Opioids. Robin Moorman Li I. OVERVIEW II. OPIOID RECEPTORS

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1 14 Opioids Robin Moorman Li I. OVERVIEW Management of pain is one of clinical medicine s greatest challenges. Pain is defined as an unpleasant sensation that can be either acute or chronic and is a consequence of complex neurochemical processes in the peripheral and central nervous systems (CNS). It is subjective, and the clinician must rely on the patient s perception and description of pain. Alleviation of pain depends on the specific type of pain, nociceptive or neuropathic pain. For example, with mild to moderate arthritic pain (nociceptive pain), nonopioid analgesics such as nonsteroidal anti-inflammatory agents (NSAIDs, see Chapter 36) are often effective. Neuropathic pain can be treated with opioids (some situations require higher doses) but responds best to anticonvulsants, tricyclic antidepressants, or serotonin/norepinephrine reuptake inhibitors. However, for severe or chronic malignant or nonmalignant pain, opioids are considered part of the treatment plan in select patients (Figure 14.1). Opioids are natural, semisynthetic, or synthetic compounds that produce morphine-like effects (Figure 14.2). These agents are divided into chemical classes based on their chemical structure (Figure 14.3). Clinically this is helpful in identifying opioids that have a greater chance of cross-sensitivity in a patient with an allergy to a particular opioid. All opioids act by binding to specific opioid receptors in the CNS to produce effects that mimic the action of endogenous peptide neurotransmitters (for example, endorphins, enkephalins, and dynorphins). Although the opioids have a broad range of effects, their primary use is to relieve intense pain, whether that pain results from surgery, injury, or chronic disease. Unfortunately, widespread availability of opioids has led to abuse of those agents with euphoric properties. Antagonists that reverse the actions of opioids are also clinically important for use in cases of overdose (Figure 14.1). II. OPIOID RECEPTORS The major effects of the opioids are mediated by three receptor families, which are commonly designated as μ (mu), κ (kappa), and δ (delta). Each receptor family exhibits a different specificity for the drug(s) it binds. The analgesic properties of the opioids are primarily mediated by the μ receptors that modulate responses to thermal, mechanical, and chemical nociception. The κ receptors in the dorsal horn also contribute to analgesia by modulating the response to chemical and thermal nociception. STRONG AGONISTS Alfentanil ALFENTA Fentanyl ABSTRAL, ACTIQ, DURAGESIC, FENTORA, LAZANDA, SUBSYS Heroin Hydrocodone LORTAB, VICODIN, VARIOUS Hydromorphone DILAUDID, EXALGO Meperidine DEMEROL Methadone DOLOPHINE Morphine AVINZA, KADIAN, MS CONTIN, ORAMORPH Oxycodone OXYCONTIN Oxymorphone OPANA Remifentanil ULTIVA Sufentanil SUFENTA MODERATE/LOW AGONISTS Codeine MIXED AGONIST ANTAGONIST AND PARTIAL AGONISTS Buprenorphine BUPRENEX, SUBUTEX Butorphanol Nalbuphine NUBAIN Pentazocine TALWIN ANTAGONISTS Naloxone NARCAN Naltrexone REVIA, VIVITROL OTHER ANALGESICS Tapentadol NUCYNTA Tramadol ULTRAM Figure 14.1 Summary of opioid analgesics and antagonists. 191

2 Opioids Natural Semisynthetic Synthetic Morphine Hydromorphone Fentanyl Codeine Hydrocodone Meperidine Oxycodone Methadone Oxymorphone Tapentadol Tramadol Figure 14.2 Summary of chemical classes of opioid agonists. Phenanthrenes Morphine Codeine Oxycodone Action on Opioid Receptors The enkephalins interact more selectively with δ receptors in the periphery. All three opioid receptors are members of the G protein coupled receptor family and inhibit adenylyl cyclase. They are also associated with ion channels, increasing postsynaptic K + efflux (hyperpolarization) or reducing presynaptic Ca 2+ influx, thus impeding neuronal firing and transmitter release (Figure 14.4). Oxymorphone Hydromorphone Hydrocodone Buprenorphine Nalbuphine Butorphanol Benzmorphan Pentazocine Phenylpiperidines Fentanyl Alfentanil Sufentanil Meperidine Diphenylheptane Methadone Partial agonist Mixed /Antagonist Mixed /Antagonist Mixed /Antagonist Figure 14.3 Origin of opioids: natural, semisynthetic, or synthetic. III. OPIOID AGONISTS Morphine [MOR-feen] is the major analgesic drug contained in crude opium and is the prototype strong μ receptor agonist. Codeine is present in crude opium in lower concentrations and is inherently less potent, making codeine the prototype of the weak opioid