Major Opioids and Chronic Opioid Therapy

General Considerations of Opioid Administration

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 then, the opium plant has yielded other byproducts, and synthetic analogs of morphine have been produced for medicinal use. The use of opioid medications in the United States has fluctuated because of various factors, including but not limited to production, availability, governmental regulation, and physician and societal attitudes. Fluctuations have also occurred because of guidelines that have shifted their positions. Over the last 20 years, the prescription pattern of opioids has escalated significantly for several reasons. The increasing 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 several decades, evidence for a sustained benefit of opioids in alleviating chronic pain has remained weak and inadequate, either with results that are not substantially positive or negative or have poor scientific quality. However, evidence of the risk associated with the use of opioid drugs has been increasingly elucidated in the literature and from public health agencies. This change in which evidence of the efficacy of opioids has not changed, whereas risk has increased, should significantly impact treatment decisions based on a critical analysis of risks and benefits. This chapter aims to review clinically relevant aspects of selected opioids, including side effects and pharmacology, and review the current consensus on rational opioid prescription.

Opioid Receptors

Endogenous opioids, in addition to multiple other endogenous systems, are involved in the modulation of pain perception. 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 play 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 µ, κ, and δ and are prominently located in the CNS, particularly in the dorsal horn of the spinal cord, as well as in the 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 pre-synaptic and post-synaptic 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. However, it also modulates chemical visceral pain. The δ receptor influences mechanical and inflammatory pain. An opioid agonist, such as morphine, binds primarily to the µ opioid receptor to produce analgesia, as well as undesired side effects, such as respiratory depression and constipation. In a study using knockout mice that lacked the µ receptor, it was found that they did not respond to morphine with respect to analgesia, respiratory depression, constipation, or physical dependence.

Distribution, Metabolism, and Excretion

The amount of opioids required to produce analgesia has significant interindividual variability. The factors responsible for this variability include opioid receptor individuality and variations in opioid absorption and clearance. Such individual variability requires careful titration of opioids to the desired response. The onset, duration, and intensity of analgesia depend on the delivery of the drug to the target and 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 depends 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 a 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 such as hydromorphone 3-glucuronide (H3G), morphine 6-glucuronide (M6G), and morphine 3-glucuronide (M3G)). These metabolites are excreted through the kidneys. Patients with renal impairment are particularly prone to the deleterious effects of 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 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 anti-convulsants such as phenytoin induce the activation of this enzyme system and increase the clearance of methadone and fentanyl. ^, The excretion of most opioid metabolites occurs 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 [the reader is directed to Chapter 13 on pharmacogenetics]. Opioid related therapies have a multiplicity of genetic factors that influence the metabolism and clearance of specified opioids. In the future, the use of regulator-approved pharmacogenomic assays may be advantageous for identifying many of these variant alleles. Understanding pharmacogenomic polymorphisms will most likely play a role in everyday clinical decision making to manage acute and chronic pain. As for 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 among 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 the other. 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 and, more recently, the Food and Drug Administration (FDA) approved transdermal patch containing buprenorphine, which, in appropriate settings, has potential safety advantages over 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 in terminally ill patients.

The pharmacologic goal of effective opioid therapy for chronic pain is to provide sustained analgesia over regular intervals. This requires consideration of several 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 specific patient settings. 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 delays in delivery that can occur with on-demand schedules. One problem for opioid-naïve patients who receive fixed doses of opioids with 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 h to reach steady state levels, whereas methadone can take up to one 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 with a short half-life, supplemented by PRN “rescue” dosing, may be used.

Analgesic therapy with long-acting opioids (LAOs) offers convenient dose intervals to attain safe, effective, and steady state levels. Several controlled-release opioids are available, including morphine (MS Contin, Oramorph SR, Kadian), hydrocodone (Hysingla), oxycodone (OxyContin, Xtampza), fentanyl (Duragesic patch), hydromorphone (Exalgo), tapentadol (Nucynta ER), and oxymorphone. Methadone may be used as a relatively LAO (longer effect than short-acting opioids [SAO] but shorter than most LAOs), but it poses specific issues and concerns for clinicians that are distinct from those of other opioids (see later discussion). Methadone has a faster onset and longer analgesic effect than many other SAOs and may be ideal in some situations. However, other properties and adverse effects may limit their use. Methadone is not specifically formulated for a sustained release like other LAOs, which essentially release an SAO throughout the drug’s passage through the gastrointestinal (GI) tract. Methadone has an intrinsically longer plasma half-life than other typical opioids, 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 patients cannot 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, potentially offering some advantages. There may be a faster onset of analgesia with less complicated access when compared with the oral route. Compared with the intramuscular route, the 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 hypogonadism. Although respiratory depression may not be as common, its potentially devastating effects make it a heightened concern. Any of these side effects can significantly limit therapy, but the resolution of most adverse effects may occur shortly after the 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 (drug effect wears off over time or higher dosage is needed to achieve the same effect) and physical dependency (sudden discontinuation produces withdrawal effects) 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; unfortunately, tolerance to it does not generally develop. Constipation can cause significant discomfort, nausea, and emesis. One of the underlying mechanisms of opioid-induced constipation is thought to be decreased gastric motility because of opioid binding to highly concentrated μ-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 and transdermal opioids are well-known to result in significant constipation, such as that associated with oral opioids, which may require aggressive management.

