Derivatives from the opium plant have been described as analgesics and used for pain control since 3500 bc . It was not until 1806 that a pure opioid substance was isolated. This substance was called “morphine,” named after the Greek god Morpheus. Since that time the opium plant has yielded other derivatives, and synthetic analogues of morphine have been produced for medicinal use. The use of opioid medications in the United States has fluctuated because of a variety of factors, including but not limited to production, availability, governmental regulation, and physician and societal attitudes. Over the last 20 years the prescribing pattern of opioids has escalated significantly for a number of reasons. The increased trend in prescription writing has been accompanied by a concordant rise in the incidence of diversion and abuse, as well as an increase in the incidence of complications, including overdose and death. Over the past decade, evidence for a sustained benefit of opioids in alleviating chronic pain has remained weak and inadequate, although evidence of risk associated with use of the drugs has clearly escalated. This change in which evidence of the efficacy of opioids has not changed whereas risk has increased should have a significant impact on treatment decisions based on risk-benefit analysis. The goal of this chapter is to review clinically relevant aspects of selected opioids, including side effects and pharmacology, and review current consensus on rational opioid prescribing.
General Considerations of Opioid Administration
Opioid Receptors
Multiple systems are involved in the modulation of pain perception, including the endogenous opioid system. The natural endogenous opioids include the endogenous peptides—β-endorphins, enkephalins, and dynorphins. Since the discovery of opioid receptors in the central nervous system (CNS) in 1973, the body of literature describing their function and location has grown immensely. Opioid receptors have integral roles in the endogenous antinociceptive system and, accordingly, are located throughout the central and peripheral nervous systems. The best described opioid receptors are labeled mu (µ), kappa (κ), and delta (δ) and are prominently located in the CNS, particularly in the dorsal horn of the spinal cord, as well as on dorsal root ganglia and peripheral nerves. The three opioid receptors identified, µ, κ, and δ, belong to a superfamily of guanine (G) protein–coupled receptors located at presynaptic and postsynaptic sites in the CNS and peripheral tissues.
The µ-opioid receptor modulates input from mechanical, chemical, and thermal stimuli at the supraspinal level. The κ receptor is similar to the µ receptor in that it influences thermal nociception but, in addition, it also modulates chemical visceral pain. The δ receptor influences mechanical and inflammatory pain. An opioid agonist such as morphine binds with an opioid receptor to produce analgesia, as well as undesired side effects, such as respiratory depression and constipation, largely via interaction with the µ receptor. In a study using knockout mice that lacked the µ receptor, it was found that they have no response to morphine with respect to analgesia, respiratory depression, constipation, or physical dependence.
Distribution, Metabolism, and Excretion
The amount of opioid required to produce analgesia has significant interindividual variability. Factors responsible for this variability include opioid receptor individuality, as well as variations in opioid absorption and clearance. Such individual variability requires careful titration of an opioid to the desired response. The onset, duration, and intensity of analgesia depend on the delivery of drug to the target and on the length of time that the receptor is occupied. The number of receptors occupied and the length of time that the opioid activates its target receptor depend on the perfusion, plasma concentration, pH, and permeability coefficient of the drug.
The metabolic pathway for each opioid is based on the molecular variables of the specific opioid. Opioids with hydroxyl groups, such as morphine and hydromorphone, undergo hepatic metabolism via uridine diphosphate glucuronosyltransferase (UGT) enzymes. UGT adds a glucuronic acid moiety to form glucuronide metabolites (hydromorphone 3-glucuronide [H3G], morphine 6-glucuronide [M6G], and morphine 3-glucuronide [M3G]). These metabolites are then excreted through the kidneys. Patients with renal impairment are particularly prone to deleterious effects from metabolite accumulation.
The cytochrome P-450 (CYP) system contains two polymorphic isoforms that metabolize certain opioids. The first CYP isoform, responsible for the biotransformation of codeine, oxycodone, and hydrocodone, is 2D6. It is estimated that up to 10% of white individuals lack this enzyme, thus making them “poor metabolizers” of certain opioids and providing another cause for the high interindividual variability seen in patients treated with opioids. The 3A4 isoform of the CYP system is involved in the biotransformation of fentanyl and methadone to their inactive forms. Because some other drugs also interact with 3A4 isoenzymes, the metabolism of methadone and fentanyl can be problematically decelerated or accelerated. For example, macrolide antibiotics inhibit the enzyme, which decreases the clearance of methadone and fentanyl, whereas anticonvulsants such as phenytoin induce the activation of this enzyme system and increase the clearance of methadone and fentanyl. Excretion of most opioid metabolites is via the kidneys, but some of the glucuronide conjugates are excreted in bile, and methadone is excreted primarily in feces.
The study of pharmacogenomic polymorphisms is important in understanding the interindividual variability in analgesic effects. Opioid-related therapies have a multiplicity of genetic factors that influence the metabolism and clearance of specified opioids. As we look to the future, the use of regulator-approved pharmacogenomic assays may be advantageous in identifying many of these variant alleles. Understanding pharmacogenomic polymorphisms will most assuredly play a role in the everyday clinical decision making for management of acute and chronic pain. As safety and patient care benefit from detailed knowledge of specified polymorphisms, this science will most likely be incorporated into the standard of care for physicians.