agonists. The currently available opioids have various differences in receptor affinity, pharmacokinetic profiles, available routes of administration, and adverse effect profiles. Comparing other available opioids to morphine is helpful in identifying the unique differences to guide the selection of a safe and effective pain management regimen (Figure 14.5). A. Morphine 1. Mechanism of action: Morphine and other opioids exert their major effects by interacting stereospecifically with opioid receptors on the membranes of certain cells in the CNS and other anatomic structures, such as the gastrointestinal (GI) tract and the urinary bladder. Morphine also acts at κ receptors in lamina I and II of the dorsal horn of the spinal cord. It decreases the release of substance P, which modulates pain perception in the spinal cord. Morphine also appears to inhibit the release of many excitatory transmitters from nerve terminals carrying nociceptive (painful) stimuli. Some therapeutic uses of morphine and other opioids are listed in Figure 14.6.

3 + III. Opioid s Actions: a. Analgesia: Morphine and other opioids cause analgesia (relief of pain without the loss of consciousness) and relieve pain both by raising the pain threshold at the spinal cord level and, more importantly, by altering the brain s perception of pain. Patients treated with opioids are still aware of the presence of pain, but the sensation is not unpleasant. The maximum analgesic efficacy for representative opioid agonists is shown in Figure b. Euphoria: Morphine produces a powerful sense of contentment and well-being. Euphoria may be caused by disinhibition of the dopamine-containing neurons of the ventral tegmental area. PRESYNAPTIC NEURON Activation of the opioid receptor decreases Ca 2+ influx in response to incoming action potential. This decreases release of excitatory neurotransmitters, such as glutamate. Opioid receptor c. Respiration: Morphine causes respiratory depression by reduction of the sensitivity of respiratory center neurons to carbon dioxide. This can occur with ordinary doses of morphine in patients who are opioid-naïve and can be accentuated as the dose is increased until ultimately respiration ceases. Respiratory depression is the most common cause of death in acute opioid overdoses. Tolerance to this effect does develop quickly with repeated dosing, which allows the safe use of morphine for the treatment of pain when the dose is correctly titrated. Synaptic vesicle Ca 2+ Ca 2+ d. Depression of cough reflex: Both morphine and codeine have antitussive properties. In general, cough suppression does not correlate closely with the analgesic and respiratory depressant properties of opioid drugs. The receptors involved in the antitussive action appear to be different from those involved in analgesia. Glutamate K + e. Miosis: The pinpoint pupil (Figure 14.8) characteristic of morphine use results from stimulation of μ and κ receptors. There is little tolerance to the effect, and all morphine abusers demonstrate pinpoint pupils. [Note: This is important diagnostically, because many other causes of coma and respiratory depression produce dilation of the pupil.] Excitatory response K + Opioid receptor f. Emesis: Morphine directly stimulates the chemoreceptor trigger zone in the area postrema that causes vomiting. g. GI tract: Morphine relieves diarrhea by decreasing the motility and increasing the tone of the intestinal circular smooth muscle. Morphine also increases the tone of the anal sphincter. Overall, morphine and other opioids produce constipation, with little tolerance developing. [Note: A nonprescription laxative combination of the stool softener docusate with the stimulant laxative senna is useful to treat opioid-induced constipation.] Morphine can also increase biliary tract pressure due to contraction of the gallbladder and constriction of the biliary sphincter. h. Cardiovascular: Morphine has no major effects on the blood pressure or heart rate at lower dosages. With large doses, hypotension and bradycardia may occur. Because of respiratory depression and carbon dioxide retention, cerebral vessels dilate and increase cerebrospinal fluid pressure. Therefore, morphine is usually contraindicated in individuals with head trauma or severe brain injury. Activation of the opioid receptor increases K + efflux and decreases the response of the postsynaptic neuron to excitatory neurotransmitters. POSTSYNAPTIC NEURON Figure 14.4 Mechanism of action of μ opioid receptor agonists in the spinal cord.