When initiating any opioid, it is important to prescribe medications to maintain regular bowel motility concomitantly. Treatment of opioid-induced constipation should include an active laxative such as senna, lactulose, or bisacodyl or osmotic agents such as polyethylene glycol; 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 may be inhibited. Alternatively, the use of an adjunctive agent with a side effect profile that includes diarrhea, such as misoprostol, can coexist well with constipation. However, misoprostol should be used with caution in women of childbearing age because it can initiate uterine contractions and miscarriage. ^,

Peripheral opioid receptor antagonists have also been shown to be effective in refractory cases of opioid-induced constipation. Methylnaltrexone, a quaternary derivative of naltrexone, contains a permanently charged tetravalent nitrogen atom and cannot cross the blood-brain barrier. ^, Methylnaltrexone is an antagonist of the µ receptor. It blocks the peripheral actions of opioids while sparing their central analgesic effects and reverses the slowing of bowel motility, which often occurs with opioid related therapy. Methylnaltrexone was approved by the United States FDA in 2008 as an indication of 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, naloxegol, and naldemedine are opioid receptor antagonists that can treat constipation without, in most cases, affecting analgesia or precipitating withdrawal. The primary indication for this medication is the avoidance of postoperative ileus following partial large or small bowel resection with primary anastomosis. ^, In addition to the opioid receptor antagonists, lubiprostone is approved by the FDA for the treatment of opioid-induced constipation. However, these options are currently proprietary and costly and are usually reserved specifically for refractory opioid-induced constipation.

Nausea and Emesis

Nausea and vomiting are frequently seen in patients who are treated with opioids, but it is usually a transient side effect that often lasts only two to three days. The underlying mechanisms of nausea and vomiting appear to be related to several causative factors. One is the activation of receptors in the brainstem, which 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, which correspond to the antiemetic agents used clinically. A potential cause of nausea is the stimulation of receptors in the vestibular apparatus. ^, Another underappreciated cause of opioid related nausea is constipation, which often responds 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 of the reported side effects. Patients who experience nausea when they are more ambulatory may be more likely to experience 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. ^, However, cardiac adverse effects may be reflected on the electrocardiogram in QTc elongation. One should also ensure that reversible metabolic causes, intracranial pathology, or other factors such as medications are not the origin of nausea or emesis before it is attributed solely to opioids.

Several approaches can be used to treat 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 nausea is protracted, one may consider changing to a different opioid. The emetogenic response to opioids is idiosyncratic. Therefore a different opioid may not produce nausea.

Pruritus

Opioid-induced pruritus occurs more frequently with opioids delivered via the intravenous or neuraxial route than with oral administration. Tolerance to pruritus usually develops reasonably quickly, but in rare cases, it can be more persistent. The underlying mechanism of pruritus appears to be related to the 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 a direct antihistaminergic effect. In patients receiving intrathecal or intravenous morphine with 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 a new medication or dose, and it has been demonstrated that patients maintained on a stable dose of opioids for seven days rarely have psychomotor impairment. The importance of this fact cannot be overemphasized because the opioid prescription for patients with cancer- and non-cancer-related pain remains substantial, if not decreasing, since the recognition of the opioid crisis. 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 one week or longer at the onset or with dose escalation of an opioid regimen.

Despite an adequate adjustment period to the opioid dose, sedation that persists can become as problematic as the pain itself. In such cases, lowering the dose of opioid to the minimally acceptable analgesic level, increasing (widening) the dosing interval, or changing to another opioid that may not be as sedating may be considered. 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).

Recent attention has raised the importance of considering sedation associated with other medication-related causes (e.g. benzodiazepines, antiemetics, tricyclics, and anti-convulsants such as gabapentin and pregabalin), renal or hepatic dysfunction leading to accumulation or progression of the patient’s primary disease state itself. Gabapentinoids are commonly prescribed for pain, and there are rising concerns that drugs such as gabapentin are abusable and, in conjunction with co-prescribed opioids, may increase the risk of respiratory depression. A 2017 study by Gomes et al. found that concomitant use of gabapentin and opioids was associated with a substantially increased risk of opioid related death. Perioperative use of gabapentinoids may increase the risk of opioid overdose and other opioid related adverse events. There are also increasing concerns that, although gabapentin does not appear to have great addiction potential, it is abused and has illicit use street value. An FDA advisory from 2019 [ https://www.fda.gov/news-events/fda-brief/fda-brief-fda-requires-new-warnings-gabapentinoids-about-risk-respiratory-depression ] stated “Reports of gabapentinoid abuse alone, and with opioids, have emerged, and there are serious consequences of this co-use, including respiratory depression and increased risk of opioid overdose death.” In light of this, the FDA has required updated labeling for gabapentinoids to warn against potential respiratory depression. According to the federal government, some states have scheduled gabapentin as a potential drug of abuse, and pregabalin is schedule 4.

Respiratory Depression

Respiratory depression is one of the most serious concerns and feared complications of opioid prescription. The underlying mechanism of respiratory depression is µ-receptor induced depression of brainstem centers that subserve respiratory drive. It has long been recognized to 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 because 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 h 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 the respiratory drive and opposes the respiratory depressant effects of opioids. In patients in whom pain relief is anticipated from a non-opioid 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 administering naloxone to patients who have been taking opioids for longer than one week or older adult patients because severe withdrawal symptoms, seizures, and severe pain can be induced. The administration of naloxone has also led to congestive heart failure in susceptible patients. Naloxone is often packaged in an ampule containing 0.4 mg for intravenous administration, 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 min.

Opioids and Immunologic Effects

Opioids have been suggested to play a role in the incidence of infection in heroin users and contribute to 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 in acute and chronic opioid administration. ^, Furthermore, it has been noted that peripheral immune cells express opioid receptors, which 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 has been suggested to be associated with a reduction in immune function. ^, ^,

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