Administration
Multiple routes of administration are one of the many clinically useful characteristics of opioids. Administration can range from intrathecal, intravenous, or oral to rectal, sublingual, buccal, intranasal, or transdermal. Depending on the clinical situation, one route may be more advantageous than another. For example, a patient who requires continuous opioid delivery but is unable to take medications orally may benefit from a transdermal delivery system, such as is currently available in a transdermal patch containing fentanyl. Fentanyl is also available as a rapid-onset transmucosal delivery product. Neuraxial routes of opioid delivery are widely used in perioperative and postoperative care, as well as for terminally ill patients.
The goal of effective opioid therapy for chronic pain is to provide sustained analgesia over regular intervals. This requires consideration of a number of factors, including knowledge of equianalgesic dosages between opioids and the pharmacologic properties and side effects of specific opioid agents. Pain in opioid-tolerant patients is particularly challenging because typical dosages for opioid-naïve patients do not apply and exact opioid requirements may require careful titration.
Whether fixed dosing is better than as-needed (PRN) dosing is controversial, with each method having advantages in particular situations. With fixed dosing there is consistent opioid delivery, which can theoretically reach steady-state levels. Presumably, this avoids the peak-and-trough effect that can be associated with on-demand dosing and may prevent the delays in delivery that can occur with on-demand schedules. One problem for opioid-naïve patients who receive fixed doses of opioids that have longer half-lives is that they may experience excessive side effects or toxicity because of the difficulty in predicting the exact opioid requirement and potential accumulation. For example, morphine may take less than 24 hours to reach steady-state levels, whereas methadone can take up to 1 week. When there is a need to assess a patient’s analgesia threshold, PRN dosing of an opioid with a short half-life may be used, or conservative fixed dosing of opioids that have a short half-life, supplemented by PRN “rescue” dosing, may be used.
Analgesic therapy with long-acting opioids (LAOs) offers convenient dose intervals that can attain safe, effective, steady-state levels. Several controlled-release opioids are available, including morphine (MS Contin, Oramorph SR, Kadian), oxycodone (OxyContin), fentanyl (Duragesic patch), and oxymorphone. Methadone can be used as an LAO, but it poses specific issues and concerns for clinicians distinct from those of other opioids (see later discussion). Methadone has a faster onset and longer analgesic effect than many other opioids do and may be ideal in some situations. However, these effects may also limit its use. Methadone is not specifically formulated for sustained release like other LAOs, which essentially release a short-acting opioid (SAO) throughout the drug’s passage through the gastrointestinal (GI) tract. Methadone simply has an intrinsically longer plasma half-life than other typical opioids do, such as hydromorphone (Dilaudid) and morphine, and can therefore be advantageous in patients with GI motility issues such as short gut syndrome.
Although sustained- and immediate-release opioid preparations have made the oral route a practical option, some cancer patients are unable to tolerate oral delivery. In such cases, transdermal, buccal, rectal, intravenous, or subcutaneous infusions are often a practical alternative option. With infusion, the first-pass effect is eliminated, thereby potentially offering some advantages. When compared with the oral route, there may be faster onset of analgesia with uncomplicated access. When compared with the intramuscular route, administration is often less painful and may be safer in patients with bleeding disorders or reduced muscle mass.
Adverse Effects
The most commonly encountered side effects associated with opioids include constipation, nausea, vomiting, sedation, urinary retention, pruritus, and respiratory depression. Any of these side effects can significantly limit therapy, but tolerance to them usually ensues shortly after initiation of opioids. However, constipation is a major exception because it does not resolve with the prolonged use of opioids. Particular attention should be given to older adults and patients with hepatic or renal insufficiency. Tolerance and physical dependency are also commonly associated with opioid therapy. These are pharmacologic properties related to opioids that are frequently misinterpreted as indicators of addiction. Addiction is also a potential risk associated with opioid use (see later discussion). Physicians should anticipate any or all of these adverse effects, remain vigilant throughout therapy, and monitor patients closely, particularly when initiating therapy and escalating opioid doses.
Constipation
The most common side effect of opioid administration is constipation, and unfortunately, tolerance to it does not generally develop. Constipation can cause significant discomfort, nausea, and emesis. The underlying mechanism of opioid-induced constipation is thought to be decreased gastric motility related to opioid binding to highly concentrated opioid receptors located in the antrum of the stomach and the proximal part of the small bowel. There is limited evidence that certain opioids at equianalgesic doses produce more or less constipation than others. Because the transdermal route bypasses initial exposure to the GI tract, transdermal fentanyl has been postulated to produce less constipation than orally administered opioids. However, current data are not convincing, particularly since transdermal opioids are well known to result in significant constipation that requires aggressive laxative therapy, irrespective of whether they produce less constipation than oral agents do.