4 Opioid Morphine Methadone Fentanyl Oxycodone Oxymorphone Hydromorphone Hydrocodone Tapentadol Codeine Meperidine Buprenorphine Routes of Administration PO (IR and ER), PR, IM, IV, SC, IA, SL, EA PO, IV, IM, SC IV, EA, IA, TD, OTFC, SL, Buccal, Nasal PO (IR and CR) PO (IR and ER), IV PO (IR and ER), PR, IV, SC, EA, IA PO (IR and ER) PO (IR and ER) PO, SC PO, IV, SC, EA, IA SL, TD, IM Comments For all drugs listed: opioid class side effects (Figure 14.9). Active metabolites are renally eliminated and accumulate in renal impairment. Metabolite M3G has no analgesic action, but can be neuroexcitatory. Metabolite M6G is two to four times more potent than parent drug; accumulation can cause oversedation and respiratory depression. No active metabolites. Racemic mixture S isomer: NMDA antagonist; aids in preventing opioid tolerance and treatment of neuropathic pain. R isomer: μ agonist in treatment of nociceptive pain. Long and variable half-life increases risks of overdose. Very lipophilic and redistributes to fat stores. Duration of analgesia is much shorter than elimination half-life. Repeated dosing can lead to accumulation. Can prolong QT interval and cause torsades de pointes. Warning: Conversion to and from methadone and other opioids should be done with great care, since equianalgesic dosing varies dramatically. No active metabolites; option for patients with renal dysfunction but should be used with caution. 100 times more potent than morphine. Less histamine release, sedation, and constipation in comparison to morphine. Metabolized by CYP2D6 and CYP3A4. Black box warning: CYP3A4 drug interactions. Less histamine release and nausea in comparison to morphine. Immediate release has longer duration of action and elimination half-life (8 hours) compared to other immediate-release opioids. Oral bioavailability increases with food. Should be administered 1 to 2 hours after eating. Bioavailability increased with coadministration of alcohol. Metabolized via glucuronidation to H6G and H3G which are renally eliminated and can cause CNS side effects in patients with renal insufficiency. Active metabolite is hydromorphone. Metabolized by CYP2D6 and CYP3A4. Centrally acting analgesic; μ agonist activity along with inhibition of norepinephrine reuptake. Efficacy in treating nociceptive and neuropathic pain. Metabolized predominately by glucuronidation; no CYP450 interactions. Seizures and serotonin syndrome can occur in predisposed patients. Prodrug: Metabolized by CYP2D6 to the active drug morphine. Rapid and poor metabolizers of CYP2D6 can experience toxicity. Inhibitors of CYP2D6 will prevent conversion of codeine to morphine, thereby preventing pain control. Do not use in patients with renal dysfunction. Use only for mild or moderate pain. Not recommended as first-line opioid choice. Active metabolite normeperidine accumulates with renal dysfunction, leading to toxicity. Naloxone does not antagonize the effects of normeperidine; could worsen seizure activity. Do not use in elderly, patients with renal dysfunction, or for chronic pain management. Long duration of action; very lipophilic. Incompletely reversible by naloxone. Drug interactions: contraindicated with atazanavir, conivaptan, MAO inhibitors; also many interactions with CYP450 system, including CYP3A4. Can prolong QT interval. Avoid use in patients with hypokalemia, atrial fibrillation, or unstable heart failure, or other predisposing factors increasing QT abnormalities. Transdermal patch is applied every 7 days. CR = controlled-release; EA = epidural anesthesia; IA = intrathecal anesthesia; IM = intramuscular; IR = immediate release; IV = intravenous; OTFC = oral transmucosal fentanyl citrate; PO = orally; PR = rectally; SC = subcutaneous; SL = sublingual; TD = transdermal; M3G = morphine-3-glucuronide; M6G = morphine-6-glucuronide; NMDA = N-methyl-D-aspartate; H6G = hydromorphone-6-glucuronide; H3G = hydromorphone-3-glucuronide Note: There are many different acronyms which may be used to indicate a medication is extended-release. Examples include CR (controlled-release), LA (long-acting), ER (extended-release). Figure 14.5 Summary of clinically relevant properties for each of the μ receptor agonists.

