non-opioid pain treatment approaches, the complexities and bias in third-party reimbursement, aggressive pharmaceutical marketing, and medico-legal concerns. These and other factors have tended to skew the standard of care toward reliance on opioids for long-term chronic pain management in the past few decades [8].

The use of patient satisfaction as a barometer of clinician skill may also influence opioid analgesic prescribing. Satisfaction with clinical care can be obtained from patient surveys, commonly including questions about how adequately their pain was addressed by the provider. Numerous for-profit provider-grading websites offer patients a forum to broadcast their opinions of care received from physicians. Healthcare professionals are likely to get a poor rating from patients who were refused opioids over abuse concerns, and reimbursement and job security can be adversely impacted by negative patient survey ratings in some institutions [65].

The financial structure of many managed care firms and third-party carriers incentivizes pain treatment and discourages substance abuse or addiction treatment. From a financial reimbursement perspective, the time spent providing patient education and counseling related to addiction issues has become one of health care's least valued commodities. This is especially the case in emergency department (ED) settings, where evaluation is often based on patient volume and not on time spent with individual patients. As such, it is faster and pays better to diagnose pain and prescribe an opioid than to diagnose and treat addiction [65].

There are a number of ways that the larger picture of opioid analgesic-related morbidity may be examined. Because the effects of opioid analgesic misuse can manifest in many ways in a variety of settings, it is important to examine data from different sources in order to get an accurate picture of opioid-related morbidity in the United States.

Opioid analgesics may result in deaths due to unintentional or intentional overdose or intoxication-related accidents. However, the majority of data focus on unintentional overdose. The rates of fatal toxicity involving prescription opioid analgesics have escalated in tandem with the increasing rates in opioid analgesic prescribing, abuse, addiction, and diversion. Unfortunately, additional valuable information is not revealed by the mortality data, such as whether the potential cause of the fatality was opioid ingestion for intoxication or for pain control, or whether the decedent was taking the medication as prescribed, using the opioid nonmedically (e.g., for insomnia control), using the medication plus someone else's prescribed opioid for poorly managed pain, or taking someone else's prescribed opioid to get high. Also unknown is the relative contribution of the opioid to the fatality. In one postmortem study of fatalities involving prescription opioids, 79% of decedents also tested positive for alcohol and other drugs [85]. In the absence of more details surrounding opioid fatalities, crafting preventive measures is difficult, and estimates of the true fatality rate from prescription opioids remain elusive.

Regional differences have been found in fatal drug overdose involving opioids, with the highest rates occurring in the Southwest and Appalachian regions. Differences between states have also been found. Data from 2021 indicate the highest fatal drug overdose rates occurred in West Virginia (90.9 per 100,000), Tennessee (56.6 per 100,000), Louisiana (55.9 per 100,000), Kentucky (55.6 per 100,000), New Mexico (51.6 per 100,000), and Ohio (48.1 per 100,000. In 2020, 91,799 drug overdose deaths occurred in the United States. The age-adjusted rate of overdose deaths increased by 31% from 2019 (21.6 per 100,000) to 2020 (28.3 per 100,000). Opioids were involved in 68,630 overdose deaths in 2020 (74.8% of all drug overdose deaths) [86]. Significant increases in drug overdose death rates during this period were primarily seen in California, Mississippi, Virginia, and South Carolina [87].

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: August 15, 2023)

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

According to one analysis, nearly one in four people on Medicaid received prescription opioids in 2015 [88]. The report analyzed 1.8 million opioid prescriptions written for 3.1 million Medicaid members across 14 states. According to the CDC, Medicaid patients are prescribed opioids at twice the rate of non-Medicaid patients and are at six times the risk of overdose [89]. However, essential information was omitted in this CDC report but uncovered by an investigation into Washington state opioid fatalities [90]. Left out of the CDC publication was the policy decision in early 2004 by the State of Washington to list methadone as a preferred opioid analgesic, as a cost-cutting measure. Morphine was the only other long-acting opioid placed on the preferred analgesics list. Methadone fatalities increased from 140 in 2002 to 256 in 2004. Many of these fatalities involved the combination of methadone and other prescribed medication, particularly benzodiazepines and antidepressants; of the 274 methadone-related fatalities in 2009, prescribed medications for anxiety or other mental-health concerns were found in 43% of decedents. The number of methadone fatalities in 2006 was 300% greater than the number attributed to any other long-acting pain reliever. Although the escalation in methadone fatalities had become obvious, the cost-cutting objectives were significant and state officials maintained the stance that methadone was safe and effective [91].

Researchers have found a distinctive pattern in the lifespans of drug abuse epidemics. This pattern reflects the escalating and declining prevalence in the use of a substance, the projected course into the near future, and prevalence rate variation across localities. The phases common to all drug epidemics are incubation, expansion, plateau, and decline in use of the drug. Arrestee data are a valuable source of information for tracking drug use trends and are consistent or slightly ahead of drug use data collected from general population studies in measuring drug epidemic phenomenon. To better understand the problem of prescription opioid abuse, information was obtained from 41,501 adult male arrestees in nine geographic locations. Arrestees provided data on their past three-day opioid analgesic use. Data from 2000–2003 were compared with data from 2007–2010. By location, the prescription opioid epidemic phase and the 2010 rate of past three-day opioid analgesic use by arrestees were [111]:

These results illustrate the uneven geographic distribution of the prescription opioid use epidemic. It is also clear that prevalence rates are stabilizing or declining in all localities. These arrestee data indicate the epidemic has likely peaked and predict the decline in first-time and past-year use and an increase in prescription opioid addiction and treatment-seeking rates. In susceptible persons, progression in severity of a substance use disorder to addiction often occurs over many years. Persons who now meet diagnostic criteria for opioid analgesic addiction, and may be seeking help, probably began their use during an earlier phase of the epidemic.

As discussed, pain treatment, especially in the context of opioid prescribing, is defined as inappropriate by its non-treatment, inadequate treatment, overtreatment, or continued use of ineffective treatment [10]. Inappropriate pain treatment with opioid analgesics elevates the risk of uncontrolled pain, possibly serious adverse side effects, and abuse and diversion. Therefore, clinicians who treat patients with chronic pain are required to use strategies that assess and mitigate the risk of abuse liability inherent in opioids. Although risk assessment and mitigation strategies have been developed to decrease the problem of prescribed opioid abuse, diversion, and overdose, their use can also reduce the development of serious side effects and help ensure the treatment selected is benefiting the patient [112].