When initiating any opioid, it is important to prescribe medications to concomitantly maintain regular bowel motility. Treatment of opioid-induced constipation should include an active laxative such as senna, lactulose, or bisacodyl; passive agents such as stool softeners or fiber-based bulking agents may be ineffective because they rely on triggering gastric motility, which in the case of opioids is usually inhibited. Alternatively, use of an adjunctive agent with a side effect profile that includes diarrhea, such as misoprostol, can coexist well with constipating opioids. However, misoprostol should be used with caution in females of childbearing age because it can initiate uterine contractions and miscarriage.
Methylnaltrexone, a quaternary derivative of naltrexone, contains a permanently charged tetravalent nitrogen atom and therefore cannot cross the blood-brain barrier. Methylnaltrexone is an antagonist at the µ receptor. It blocks the peripheral actions of opioids while sparing their central analgesic effects and reverses the slowing of bowel motility that can often occur with opioid-related therapy. Methylnaltrexone was approved by the U.S. Food and Drug Administration (FDA) in 2008 as an indication for opioid-induced constipation. Alvimopan, which was also approved in 2008 by the FDA, functions as a peripherally acting µ-opioid antagonist with limited ability to cross the blood-brain barrier. Alvimopan can treat constipation without affecting analgesia or precipitating withdrawal. The primary indication for this medication is in patients to avoid postoperative ileus following partial large or small bowel resection with primary anastomosis.
Nausea and Emesis
Nausea and vomiting are frequently seen in patients who take opioids, but it is usually a transient side effect that often only lasts 2 to 3 days. The underlying mechanism of nausea and vomiting appears to be related to several causative factors. One is activation of receptors in the brainstem site that produces afferent input to the medullary chemoreceptor trigger zone, which is responsible for afferent input to the emetic center of the brain. These areas are dense in neurotransmitter receptors that correspond to the antiemetic agents used clinically. A potential cause of nausea is stimulation of receptors in the vestibular apparatus. Another underappreciated cause of opioid-related nausea is constipation, which will often respond to treatments that increase motility.
In evaluating a patient who reports nausea and vomiting while taking opioids, one should determine important history-related factors involved in the genesis of nausea, such as the time of the last bowel movement, whether it worsens with movement, or whether there is a temporal relationship between opioid ingestion and the onset of nausea. The choice of antiemetic agent depends on the historical aspects surrounding the reported side effect. Patients who experience nausea when they are more ambulatory may be more likely to have vestibule-related nausea. In such cases, drugs such as meclizine, promethazine, or scopolamine may be useful in relieving this type of induced nausea. Droperidol, prochlorperazine, ondansetron, or hydroxyzine may have greater benefit for nausea that is not associated with movement, a type of nausea thought to be related to chemoreceptor trigger zone–associated activation. One should also ensure that reversible metabolic causes, intracranial pathology, or other factors such as medications are not the origin of the nausea or emesis before it is attributed solely to opioids.
Several approaches can be taken when treating opioid-induced nausea and vomiting. An antiemetic may be added, often choosing an agent that offers secondary benefits such as promotility, sedative, antipruritic, anxiolytic, or antipsychotic effects, depending on the needs of the individual patient. Another option to reduce the frequency and severity of side effects is to decrease the opioid dose to the minimum acceptable dose that will still achieve adequate analgesia. Based on the observation that tolerance to opioid-induced nausea accrues rapidly, the dose that had previously been reduced may be titrated upward slowly to increase analgesia without inducing nausea. If the nausea is protracted, one may consider changing to a different opioid. The emetogenic response to opioids is idiosyncratic, and therefore a different opioid may not produce nausea.
Pruritus
Opioid-induced pruritus occurs more frequently with opioids delivered by the intravenous or neuraxial route than with oral administration. Tolerance to pruritus usually develops fairly quickly, but in rare cases it can be more persistent. The underlying mechanism of pruritus appears to be related to release of histamine, which activates C-fiber itch receptors on C fibers that are distinct from pain-transmitting C fibers. Clinically, pruritus is often limited to the face and perineum but can become generalized and severe. Treatment includes antihistamines, but the therapeutic effect may be related more to sedation than to a direct antihistaminergic effect. In patients receiving intrathecal or intravenous morphine who have significant pruritus that is unresponsive to antihistamines, low dosages of nalbuphine, a µ-receptor antagonist and κ-receptor agonist, may effectively reduce pruritus without reversing the analgesia.
Sedation
Opioid-naïve patients or those chronically taking opioids who are undergoing dose escalation often experience sedation and drowsiness. Sedation is usually temporary as patients accommodate to the new medication or new dose, and it has been demonstrated that patients maintained on a stable dose of opioids for 7 days rarely have psychomotor impairment. The importance of this fact cannot be overemphasized because patients are increasingly being prescribed opioids for cancer- and non–cancer-related pain. Patients and others may question whether it is safe to operate a motor vehicle while taking opioids. This is a controversial issue, and strong arguments can be made on both sides. Some physicians may recommend taking no precautions, whereas others may counsel their patients to never drive while taking opioids. Emerging evidence is not completely clear on this issue, but some studies have suggested that patients managed with long-term opioid therapy may be alert enough to drive safely. However, it seems prudent to restrict driving, at least for 1 week or longer at the onset or with dose escalation of an opioid regimen.
