#95142: Optimizing Opioid Safety and Efficacy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(https://painphysicianjournal.com/current/pdf?article=NDIwMg%3D%3D&journal=103 Last Accessed: May 22, 2023)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Inactive/Absent Activity (Poor Metabolizers)

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

Underactive Activity

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

Full Activity

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

Overactive Activity

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

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

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

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

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

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

Codeine

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

Tramadol

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

Oxycodone

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

Hydrocodone

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

Methadone

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

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

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

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

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

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

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

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

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

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

Contraindications to ER/LA Opioid Formulations

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Tolerance

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

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

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

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

Opioid-Induced Hyperalgesia

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

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

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

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

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

Oral Opioids and GI Malabsorption

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

Endocrinopathy

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

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

Patient Nonadherence

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

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