The 2011 Institute of Medicine report Relieving Pain in America reinforced the importance of framing chronic pain as a unique chronic disease state with complex neurophysiological, emotional, and social components, making its management distinct from that of acute pain [7]. Treating chronic pain differs from acute pain by the duration, multimodal approach, and risk mitigation of the therapy. Clinicians may fear that managing the issues surrounding opioid analgesic prescribing render the practice too difficult or complex [112]. To assist in the dual need of protecting one's clinical practice while reducing opioid abuse, the FSMB released a model policy for opioid analgesic prescribing in 2013. This policy was the result of identification of harmful but remediable factors contributing to pain undertreatment and inappropriate opioid prescribing, including [10]:

Prescribers were held to a standard of safe and best clinical practice, the general points of which include [10]:

The model policy additionally stated that physicians would not be sanctioned on the sole basis of medically legitimate opioid prescribing (Table 8).

In 2015, the FSMB appointed a workgroup to review and analyze the original policy document as well as other state and federal policies on the prescribing of opioids in pain treatment, including advisories issued by the CDC and the FDA [113]. In April 2017, the FSMB adopted the Guidelines for the Chronic Use of Opioid Analgesics, an update to the original model policy that includes recommendations identified by the workgroup. The stated goal of this document is to provide state medical and osteopathic boards with an updated guideline for assessing physician management of pain, so as to determine whether opioid analgesics are used in a manner that is both medically appropriate and in compliance with applicable state and federal laws and regulations [113].

The FSMB 2017 Guidelines communicate the message that pain management is an important area of patient care, integral to medical practice; and that opioid analgesics may be necessary for pain control. In order to implement best practices for responsible opioid prescribing, clinicians should understand the relevant pharmacologic and clinical issues in the use of opioid analgesics and should obtain sufficient targeted continuing education and training on the safe prescribing of opioids and other analgesics as well as training in multimodal treatments. The Guidelines focus on the general overall safe and evidence-based prescribing of opioids and treatment of chronic, non-cancer pain, with the specific limitation and restriction that they do not operate to create any specific standard of care. A variety of strategies may be used to achieve the goals of the Guidelines, including the patient's level of pain, preferences of the clinician and the patient, available resources, and other concurrent issues. The Guidelines do not encourage the prescribing of opioids over other pharmacological and nonpharmacological means of treatment. Pain management should be viewed as essential to both the quality of medical practice and to the quality of life for patients who suffer from pain. The Guidelines are not intended for the treatment of acute pain, acute pain management in the perioperative setting, emergency care, cancer-related pain, palliative care, or end-of-life care. They apply most directly to the treatment of chronic pain lasting more than three months in duration or past the time of normal tissue healing [113].

In deciding whether to prescribe an opioid analgesic for chronic pain, clinicians should perform, and document in the record, an assessment of the potential benefits and risks to the patient. The elements of such an assessment include [113]:

If there is a history of substance abuse, active or in remission, consult an addiction specialist before starting opioids [113]. In active substance abuse, do not prescribe opioids until the patient is engaged in a treatment/recovery program or other arrangement made, such as addiction professional co-management and additional monitoring. When considering an opioid analgesic (particularly ER or LA types), one must always weigh the benefits against the risks of overdose, abuse, addiction, physical dependence and tolerance, adverse drug interactions, and accidental ingestion by children [114].

Risk assessment involves a determination of whether potential opioid benefits outweigh the potential risks. The individual and public health consequences of prescription opioid abuse, addiction, diversion, and overdose justify assessment and risk stratification in every patient considered for long-term opioid therapy [115]. Patients with chronic pain and past or current alcohol or drug abuse, psychiatric illness, or serious aberrant drug-related behaviors should still be considered for opioid therapy, but with tighter monitoring conditions and consultation from mental health or addiction specialists. Pain management outcomes are negatively affected by untreated psychiatric comorbidity, and proper assessment can identify and lead to the treatment of these conditions [116]. Periodic reassessment is necessary because patient circumstances and the benefit/risk balance of opioid therapy can change, due to alterations in the primary pain condition, comorbid disease, or psychological or social circumstances [115].

Before Opioid Therapy Initiation

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: August 15, 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)

Screening and assessment tools can help guide patient stratification according to risk level and inform the appropriate degree of structure and monitoring in the treatment plan. It should be noted that despite widespread endorsement of screening tool use to help determine patient risk level, most screening tools have not been extensively evaluated, validated, or compared to each other, and evidence of their reliability is poor [97]. In addition to screening and assessment tools, urine drug testing, monitoring of prescribing practices, prescription monitoring programs, opioid treatment agreements, and utilization of universal precautions are essential. Presently, a combination of strategies is recommended to stratify risk, to identify and understand aberrant drug-related behaviors, and to tailor treatments accordingly [117].

Opioid Risk Tool

The Opioid Risk Tool (ORT) is a five-item assessment to help predict aberrant drug-related behavior. It is also used to establish patient risk level through patient categorization into low, medium, or high levels of risk for aberrant drug-related behaviors based on responses to questions of previous alcohol/drug abuse, psychological disorders, and other risk factors [27].

Screener and Opioid Assessment for Patients with Pain–Revised

The Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R) is a patient-administered, 24-item screen with questions addressing history of alcohol/substance use, psychologic status, mood, cravings, and stress. Like the ORT, the SOAPP-R helps assess risk level of aberrant drug-related behaviors and the appropriate extent of monitoring [118].

CAGE and CAGE-AID

The original CAGE (Cut down, Annoyed, Guilty, and Eye-opener) Questionnaire consists of four questions designed to help clinicians determine the likelihood that a patient is misusing or abusing alcohol. These same four questions were adapted to include drugs (CAGE-AID), and this tool may be used to assess the likelihood of current substance abuse [119].

Diagnosis, Intractability, Risk, Efficacy Tool

The Diagnosis, Intractability, Risk, Efficacy (DIRE) tool is a clinician-rated questionnaire used to predict patient compliance with long-term opioid therapy [120]. Patients scoring lower on the DIRE tool are poor candidates for long-term opioid analgesia.