Sedation that persists despite an adequate adjustment period to the opioid dose can become as problematic as the pain itself. In such cases, lowering the dose of opioid to the minimal acceptable analgesic level, increasing (widening) the dosing interval, or changing to another opioid that may not be as sedating may be considered. It is important to consider additional causes of sedation such as other medications (e.g., benzodiazepines, antiemetics, tricyclics, muscle relaxants), renal or hepatic dysfunction leading to accumulation, or progression of the patient’s primary disease state itself. If the sedation is thought to be secondary to accumulating levels of the drug or its metabolites, changing to a different agent that is not as dependent on renal clearance or does not have active metabolites, such as fentanyl, may reduce the sedation. In patients with continued unremitting sedation after limiting CNS depressants, attempting opioid dose reduction, and excluding all other underlying causes, psychostimulants may be useful (e.g., amphetamines, modafinil).
Respiratory Depression
One of the most serious concerns and feared complications of opioid prescribing is respiratory depression. The underlying mechanism of respiratory depression is µ-receptor–induced depression of brainstem centers that subserve respiratory drive. It has long been recognized that depressed respiratory drive may occur more rapidly in patients who have received combined intrathecal-epidural and oral or intravenous opioids. Although there is minimal evidence to support this claim, recognizing that this is a possible risk often supports an acceptable risk management–oriented approach to opioid administration. In addition, combining opioids with other sedating drugs can hasten respiratory depression. This is particularly important in view of the escalating rates of unintended overdose deaths associated with opioids, many involving multiple drugs that include additional respiratory depressants such as benzodiazepines. Clinically, the patient manifests sedation as the first sign of respiratory depression, which can pose a problem in detection during the evening hours when the patient is sleeping. Because respiratory depression can occur after the administration of epidural and intrathecal opioids and is often delayed and does not appear until approximately 12 hours after injection, the signs of sedation may be lost during sleep. Therefore, it is advisable to use alarmed pulse oximetry in patients in whom clinical suspicion is warranted.
Pain is a powerful physiologic stimulant of respiratory drive and opposes the respiratory depressant effects of opioids. In patients in whom pain relief is anticipated from a nonopioid analgesic treatment (e.g., neurolytic procedure, radiation therapy, adjuvant analgesics, surgery), a reduction in opioid dose may be required.
If a patient cannot be aroused and opioid-induced respiratory depression is suspected, the specific opioid receptor antagonist naloxone should be administered. Care must be taken when giving naloxone to patients who have been taking opioids for longer than 1 week or to older adult patients because severe withdrawal symptoms, seizures, and severe pain can be induced. Administration of naloxone has also led to congestive heart failure in susceptible patients. Naloxone is often packaged in an ampule containing 0.4 mg, which can then be diluted in 10 mL of normal saline and administered as 0.5-mL boluses (0.02 mg/0.5 mL) every 2 minutes.
Opioids and Immunologic Effects
Opioids have been suggested to play a role in the incidence of infection in heroin addicts and act as a contributing factor in the pathogenesis of human immunodeficiency virus. Of note, despite the suggestion that exogenous opioids may cause immunosuppression, endogenous opioids such as endorphins promote immunoactivation. Inhibitory effects on antibody and cellular immune responses, natural killer cell activity, cytokine expression, and phagocytic activity have all been implicated with acute and chronic opioid administration. Furthermore, it has been noted that peripheral immune cells express opioid receptors and this allows intricate communication between cells and cytokines. Opioid-induced alteration of immune function can be categorized into central and peripheral components. It has been postulated that central opioid receptors mediate peripheral immunosuppression via the hypothalamic-pituitary-adrenal axis and autonomic nervous system. Interestingly, severe chronic pain in and of itself has been suggested to be associated with a reduction in immune function.
Opioids and Hormonal Changes
The oral, intravenous, and intrathecal routes of administration of chronic opioid therapy have been well described to alter hormonal effects in both men and women. Mendelson and colleagues found that in illicit drug users, serum hormones that were altered by opioid administration subsequently returned to normal following suspension of the drug. Hormones disrupted by opioids are not relegated to testosterone (both total and free) but also include estrogen (estradiol), luteinizing hormone, gonadotropin-releasing hormone, dehydroepiandrosterone, adrenocorticotropin, corticotropin-releasing hormone, and cortisol. Opioid-related endocrinology research focuses on androgen hormones because of the well-described symptomatic side effects. Sexual dysfunction (erectile dysfunction, decreased libido), depression, and fatigue are some of the many side effects that men may experience when prescribed chronic opioid therapy. Many of the aforementioned side effects have been correlated with hypogonadism. Symptoms such as depression and sexual dysfunction are not relegated just to men; women can experience such side effects as well. Women also experience dysmenorrhea and potentially reduced bone mineral density. Testosterone levels likewise appear to be reduced in women and may have some correlation with body mass index.
Opioid-Induced Sleep Disturbances
A considerable amount of study on the effects of chronic opioid therapy on sleep is still needed. Despite the paucity of data, some research suggests that opioids increase the number of shifts in sleep-waking states and reduce total sleep time, sleep efficiency, delta sleep, and rapid eye movement (REM) sleep. In various studies it is difficult to separate the effect of opioids on sleep from those of comorbid condition (e.g., cancer, addiction or dependence, postoperative pain). Research suggests that γ-aminobutyric acid (GABAergic) signaling via inhibition of acetylcholine release in the medial pontine reticular formation is the primary focus for disruption of sleep by opioids. Morphine has been demonstrated to reduce REM sleep. The resulting disruption in sleep architecture affects the state of arousal during wakefulness.
Opioid Tolerance and Physical Dependence
There are substantial differences that distinguish tolerance, dependence, and addiction from each other. Unfortunately, these concepts are frequently misunderstood. In 2001, the American Pain Society, American Academy of Pain Medicine, and American Society of Addiction Medicine approved definitions of addiction, physical dependence, and tolerance in the hope of reducing misguided treatment of patients who require opioids for pain treatment. In a patient who is chronically administered opioids, it should be anticipated that physical dependence and tolerance will develop, but the maladaptive changes in behavior witnessed in patients with addiction (see later discussion) should not necessarily follow.
Tolerance
The term opioid tolerance is often used to describe the phenomenon that occurs when a fixed dose of an opioid results in decreasing analgesia, thus requiring higher doses of medication to achieve the same or less effect over time. The mechanisms responsible for this phenomenon are not entirely understood, but the N -methyl- d -aspartate (NMDA) receptor has been demonstrated to be involved. The clinical usefulness of NMDA receptor involvement has yet to be determined fully, but nonhuman studies have continued to promulgate the potential for using NMDA receptor antagonists in conjunction with opioids to attenuate tolerance and physical dependence. A subpopulation of dorsal horn neurons expressing NMDA receptors and treated with high-dose morphine have been shown to have enhanced NMDA receptor–mediated activity. Furthermore, µ-receptor antagonist and NMDA receptor antagonist treatment of this subpopulation has attenuated the increased activity. Another study has demonstrated that in “morphine-tolerant” rats treated with an NMDA receptor antagonist, the morphine-induced tolerance reversed. The relevance of these findings at the bedside have, to date, not been clear.
Human studies on the effect of the NMDA receptor on tolerance have been less promising. There has been great hope that NMDA receptor antagonists such as ketamine or dextromethorphan might potentiate the analgesic effect of opioids, but not much convincing evidence has emerged from replicated trials. In a double-blind controlled clinical trial comparing morphine and a combination of morphine and dextromethorphan, statistical differences in analgesia or dose were not seen between groups. Nonetheless, basic concepts continue to support the understanding that the NMDA receptor is a key component in the development of opioid-induced tolerance. In particular, ketamine continues to be a drug of major interest because of its potential to improve opioid performance through preventing tolerance and enhancing opioid-induced analgesia.
When it is suspected that a patient has become tolerant to one medication, the cause may be opioid tolerance, but it may also relate to increased pain, which requires adjustment in dosing. The need for dose escalation in a patient treated with chronic opioids should always stimulate consideration that the underlying disease may be progressing. When opioid-induced tolerance is present, opioid rotation can be performed. This is based on the clinical observation that patients often have intraindividual analgesic responses to different opioids and that improved analgesia with fewer side effects may occur when a different opioid is used. Although the full mechanism of this phenomenon is not completely understood, it is usually thought to occur because of incomplete tolerance, possibly related to differing µ-opioid and other opioid receptor affinities of one opioid versus another. When opioid rotation is performed in an opioid-tolerant as opposed to an opioid-naïve patient, equal analgesic doses may not be necessary. The patient may respond with analgesia to half the equianalgesic dose, and if not, the dose may be titrated to an adequate analgesic effect that is less than would be expected by calculation of equianalgesic conversion from standard formulas. This is a potentially useful phenomenon whereby the overall opioid requirement of the patient may be reduced, thereby achieving an opioid-sparing effect.
Physical Dependence and Withdrawal
Physical dependence is a physiologic state that occurs when a medication is abruptly stopped and a withdrawal syndrome results. It is not synonymous with addiction. This separation of physical dependence and addiction is supported by evidence of two distinct anatomic areas within the CNS that are involved in physical dependence versus addiction. Noradrenergic neurons within the locus coeruleus are implicated in the maintenance of dependence and development of withdrawal, whereas the ventral tegmental dopaminergic area and orbitofrontal glutamatergic projections to the nucleus accumbens are particularly thought to subserve addiction. It has been shown that drugs of abuse such as heroin, cocaine, nicotine, alcohol, phencyclidine, and cannabis initiate their habit-forming actions by activating a common reward pathway in the brain. There is also evidence for the involvement of noradrenergic neurons in the development of withdrawal. Not only do norepinephrine levels change in the brain following opioid dependence, but the administration of an α 2 -agonist such as clonidine or a β-antagonist such as propranolol also attenuates many of the symptoms of opioid withdrawal but does not reverse addiction.