Mental Health Screening Tool

The Mental Health Screening Tool is a five-item screen that asks about a patient's feelings of happiness, calmness, peacefulness, nervousness, and depression in the past month [121]. A lower score on this tool is an indicator that the patient should be referred to a specialist for pain management.

Common to most clinical practice guidelines, and discussed in the FSMB 2017 Guidelines, is patient stratification by level of risk [113]. All practice guidelines for opioid analgesic prescribing recommend assessing the risk of misuse, abuse, or addiction in all patients before initiating long-term (≥90 days) opioid therapy and in high-risk patients prior to acute pain therapy. Patient risk level is designated as low, medium, or high based on background and clinical characteristics (Table 9) [97].

Low-risk patients receive the standard level of monitoring, vigilance, and care. Moderate-risk patients should be considered for an additional level of monitoring and provider contact, and high-risk patients are likely to require intensive and structured monitoring and follow-up contact, additional consultation with psychiatric and addiction medicine specialists, and limited supplies of short-acting opioid formulations [21].

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: August 15, 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)

The initial opioid prescription is preceded by a written informed consent or "treatment agreement" [113]. This agreement should address potential side effects, tolerance and/or physical dependence, drug interactions, motor skill impairment, limited evidence of long-term benefit, misuse, dependence, addiction, and overdose. Informed consent documents should include information regarding the risk/benefit profile for the drug(s) being prescribed. The prescribing policies should be clearly delineated, including the number/frequency of refills, early refills, and procedures for lost or stolen medications [113].

The treatment agreement also outlines joint prescriber and patient responsibilities [113]. The patient agrees to using medications safely, refraining from "doctor shopping," and consenting to routine urine drug tests (UDTs). The prescriber's responsibility is to address unforeseen problems and prescribe scheduled refills. Reasons for opioid therapy change or discontinuation should be listed [113]. Agreements can also include sections related to follow-up visits, monitoring, and safe storage and disposal of unused drugs.

Opioid therapy should be presented as a trial for a pre-defined period (usually no more than 30 days). The goals of treatment should be reasonable improvements in pain, function, depression, anxiety, and avoidance of unnecessary or excessive medication use [113]. The treatment plan should describe therapy selection, measures of progress, and other diagnostic evaluations, consultations, referrals, and therapies.

In opioid-naïve patients, start at the lowest possible dose and titrate to effect. Dosages for opioid-tolerant patients should always be individualized and titrated by efficacy and tolerability [113]. The need for frequent progress and benefit/risk assessments during the trial should be included in patient education. Patients should also have full knowledge of the warning signs and symptoms of respiratory depression.

Prescribers should be knowledgeable of federal and state opioid prescribing regulations. Issues of equianalgesic dosing, close patient monitoring during all dose changes, and cross-tolerance with opioid conversion should be considered. If necessary, treatment may be augmented, with preference for nonopioid and immediate-release opioids over ER/LA opioids. Taper opioid dose when no longer needed [114].

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: August 15, 2023)

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

When implementing a chronic pain treatment plan that involves the use of opioids, the patient should be frequently reassessed for changes in pain origin, health, and function [113]. This can include input from family members and/or the state prescription drug monitoring program (PDMP) [113]. During the initiation phase and during any changes to the dosage or agent used, patient contact should be increased. At every visit, chronic opioid response may be monitored according to the 5 A's [10]:

Urine Drug Testing

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: August 15, 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)

UDTs may be used to monitor adherence to the prescribed treatment plan and to detect unsanctioned drug use [113]. They should be used more often in patients receiving addiction therapy, but clinical judgment is the ultimate guide to testing frequency (Table 10) [128]. High-quality evidence supporting the benefits of UDTs in improving patient care are lacking, as much of the existing evidence comes from industry-sponsored studies that can portray a biased perspective, usually by stressing the prevalence of aberrant behaviors in patients who then require more frequent UDT monitoring [129].

MONITORING FREQUENCY ACCORDING TO PATIENT RISK

Monitoring Tool	Patient Risk Level
	Low	Medium	High
Urine drug test	Every 1 to 2 years	Every 6 to 12 months	Every 3 to 6 months
State prescription drug monitoring program	Twice per year	3 times per year	4 times per year

Table 10

Source: [128]

Initially, testing involves the use of class-specific immunoassay drug panels [10]. If necessary, this may be followed with gas chromatography/mass spectrometry for specific drug or metabolite detection. It is important that testing identifies the specific drug rather than the drug class, and the prescribed opioid should be included in the screen. Any abnormalities should be confirmed with a laboratory toxicologist or clinical pathologist. Immunoassay may be used point-of-care for "on-the-spot" therapy changes, but the high error rate prevents its use in major clinical decisions unless liquid chromatography is coupled with mass spectrometry confirmation.

Urine test results suggesting opioid misuse should be discussed with the patient using a positive, supportive approach. The test results and the patient discussion should be documented.

Ethical Concerns with UDTs

It is important to appreciate the limitations of UDTs. Healthcare providers are increasingly relying on UDTs as a means to reduce abuse and diversion of prescribed opioids. This has led to a proliferation in diagnostic laboratories that offer urine testing. With this increase have come questions of whether these business interests benefit or hinder patient care, what prescribers should do with the information they obtain, the accuracy of urine screens, and whether some companies and clinicians are financially exploiting the UDT boom [129]. A random sample of UDT results from 800 patients with pain treated at a Veterans Affairs facility found that 25.2% were negative for the prescribed opioid and 19.5% were positive for an illicit drug/unreported opioid [130]. However, a negative UDT result for the prescribed opioid does not necessarily indicate diversion; it may indicate the patient halted its use due to side effects, lack of efficacy, or pain remission. The increasingly stringent climate surrounding clinical decision-making regarding aberrant UDTs is concerning. In many cases, a negative result for the prescribed opioid or a positive UDT serves as the pretense to terminate a patient rather than an impetus to guide him or her into addiction treatment or an alternative pain management program [129].

In principle, and ideally in practice, UDTs are a worthwhile element of effective pain management and pharmacovigilance when used to enhance the diagnostic and therapeutic objectives of pain therapy. However, when UDT use is motivated by fear, coercion, or profiteering, patients may be offended or feel intimidated by the practice [129].