The clinical manifestations of opioid withdrawal usually begin with irritability, anxiety, insomnia, diaphoresis, yawning, rhinorrhea, and lacrimation. If it progresses without intervention, a flu-like condition develops, with chills, myalgia, fever, abdominal cramping, nausea, diarrhea, tachycardia, and other features of a heightened adrenergic state occurring. Though uncomfortable for patients, it is self-limited and lasts approximately 3 to 7 days. Opioid withdrawal may occur in patients who abruptly discontinue opioids or who have relative discontinuation because of taking SAOs after accommodating to the longer plasma half-life of LAOs.
It is usually possible to taper patients from opioids to prevent withdrawal symptoms. Although faster tapering can be accomplished without the advent of withdrawal symptoms, if time allows, few patients will be symptomatic if the dose is decreased by 10% to 20% every 48 to 72 hours over a prolonged period (usually 2 to 3 weeks, depending on the dose). If, however, symptoms of withdrawal develop during discontinuation or taper, clonidine, 0.2 to 0.4 mg/day, may be used to decrease discomfort. Clonidine is often maintained for 4 days during taper of an SAO and for 14 days during taper of an LAO. Once opioids have been discontinued, clonidine can be tapered over a period of approximately 1 week.
Addiction
Opioids are associated with addiction at a rate that is high enough to be a significant concern; however, the exact rate of addiction as a result of therapeutic opioid use is controversial. Opioid addiction is a disorder characterized by opioid use that results in physical, psychological, or social dysfunction (or a combination of these), as well as continued use of the opioid despite the dysfunction. Neurobiologic evidence has suggested that this phenomenon may be subserved by positive reinforcement and sensitization of the dopaminergic system in the brain, which may explain the continued seeking of a substance destructive to the patient’s life. Patients who are receiving an inadequate dose of opioid medication may engage in drug-seeking behavior to obtain more pain medication for relief of pain, which can be mistaken for the drug-seeking behavior associated with addiction. Physicians are often challenged to distinguish true addiction from undertreated pain because on the surface, undertreated pain may appear similar to addiction because of features such as drug seeking and self-escalation. However, unlike addiction, with increased doses of opioids, an undertreated patient experiences pain relief and improved function. Whereas undertreated pain should resolve when the patient obtains adequate analgesia, true addictive behavior does not. Addiction exists in direct contradistinction to what is seen in a patient with undertreated pain who goes through dose escalation. With opioid addiction, the aberrant behavior not only continues despite an increase in opioid but is also usually further stimulated and promoted by increased exposure to the addicting drug. It is difficult to make a prospective diagnosis of addiction because there is no single behavior or diagnostic test that can confirm the diagnosis. The Committee on Pain of the American Society of Addiction Medicine has defined addiction in the context of pain treatment with opioids as a persistent pattern of dysfunctional opioid use. Patient behavior may be used cumulatively to support the diagnosis of addiction, but absolute conclusions cannot always be made, particularly without longitudinal information over extended periods. Many types of behavior may indicate the possibility of addiction to some degree ( Box 36.1 ).
Behavior Less Indicative of Addiction
Expresses anxiety or desperation over recurrent symptoms
Hoards medications
Takes someone else’s pain medications
Aggressively complains to the physician for more drugs
Requests a specific drug or medication
Uses more opioids than recommended
Drinks more alcohol when in pain
Expresses worry over changing to a new drug, even if it offers potentially fewer side effects
Takes (with permission) someone else’s prescription opioids
Raises the dose of opioids on one’s own
Expresses concern to the physician or family members that pain might lead to the use of street drugs
Asks for a second opinion about pain medications
Smokes cigarettes to relieve pain
Has used opioids to treat other symptoms
Behavior More Indicative of Addiction
Buys pain medications from a street dealer
Steals money to obtain drugs
Tries to get opioids from more than one source
Performs sex for drugs
Sees two physicians at once without them knowing
Performs sex for money to buy drugs
Steals drugs from others
Prostitutes others for money to obtain drugs
Prostitutes others for drugs
Forges prescriptions
Sells prescription drugs
Nonadherence to opioid therapy may be related to many possibilities, including adverse effects, forgetfulness, incompatibility with lifestyle, and confusion about the drug regimen. It may rarely be related to aberrant behavior such as diversion or drug abuse, and an astute physician will maintain a position of vigilance without feeling compelled to reach immediate conclusions. If a physician chooses to pursue pain treatment with an abusable drug in a patient at risk for addiction, collaboration with an addiction specialist or addiction psychiatrist is advised to ensure that the necessary resources to support an appropriate risk management program are available. Such resources are usually far greater than those available to the average prescriber, and without the necessary resources to ensure safety, prescribing should not begin. As always, high vigilance and tempered judgment are required.
The prevalence of addiction, abuse, or dependence in patients with chronic pain is not known exactly but is estimated to range from 3% to 19%. Treating chronic pain in a person with a history of addiction is challenging but is not an absolute contraindication. Nonetheless, responsible prescribers of opioids must ensure that the appropriate resources for safe use are in place before initiating treatment. If appropriate risk management is not available, treatment should not be started. Moreover, treatment should not be started unless it can be terminated when necessary.
Although a low percentage of the population with chronic pain appears to have an addiction problem, the remainder of the population has been shown to receive suboptimal analgesia because of prescribers’ fears of patient misuse of the opioid. A growing debate has emerged that focuses on understanding how opioids should be used in the setting of substantial rates of chronic pain while balancing the imperative for vigilant use of opioids with sufficient risk management for acceptable safety.
Selected Opioids
Although therapeutic options to provide analgesia continue to emerge, opioids remain the “ gold standard” of currently available analgesics . Despite the widespread use of opioids for the treatment of acute and chronic pain, controversy exists over whether opioids should be used for the treatment of chronic nonmalignant pain. There are proponents on each side of the controversy, and part of the fear of prescribing opioids stems from an inaccurate understanding of appropriate outcomes for prescribing opioids and the risk for abuse or side effects. Although opioids can be a useful tool to provide adequate analgesia for patients, fear of the development of addiction, dependence, or untoward side effects often precludes physicians from prescribing opioids. If it is decided to initiate opioid therapy in patients with chronic nonmalignant pain, the decision should be based on a well–thought-out rationale for treatment, with clear end points in mind.
SAOs are generally used for acute pain, whereas LAOs are prescribed for patients with chronic pain syndromes. Because SAOs have relatively brief peak serum blood levels of active analgesic metabolites, using them to treat persistent baseline chronic pain will require frequent dosing. This roller coaster effect is thought to promote nonoptimal pain-related behavior, which is why LAOs have been considered more appropriate in such cases. However, science has not clearly demonstrated such an advantage.
SAOs are often combined with other analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or aspirin, which may offer drug-sparing effects because less medication may be used. Although combination opioids may help reduce potential opioid-related side effects and toxicity, there is a potential for harm to major organs from the nonopioid components (e.g., acetaminophen, NSAIDs, aspirin). When using combination opioids, physicians must be aware of renal and liver function problems, as well as the potential harm that could occur to the GI system. Patients must be educated about the risks of taking other analgesics such as acetaminophen, NSAIDs, and aspirin in conjunction with the combination opioids. Moreover, physicians must also consider that the compounded nonopioid drug is likely to have a ceiling effect beyond which it is no longer efficacious. Because opioids induce tolerance and have no ceiling effect, the pharmacologically appropriate need for increased opioid may inadvertently push the dose of a combination drug to appropriate levels of the opioid component but to toxic levels of the nonopioid agent. Although reviewing all available opioids is beyond the scope of this chapter, we will review the most commonly used opioids for pain management. Minor opioids such as hydrocodone are discussed in Chapter 37 .
Codeine
Codeine is an alkaloid found in very low concentrations in opium; it is now derived from morphine. Codeine is frequently administered in combination with acetaminophen, butalbital, and caffeine. It has been shown to be an effective analgesic for chronic nonmalignant pain, but with limitations. It is a weak µ-opioid agonist and has a half-life of 2.5 to 3 hours. The major metabolic pathway leads to glucuronidation of codeine to codeine 6-glucuronide, with a minor metabolic pathway catalyzed by the polymorphically expressed enzyme CYP2D6 through N -demethylation of codeine to norcodeine and O -demethylation of codeine to morphine. Evidence has suggested that the analgesic effects of codeine rely on its conversion to morphine, and patients with genetic variations in the enzymes needed to make this conversion may find codeine to be less effective. The genetic polymorphism of CYP2D6 is responsible for the variable response to the medication. Patients with the genotype CYP2D6 PM (poor metabolizers) do not achieve adequate analgesia with codeine. In addition, certain medications that inhibit CYP2D6, such as quinidine, paroxetine, fluoxetine, and bupropion, can alter the phenotype of normal patients with normal genetics and thus decrease the therapeutic analgesic effect of codeine. Urinary excretory products of codeine include codeine (70%), norcodeine (10%), morphine (10%), normorphine (4%), and hydrocodone (1%). This may be important to remember when interpreting the urine toxicology screens of patients taking codeine.
Morphine
Morphine, a hydrophilic phenanthrene derivative, is the prototypical opioid against which all other opioids are compared for equianalgesic potency. Because of its hydrophilic nature, it exhibits delayed transport across the blood-brain barrier, thus delaying its onset of action. Conversely, it has a longer duration of action, 4 to 5 hours, than its plasma half-life of 2 to 3 hours. Metabolism of morphine to its two major metabolites, M6G and M3G, occurs mainly in the liver (see Table 36.1 ). Although the parent compound produces analgesia and side effects, M6G may also produce some analgesia along with some adverse effects. M6G accounts for 5% to 15% of morphine’s metabolites and is a µ- and δ-agonist, which accounts for its analgesic effects. It has been demonstrated that M6G does not exert antinociceptive effects in knockout mice lacking the µ receptor.