As a side note, cannabis use by patients with chronic pain receiving opioid therapy has traditionally been viewed as a treatment agreement violation that is grounds for termination of opioid therapy. However, some now argue against cannabis use as a rationale for termination or substantial treatment and monitoring changes, especially considering the increasing legalization of medical use at the state level [24].

It is important to seek consultation or patient referral when input or care from a pain, psychiatry, addiction, or mental health specialist is necessary. Clinicians who prescribe opioids should become familiar with opioid addiction treatment options (including licensed opioid treatment programs for methadone and office-based opioid treatment for buprenorphine) if referral is needed [113].

Ideally, providers should be able to refer patients with active substance abuse who require pain treatment to an addiction professional or specialized program. In reality, these specialized resources are scarce or non-existent in many areas [113]. Therefore, each provider will need to decide whether the risks of continuing opioid treatment while a patient is using illicit drugs outweigh the benefits to the patient in terms of pain control and improved function [24].

Documentation is a necessary aspect of all patient care, but it is of particular importance when opioid prescribing is involved. All clinicians should maintain accurate, complete, and up-to-date medical records, including all written or telephoned prescription orders for opioid analgesics and other controlled substances, all written instructions to the patient for medication use, and the name, telephone number, and address of the patient's pharmacy [113]. Good medical records demonstrate that a service was provided to the patient and that the service was medically necessary. Regardless of the treatment outcome, thorough medical records protect the prescriber.

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: August 15, 2023)

Level of Evidence: Expert Opinion/Consensus Statement

The decision to continue or end opioid prescribing should be based on a joint discussion of the anticipated benefits and risks. An opioid should be discontinued with resolution of the pain condition, intolerable side effects, inadequate analgesia, lack of improvement in quality of life despite dose titration, deteriorating function, or significant aberrant medication use [113].

Clinicians should provide physically dependent patients with a safely structured tapering protocol. Withdrawal is managed by the prescribing physician or referral to an addiction specialist. Patients should be reassured that opioid discontinuation is not the end of treatment; continuation of pain management will be undertaken with other modalities through direct care or referral.

In response to the rising incidence in prescription opioid abuse, addiction, diversion, and overdose since the late 1990s, the FDA has mandated opioid-specific REMS to reduce the potential negative patient and societal effects of prescribed opioids. Another element of opioid risk mitigation is FDA partnership with other governmental agencies, state professional licensing boards, and societies of healthcare professionals to help improve prescriber knowledge of appropriate and safe opioid prescribing and safe home storage and disposal of unused medication [123].

The FDA Amendments Act (FDAAA) of 2007 gave the FDA authority to require REMS from manufacturers to ensure that benefits of a drug or biological product outweigh risks. REMS replaced the previously existing risk management programs, termed Risk Minimization Action Plans (RiskMAPs). An important distinction between the two programs is that the FDA did not have authority to require or enforce a RiskMAP after product approval. The FDA now has the authority to require REMS as part of the approval process for a new medication or post-approval if the agency becomes aware of new safety information pertaining to serious medication-associated risks following approval for marketing [114].

As defined by the FDAAA, REMS may include a medication guide, a patient education package insert, a communication plan, and other elements to assure safe use (ETASUs). ETASUs must address the goals to mitigate a specific serious risk listed in the labeling of the drug and may include [114]:

The FDA maintains a list of current opioid analgesic REMS at https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm [134].

In 2011, the FDA announced the components of REMS that would apply to all ER/LA opioid formulations. The decision to not include short-acting formulations was based on the substantially greater opioid amount in ER/LA formulations and the corresponding greater risk of serious adverse outcomes, including fatality, when taken by someone for whom they were not prescribed, by patients who succeed in defeating the delayed-release mechanism, or by any user co-ingesting alcohol, benzodiazepines, or other respiratory suppressant substances. Primary elements of the ER/LA REMS include changes in product labeling and the requirement that all ER/LA opioid formulation manufacturers provide specific information to prescribers and patients [135]. For example, there is a new indication for all ER/LA opioids that the pain must be severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. The original indication for the treatment of "moderate" pain was eliminated. In addition, the distinctions between cancer pain and chronic noncancer pain were removed. Prescriber education regarding ER/LA opioids is provided through accredited continuing education activities supported by independent educational grants from ER/LA opioid analgesic companies. This includes guidance regarding patient education on the risks and benefits of ER/LA opioid analgesics [135].

In 2012, the FDA issued a class-specific REMS for all transmucosal immediate-release fentanyl (TIRF) opioid products. Training was required for all prescribers, pharmacies, distributors, and outpatients who prescribed, dispensed, or received TIRF products [136]. In December 2020, the FDA approved modifications to this REMS. The modified TIRF REMS consists of a restricted distribution program to ensure the safe use of TIRF medicines, including use only in opioid-tolerant patients [136]. The modified REMS requires that prescribers document a patient's opioid tolerance; that outpatient pharmacies dispensing TIRF medicines document and verify a patient's opioid tolerance prior to dispensing; that inpatient pharmacies develop internal policies to verify opioid tolerance in patients who require TIRF medicines while hospitalized; and that a new patient registry be established to monitor accidental exposure, misuse, abuse, addiction, and overdose [136].

Several ADF opioids have received approval for marketing in the United States; others are in the process of evaluation, and one ADF was released for marketing and subsequently recalled by the manufacturer [138,143]. These formulations use different strategies to prevent misuse, with varying advantages and disadvantages (Table 11) [138].

While all ADF strategies may potentially deter tampering, physical barriers to crushing or chewing appear to be the only strategy that benefits nonabusers and abusers alike by preventing accidental crushing or chewing and not inducing adverse events. This contrasts with strategies that precipitate adverse events to deter inappropriate use, such as ADFs that use sequestered aversive agents that will induce adverse events in patients who chew or crush the tablets, accidentally or without intent of abuse. The extent of deterrence from these formulations is unclear because some persons are willing to endure discomfort from the aversive agent in order to obtain the more intense high from tampering. Sequestered opioid antagonists may offer a more effective approach in pharmacologic abuse deterrence by rendering the opioid ineffective, but they can induce sudden and severe opioid withdrawal in physically dependent patients who accidentally chew the tablet [138].

Although opioid ADFs have been introduced into widespread clinical use relatively recently, several studies of their efficacy have already been published. These reports have documented significantly reduced abuse rates of ADF opioids after they have fully replaced the original formulations, but no effect on the overall rates of opioid abuse. For example, data were obtained on 140,496 persons assessed for substance abuse treatment, spanning from one year before ADF OxyContin (Oxy ADF) introduction to two years post-Oxy ADF introduction. Abuse of OxyContin was 41% lower with the ADF versus the original formulation, including a 17% decrease in oral abuse and a 66% decrease in abuse through non-oral routes. Meaningful reductions in ER morphine and ER oxymorphone abuse rates were not found. The authors concluded that conversion of OxyContin to an ADF formulation was successful in reducing non-oral administration that requires tampering [145]. Another study found that following OxyContin ADF introduction, poison center exposures for oxycodone ER abuse declined 38% per population and 32% per unique recipients of dispensed drug. Therapeutic error exposures declined 24% per population and 15% per unique recipients of dispensed drug, and diversion reports declined 53% per population and 50% per unique recipients of dispensed drug. The declines were greater than those observed for other prescription opioids in aggregate [146]. However, several published reports have documented the abandonment of opioid analgesics and a migration to heroin use by previous OxyContin abusers following the introduction of ADF OxyContin [147,148].

The FDA has prohibited labeling or marketing claims of abuse resistance or abuse deterrence to be used in any ADF opioid product because supportive epidemiologic data have not yet been published [149]. Any future label claim of abuse deterrence must be supported by post-marketing data [138].

In 2013, Purdue Pharma and Endo Pharma, the makers of OxyContin and Opana ER, respectively, requested a ruling from the FDA that the original formulations were removed from market and replaced by ADFs because of safety or efficacy concerns. Such a ruling would render the original formulations ineligible for generic replication, thus protecting ADF OxyContin and Opana ER market share from generic non-ADF competition [150]. The FDA ruled in favor of this request for Purdue but not for Endo. The basis for the decision was the extent of abuse liability with the original OxyContin preparation and insufficiency in the abuse deterrence with the ADF formulation to block future applications to produce generic versions of the non-ADF Opana ER [151]. Interestingly, this favorable ruling for Purdue Pharma was made on April 16, 2013, the exact date of patent expiration for OxyContin [150].

In 2013, the FDA issued a draft document to guide pharmaceutical companies in developing ADF opioid products. Although the FDA strongly encourages industry to employ ADFs in new opioid products, the guidance document fell short of a mandate [142]. Later that year, the FDA approved an ER formulation of hydrocodone (Zohydro) that lacks abuse-deterrent properties, which seemed contradictory to the FDA stance on ADF product development [152].

In June 2017, the FDA requested that Endo Pharma remove the reformulated Opana ER from the market based on concerns that the benefits of the drug may no longer outweigh the risks [153]. This is the first time the FDA has taken steps to remove a currently marketed opioid pain medication. The agency's decision was based on a review of available postmarketing data, which demonstrated a significant shift in the route of abuse of Opana ER from nasal to injection following release of the ADF formulation. Injection abuse of reformulated Opana ER has been associated with a serious outbreak of HIV and hepatitis C and with cases of thrombotic microangiopathy [153].

Several regulations and programs at the state level have been enacted in an effort to reduce prescription opioid abuse, diversion, and overdose, including [157]:

Enactments of restrictive mandates to govern opioid analgesic prescribing and dispensing have created difficulty for patients in accessing legitimate opioid therapeutics. This has been especially well documented in the state of Washington, but it is highly prevalent in general. Concerns have been voiced by numerous key opinion leaders and prominent individuals in the pain treatment profession and community in an effort to draw attention to regulatory and law enforcement overreach at the expense of patients suffering in pain who require access to opioid analgesics.

One example is Jan Chambers, president of the National Fibromyalgia and Chronic Pain Association (NFMCPA). For incorporation into a position paper on patient rights to access pain medication, Chambers sought input from members requiring prescribed opioids for their pain condition. In the open letter encouraging member input, Chambers expressed concern over federal law enforcement and regulatory overreach involving heightened scrutiny of prescription filing and dispensing. Mandates cited as especially harmful were patient-prescriber opioid contracts required to specify a single pharmacy, a 30-day maximum supply of opioids and no refills, and prohibition of faxing or phoning opioid prescriptions to a pharmacy. Also mentioned was the increasing rate of pharmacy refusal to dispense opioids, the result of greater pressures imposed by the DEA on pharmacy networks to obtain additional patient information to verify legitimacy. These pharmacy networks, in turn, have transferred this burden to individual pharmacists, who, similar to prescribers, have become fearful of attracting DEA scrutiny over opioid prescription dispensing. The end result has been difficulty finding a pharmacy to fill opioid prescriptions [158].

Similar concerns over negative unintended patient impact were communicated by Amy Abernethy, president of the American Academy of Hospice and Palliative Medicine (AAHPM) to the National Conference of Insurance Legislators (NCOIL). NCOIL is an organization of state legislators involved in insurance legislation and regulation, and her response concerned several recommendations in a proposed set of best practices guidelines to reduce opioid abuse that were released by NCOIL in 2013. Strategies included in the NCOIL draft were those already implemented at the state level that led to measurable reductions in abuse and overdose. Abernethy countered by arguing that the narrow measure of success came at the expense of patients and providers [159].

With a shortage of pain medicine specialists in the United States, most chronic pain care is provided at the primary care level, and in some states (e.g., Washington), many primary care practices display signs in offices stating they no longer prescribe opioids. Interestingly, a small number of primary care physicians have chosen to transform their practices into cash-only entities and charge very high fees for what amounts to the sole prescribing of opioid analgesics. Patients requiring opioids to maintain pain control and quality of life are forced to seek treatment from these physicians because many others have become intimidated by the new legislation [5].

An element of the backlash against escalating opioid prescribing and associated problems has been intense lobbying by some pain professionals to impose pre-established dose ceiling on opioid prescribing, such that a maximum daily dosage cannot be exceeded. Prominent among these groups has been Physicians for Responsible Opioid Prescribing (PROP) and the advocacy group Public Citizen. The imposition of a 100-mg MED maximum daily ceiling and a maximum prescribing duration of 90 consecutive days was requested for noncancer pain. The groups cited observational study findings of a correlational relationship between prescribed opioid dose and overdose risk as evidence, but these recommendations were rejected by the FDA [160].