| Opioid | Availability (%) | Half-Life (hr) | Duration of Action (hr) | Metabolites |
|---|---|---|---|---|
| Morphine | 10-45 | 2-3 | 4-5 | M6G, M3G |
| Oxycodone (OxyContin) | 60-80 | 4.5 | 12 | Oxymorphone, noroxycodone |
| Methadone | 60-95 | 8-80 (average, 27) | 6-8 | — |
| Hydromorphone | 24 | 2.3 | 3-4 | H3G |
| Oxymorphone (Opana ER) | 10 | 9 ± 3 | 12 | O3G, 6-hydroxyoxymorphone |
M3G, which accounts for 50% of morphine’s metabolites, does not appear to possess opioid agonism but may produce effects that oppose morphine’s analgesic actions, such as allodynia, hyperalgesia, myoclonus, and seizures. Oral administration of morphine has been shown to result in higher levels of M3G and M6G than achieved with the intravenous, intramuscular, or rectal routes, which bypass hepatic metabolism. Chronic administration of morphine ultimately results in higher circulating levels of M3G and M6G metabolites than the parent compound. It has been found that patients receiving chronically high morphine doses metabolize morphine to hydromorphone and test positive for hydromorphone on urine toxicology screens. This is of critical importance in patients using morphine for chronic pain who undergo urine drug screening.
Although extrahepatic metabolism of morphine has been shown to occur in gastric and intestinal epithelia, morphine should be used with caution in patients with decreased hepatic function, such as those with cirrhosis. In addition, glucuronides have been shown to undergo deconjugation back to the parent compound by colonic flora and to be reabsorbed as morphine. Morphine metabolites are excreted by the kidneys, so caution should also be taken when prescribing morphine to patients with renal impairment because accumulation of M6G and M3G can be toxic. Currently available forms of morphine include short- and long-acting preparations. Short-acting agents may be compounded for almost any route of administration, and long-acting preparations generally use specialized sustained-release matrix technology, such as found in MS Contin, Kadian, Oramorph SR, and Avinza.
Oxycodone
Oxycodone is a semisynthetic opioid that is closely related to morphine. It has been available for analgesia since 1917, when it was introduced into clinical practice in Germany. It is processed from thebaine, an organic compound found in opium. Like morphine, currently available forms of oxycodone include short- and long-acting preparations. Short-acting oxycodone may be used alone (e.g., Roxicodone) or may be compounded with acetaminophen (e.g., Percocet, Roxicet, Endocet) or aspirin (e.g., Percodan). Long-acting oxycodone preparations are designed for oral administration and involve the use of specialized sustained-release technology (e.g., OxyContin and similar generics).
Oxycodone has high bioavailability, 60%, when compared with morphine, which has a bioavailability of 33%, thus making oxycodone almost twice as potent as morphine. Oxycodone is a prodrug that undergoes hepatic metabolism via the CYP2D6 isoenzyme, whereby it is converted into its active metabolite oxymorphone, a µ-opioid agonist, and its inactive metabolite noroxycodone. Oxymorphone is reportedly often undetectable and is 14 times more potent than the parent compound.
Similar to codeine, there is genetic polymorphism in 10% of the population, which accounts for significant variation in the metabolism of oxycodone. This variation explains why some patients require higher than usual doses of oxycodone to achieve analgesia. Another factor to be considered when prescribing oxycodone is whether other potential competitors of the CYP2D6 isoenzyme are being prescribed. Such interacting medications include neuroleptics, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs). Cases of serotonin syndrome have been described in the literature when SSRIs and oxycodone were used concomitantly.
Meperidine
The use of meperidine for analgesia has been declining recently because of its potential for neurotoxicity. It is a weaker µ-opioid agonist than morphine with 10% of its potency, more rapid onset, and a shorter duration of action. The half-life of meperidine is 3 hours, and it is hepatically demethylated to its neurotoxic metabolite normeperidine, which has a half-life of 12 to 16 hours. Normeperidine has been well documented to cause CNS hyperactivity and seizures. Excretion of normeperidine is via the kidneys; therefore, caution should be taken when administering meperidine to patients with renal impairment or those prone to CNS hyperactivity. Initially, the toxic effects may be seen as subtle changes in mood that can progress to naloxone-irreversible tremors, myoclonus, and seizures. Chronic administration of meperidine to patients with normal renal function and administration of meperidine in conjunction with SSRIs, monoamine oxidase inhibitors, tramadol, and methadone can also result in neurotoxic side effects.
Hydromorphone
Hydromorphone has strong affinity for the µ receptor. It is a hydrogenated ketone analogue of morphine and can be formed by N -demethylation of hydrocodone. Hydromorphone is similar to morphine in that it is hydrophilic and has a comparable duration of analgesia, but it differs with respect to side effects and potency. Pruritus, sedation, nausea, and vomiting occur less frequently. Furthermore, hydromorphone is five times more potent than morphine when administered orally (see Table 36.2 ) and seven times more potent when administered parenterally. Though essentially hydrophilic, it is 10 times more lipophilic than morphine. This lipophilicity may be an advantage when treating patients who are unable to take oral medications and cannot maintain intravenous access, such as is in hospice environments. It can be given subcutaneously at a dose of 10 or 20 mg/mL; this route delivers approximately 80% of the dose absorbed through intravenous delivery. The onset of analgesia occurs in 30 minutes after oral administration and 5 minutes after intravenous administration, with peak analgesic effects occurring within 8 to 20 minutes.