Despite FDA rejection of a mandate for daily dose ceilings, many practitioners believe that high-dose prescribing is irresponsible and without medical legitimacy. This view was disseminated and seemingly legitimized by the 2009 opioid prescribing guidelines published by the APS and the AAPM, which stated that no existing evidence supports daily opioid doses ≥200 mg MED [115]. The validity of these assertions has been undermined by several findings of differences between patients in the opioid dose necessary to achieve sufficient pain control, which can vary 40-fold for the same clinical condition [161]. While ultra-high-dose opioid prescribing remains controversial, a small subset of patients do require massive doses of opioids for chronic pain. Authors and guidelines statements of the contrary are based on opinion without empirical support [162].

Patients with chronic pain who require ultra-high-dose opioids, in some cases more than 2,000 mg/day MED, are likely to be labeled as addicts or abusers by healthcare professionals and family members alike. In general, these patients are profoundly ill, impaired, and/or bed- or house-bound due to severe unremitting pain refractory to analgesic efforts using lower-dose opioids. The reason some patients require ultra-high opioid doses remains unclear, but it is very likely that some, and perhaps the majority, possess a cytochrome P450 polymorphism or other genetic abnormality [163].

Patients with chronic pain who legitimately require ultra-high-dose opioids also require supplemental management considerations in addition to those applied to all patients with chronic pain prescribed opioids. Patients and their caregivers should receive education on recognizing overmedication and overdose and what to do if these occur, especially before tolerance has developed. Patients should be restricted from use of benzodiazepines, muscle relaxants, sedatives, and any other potential respiratory depressant medication. While not used in most pain medicine settings, blood levels of opioids have value when a significant discrepancy is observed between prescribed dose and apparent drug effect; serum level results can suggest metabolic variation that impacts opioid dose-response. Serum opioid level testing in these patients can also establish baseline for comparison against future tests. In the unfortunate event of patient death while receiving ultra-high-dose opioids, documenting high serum opioid level while the patient was ambulatory and functional can defend the prescriber against accusation of responsibility for the patient's overdose death when coroner findings reveal high serum opioid levels in the absence of other explanatory findings [162].

Some complications are highly probable with ultra-high-dose opioid therapy that may not occur with lower doses. Endocrine suppression is likely to occur, with testosterone suppression possible in men and some women. Sudden suppression of adrenal corticoids in an opioid-maintained patient manifests in nausea, weakness, and a drop in blood pressure. For these patients, hormone replacement is necessary if opioids remain essential for pain control. Movement and physical exercises are strongly recommended. Almost without exception, patients who require ultra-high opioid dosages have been too ill to engage in normal social or family functions and usually require resocialization counseling for guidance and motivation to resocialize and begin a new quality of life [162].

Activities by the DEA to curb prescription opioid abuse and diversion have been identified in particular as potentially excessive and inappropriate. The U.S. Congress has pressured the DEA to reduce the diversion of prescribed opioids, which the DEA initially achieved through the successful raiding and closure of many pill mills and rogue Internet pharmacies. The focus of the agency has now shifted to reducing opioid supply by targeting wholesalers and pharmacies within the legitimate supply chain. Many complaints have centered on DEA use of tactics identical to those use in combating illegal drug cartels, such as wiretaps, undercover operations, and informants. Retail and wholesale pharmacies raided by DEA tactical squads have complained of being treated as if they were armed criminal organizations [164].

The DEA has accelerated the use of audits and inspections to identify and sanction drug wholesalers, levying millions of dollars in fines for what it has claimed were violations of the law. In 2012, the DEA suspended the license of drug wholesaler Cardinal Health, Inc., prohibiting opioid analgesic sales from its central Florida center. The DEA rationale was failure to detect suspicious order volume from several of Cardinal Health's pharmacy customers. Numerous Walgreens and CVS pharmacies and distribution centers were also raided [164].

The DEA has justified their tactics on the basis of Congressional pressure to contain opioid diversion, with agency success measured by disruption and destruction of organizations and networks feeding the problem. However, John Burke, president of the nonprofit National Association of Drug Diversion Investigators (NADDI), stated that DEA behavior reflects a mindset that retail and wholesale pharmacies comprise an enemy requiring containment. Concerns have been raised over the potential of DEA activity to adversely and negatively impact legitimate medical practice. This has led several congressional members to request that the Government Accountability Office investigate the effect of DEA conduct on medication shortages for patients with pain [164].

Actions of the DEA have produced widespread fear among prescribers and retail pharmacists regarding the prescribing or dispensing of opioids. In some localities, pharmacists greatly restrict dispensing opioids by refusing to fill prescriptions paid for in cash, from customers not well known to them, or from customers from certain geographic areas. Other pharmacy chains have stopped filling opioid prescriptions from higher-volume opioid prescribers. Prescribers report feeling burdened by mandates to tighten patient monitoring by increasing UDTs, documentation, and pill counts [164].

The DEA is also tasked with the oversight and control of ingredients allocated to drug manufacturers for drug production that are deemed an abuse liability. This task is performed annually and is based on manufacturer projection of legitimate patient needs. Manufacturers of drug products with abuse liability complain of DEA failure to authorize sufficient materials for adequate customer supply, which the DEA defends as resulting from poor business decisions by the manufacturers. This has contributed to patient inability to access needed prescribed opioids [164].

Of great concern is the likelihood that persons addicted to prescription opioids will switch to heroin if their preferred opioid becomes difficult to obtain or extract from ADF opioid preparations. Some experts predicted a resurgence of heroin abuse and fatal overdose, largely driven by opioid analgesic prescribing restrictions and by replacement of some opioid preparations by ADFs [165,166,167].

Statistics seem to bear this out. In 2014, the percentage of prescription opioid abuse was lower than the percentages in most years from 2002 to 2012 (although similar to the percentage in 2013) [167]. At the same time, heroin use increased. In 2014, the estimates of both current and past heroin use were higher than the estimates for most years between 2002 and 2013 [168]. In addition, first-time past-year use nearly doubled between 2006 and 2012 [169]. Heroin use continued to increase in 2021 [170]. Past-year heroin initiation rose sharply in all regions in the United States, except the South. Unfortunately, the data do not provide estimates of patients with chronic pain resorting to heroin use when their opioid analgesic prescriptions are decreased or discontinued.

One study examined the impact of ADF OxyContin introduction on the abuse of OxyContin and other opioids. Researchers analyzed the results of surveys given to 2,566 patients entering treatment for opioid addiction between July 2009 and March 2012, before and after the 2010 introduction of ADF OxyContin [171]. During the 21-month post-ADF period, endorsement of hydrocodone or oxycodone agents other than OxyContin as the preferred opioid changed little from before ADF introduction, but endorsement of high-potency fentanyl or hydromorphone as the preferred opioid rose from 20.1% to 32.3%. Of opioids used in the past 30 days to get high, OxyContin fell from 47.4% to 30%, while heroin nearly doubled. More detailed questioning of 103 abusing patients found unanimous preference for the old OxyContin formulation, and 66% of those preferring pre-ADF OxyContin switched to another opioid, most commonly heroin. This switch appeared to be causally linked. No evidence suggested that OxyContin abusers quit using opioids as the result of ADF introduction; instead, they shifted their drug of choice to other opioids, primarily heroin. The authors concluded that ADF OxyContin successfully reduced OxyContin abuse, but also led to increased abuse of replacement opioids [171].

Analysis of data from the National Poison Data System, which covers the reporting from all U.S. poison centers, indicated that, in the period after ADF OxyContin introduction, abuse exposures decreased 36% for ADF OxyContin, increased 20% for other single-entity oxycodone, and increased 42% for heroin. Accidental opioid exposures decreased 39% for ADF OxyContin, increased 21% for heroin, and remained unchanged for other single-entity oxycodone products. The authors conclude that opioid analgesic ADFs can reduce abuse of the specific opioid product but may also lead to switching to other accessible non-ADF opioids [172].

Thus, the introduction of ADF opioids has driven a movement away from prescription opioids and to heroin and has increased the illicit price of traditional non-ADF opioids as they are phased out of the supply chain. During this abandonment by abusers and addicts of the precisely measured amount of pure drug in prescription opioids for the illicit street market of drug dealers, needles, and kitchen table chemists, public health officials and law enforcement agencies are noting increases in heroin overdoses, crime, and other public health problems [173]. These unanticipated negative consequences provide a compelling reminder that societal problems of substance abuse and addiction are complex and multifaceted. Simplistic solutions seeking only to restrict drug supply have never succeeded in reducing drug demand.

Restricted access to opioid analgesics is also negatively impacting patients attempting to access treatment for opioid addiction. The opioid analgesics methadone and buprenorphine comprise the backbone of outpatient multidisciplinary treatment of opioid addiction in the United States. A 2013 press release by the ASAM states that investigation into state Medicaid and private insurance coverage found increasing restrictions due to policy changes over coverage, daily dose, prior authorizations, and the requirement of previous failed treatment approaches. The end result of these imposed barriers to accessing opioid addiction medications is an increase in patient denial of services, which ASAM states is senseless and unethical considering the epidemic-level rates of opioid addiction and overdose deaths [174].

Several clinical practice guidelines for safe opioid prescribing explicitly endorse patient termination in the event of abnormal UDT results, aberrant drug-related behaviors, other violations of the patient-provider contract, or deterioration in the provider-patient relationship [97]. This approach is controversial, and as stated by Ballantyne, "The surest way to hurt patients (and society) is to abandon them when they deviate from the constructive relationship envisaged by the treating practitioner, only to trail from physician to physician to obtain the drug they need, or worse still, seek illicit supplies" [175].

Clinician response to aberrant behaviors should involve an assessment of seriousness, underlying cause, likelihood of recurrence, and clinical context of the aberrant behavior [115]. Occasional episodes of non-serious violations can be managed by patient education and enhanced monitoring [176]. The basis of opioid analgesic termination should be consistent with those for any other medication class, where discontinuation is prompted when opioid therapy benefits are outweighed by harms. Reasons given for termination include [177]:

Not infrequently, primary care providers do not have access to specialized addiction professionals or programs for patient referral. Although coexisting pain and addiction rank among the most challenging conditions to manage in primary care, recovery is possible. Providers should practice patience, flexibility, and consistent motivational support with the patient. When addiction specialists are lacking, clinicians should [178]:

The goals of treatment include avoiding harmful use of substances and achieving physical, psychological, and spiritual well-being. In patients with chronic pain with substance abuse disorders, there is a degree of overlap when substance abuse disorder treatment involves a biopsychosocial approach, as it ideally does. Effective approaches for substance abuse disorder include a combination of [178]:

A full evaluation, including radiographic studies and consultation with psychiatry and physical therapy, is completed. The working diagnosis for the patient's acute illness is toxic encephalopathy caused by the sedative side effects of opioid medication on the CNS. It is explained that the combination of his advancing age and diabetes likely reduced the efficiency of his kidneys in clearing the medication and its metabolites, making him more susceptible to CNS sedation. It is noted that the patient and his wife have little understanding of the rationale, proper use and safeguards, potential side effects, and limited effectiveness of opioid use for chronic pain.

In addition, the patient is diagnosed with poorly controlled chronic pain syndrome secondary to osteoarthritis and degenerative disc disease; exacerbating factors include deconditioning and reactive depression. The use of an opioid analgesic, at least for the near term, is considered appropriate, if dosed properly, monitored closely, and integrated into a comprehensive, multidisciplinary plan that includes treatment of depression and the use of adjunctive, nonpharmacologic modalities of care. In the setting of possible early diabetic nephropathy, the option of utilizing an NSAID, except for very brief periods of breakthrough pain, is not considered to be a safe option.

At discharge, and in consultation with his primary care physician, a written treatment and management plan addressing all aspects of the patient's care is presented to the patient and his wife for discussion and consent. Among the key issues addressed are:

On follow-up six weeks after discharge, the patient is noticeably improved. He reports that he feels stronger and is sleeping better. His affect is brighter, and he is getting out more. He has maintained his physical therapy and exercise routine and is compliant with his medication. Though he still has pain, it is noticeably less and he is coping better. He and his wife are encouraged by his progress, particularly in regard to his improved functional status.

Publication bias occurs when trials showing statistically significant and positive results are disproportionately published, relative to trials with negative or inconclusive findings. This type of bias is common in published pharmacological research. Pharmaceutical industry research sponsorship is associated with significantly higher rates of pro-industry conclusions, publication constraints, and propensity to ignore the publication of negative findings [202,203,204,205,206,207].

Reporting bias includes a diverse range of bias, misrepresentation, distortion, omission, exaggeration, or dismissal of data reported by the authors of a study or of data from other publications [208]. The effect, if not the intent, of reporting bias is to influence reader perception through a persuasive argument that favors the agenda, paradigm, or interest of the author, agency, or institution, or to diminish or discount a competing or opposing perspective. Reporting bias is just as widespread in pain research as it is in other areas of medicine, often appearing as concluding statements of safety or efficacy that are not supported by the actual evidence.

A medical issue or problem is considered "hot" when it becomes the focal point of publicity and intense investigation. Reports of research findings are less likely to be true in hotter areas of research. Prejudice can dominate a hot medical field to further undermine the validity of research findings. Highly prejudiced stakeholders can also create obstacles and obstruct efforts to publish information with opposing results [209].

Pressures of vested interests can lead to disappointing research outcomes being "spun" to present the findings in a more favorable light by creative use of data, statistics, and linguistics. Examples of linguistic spin include [210]:

The use of "spin"—claiming treatment benefit without any supporting evidence from the data—is common, and safety claims with spin without supporting data also occur [211,212,213].

Concerns have sometimes been raised regarding bias in the development of clinical practice guidelines, involving the reviewed research, misrepresentation of the data, or failure to assess the quality of the evidence supporting the recommendations. Inadequate or weak evidence may lead to conclusions based on value judgments, organizational preferences, or opinion. Guidance is frequently misinterpreted as mandate, when individualized treatment is the best practice [214]. Clinical practice guideline authority and influence usually comes from the sponsoring organization and status of the publishing journal. Once issued, the organization may become the promoter and defender of the guidelines, and panel members the stakeholders in the acceptance of their recommendations [115,215].

Bias can also negatively affect the validity of systematic reviews and meta-analyses that can form the basis of clinical practice guidelines. For example, several practice guidelines on long-term opioid therapy for chronic pain were published between 2008 and 2011. Although each guideline was based on analysis of essentially the same body of published research, the guideline conclusions differed markedly. The educated reader may look deeper for possible explanations for these discrepancies, including bias. Areas to explore would include the source of funding or sponsorship for development and financial and other material ties of the authors to industry, organization, or agency (e.g., slanted reporting of findings, conclusions consistent with industry of agency interests or agenda); the quality of evidence used to support a recommendation (by either endorsing or discouraging use of a drug, dose level, or therapy duration) and, in particular, weak evidence used inappropriately as definitive proof; whether the authors solely used published studies; and whether the studies used were industry funded [216].

Fallacies of evidence or argument are used in pain medicine research to support or defend a false conclusion (Table 12). Many are intended to convince the reader of a cause-effect relationship when the actual evidence is weak or absent. Considerable evidence is required to establish a true cause-effect relationship, and the evidence purported to show causation may actually reflect association instead. It is important to maintain a degree of critical thinking to avoid being persuaded into accepting a falsehood or rejecting a truth.

Cum Hoc, Ergo Propter Hoc Fallacy

A prototypical example of this type of fallacy comes from the 2011 CDC reporting of the same data in three publications related to a stated epidemic in opioid analgesic deaths and addiction and their direct relation to increasing opioid prescribing as reflected by sales data. Evidence to support this argument came from simultaneously increased trends in opioid analgesic sales, opioid analgesic overdose deaths, and addiction treatment admissions for opioid analgesics [212,213,219]. Many professionals found this persuasive evidence of a cause-effect relationship, and this conclusion was also reported by the news media and widely referenced in academic papers.

With causation inferred from correlational data, the fallacy in this reporting was that few alternate explanations for the correlations were presented. One credible explanation would have been exaggeration in the true rates of unintended overdose fatalities directly caused by opioid analgesics, a fact conceded by the CDC. Omitted entirely was discussion of the escalating population of patients with chronic pain. Sicker patients may also have been increasingly prescribed multiple medications with overdose potential for their disorders, including opioids.

Another reason that causal inference from correlational data is erroneous is that when causation is based on simultaneously occurring events, it is not possible to determine which event came first. The true direction of causation may actually be the reverse of that reported by researchers. For instance, studies finding a significant correlation between fibromyalgia and obesity in women concluded these female patients developed fibromyalgia because they were overweight. The order of events, such as whether obesity or fibromyalgia came first, was never examined, and it is just as likely the pain and disability associated with fibromyalgia promoted activity avoidance and weight gain or that medications used to treat fibromyalgia promoted weight gain or that medications used to treat fibromyalgia promoted weight gain.

False conclusions of a cause-effect relationship may also occur when data used in support of a conclusion come from small but statistically significant outcomes in a measure of effect, when broader examination of the data suggests otherwise. One example is the conclusion of a cause-effect relationship between higher methadone dose and frequency of the serious adverse cardiac event of QTc interval prolongation. The basis of this conclusion of causality was the finding of a modest yet statistically significant correlation between higher dose and adverse event [220,221]. However, the conclusion is false because correlation does not equate with causality, and a closer look at the actual data revealed that increased QT interval occurred only in the subgroup who were abusing cocaine, a drug with well-known cardiotoxic effects.

Post Hoc Fallacy

An example of post hoc fallacy in reasoning comes from a prospective, observational, open-label study in which single-dose intrathecal midazolam was used in patients with failed back surgery syndrome. The patients showed significant pain reduction and few side effects, and the researchers concluded that single-dose intrathecal midazolam was an effective supplement to standard analgesic therapy [222].

This study was criticized for using a post hoc, ergo propter hoc argument as the basis for causation in a commentary published in the same journal issue [223]. The commentary noted that just because patients improved after midazolam treatment did not mean they improved because of midazolam treatment. From an evidence-based perspective, the study evidence would also be regarded as low quality because it lacked a control group and the open-label design did not control for placebo response.