5 III. Opioid s 195 i. Histamine release: Morphine releases histamine from mast cells causing urticaria, sweating, and vasodilation. Because it can cause bronchoconstriction, morphine should be used with caution in patients with asthma. j. Hormonal actions: Morphine increases growth hormone release and enhances prolactin secretion. It increases antidiuretic hormone and leads to urinary retention. k. Labor: Morphine may prolong the second stage of labor by transiently decreasing the strength, duration, and frequency of uterine contractions. 3. Pharmacokinetics: a. Administration: Because significant first-pass metabolism of morphine occurs in the liver, intramuscular, subcutaneous, and IV injections produce the most reliable responses. Absorption of morphine from the GI tract after oral absorption is slow and erratic. When used orally, morphine is commonly administered in an extended-release form to provide more consistent plasma levels. It is important to note that morphine has a linear pharmacokinetic profile that allows dosing to be more predictable and more flexible. b. Distribution: Morphine rapidly enters all body tissues, including the fetuses of pregnant women. It should not be used for analgesia during labor. Infants born to addicted mothers show physical dependence on opioids and exhibit withdrawal symptoms if opioids are not administered. Only a small percentage of morphine crosses the blood brain barrier, because morphine is the least lipophilic of the common opioids. In contrast, the more lipid-soluble opioids, such as fentanyl and methadone, readily penetrate into the CNS. c. Fate: Morphine is conjugated with glucuronic acid in the liver to two main metabolites. Morphine-6-glucuronide is a very potent analgesic, whereas morphine-3-glucuronide does not have analgesic activity, but is believed to cause the neuroexcitatory effects seen with high doses of morphine. The conjugates are excreted primarily in urine, with small quantities appearing in bile. The duration of action of morphine is 4 to 5 hours when administered systemically to morphine-naïve individuals, but considerably longer when injected epidurally because the low lipophilicity prevents redistribution from the epidural space. [Note: Age can influence the response to morphine. Elderly patients are more sensitive to the analgesic effects of the drug, possibly due to decreases in metabolism, lean body mass, or renal function. Lower starting doses should be considered for elderly patients. Neonates should not receive morphine because of their low conjugating capacity.] Therapeutic Use Analgesia Treatment of diarrhea Relief of cough Treatment of acute pulmonary edema Anesthesia Comments Morphine is the prototype opioid agonist. Opioids are used for pain in trauma, cancer, and other types of severe pain. Opioids decrease the motility and increase the tone of intestinal circular smooth muscle. [Note: Agents commonly used include diphenoxylate and loperamide (see Chapter 31).] Morphine does suppress the cough reflex, but codeine and dextromethorphan are more commonly used. Intravenous morphine dramatically relieves dyspnea caused by pulmonary edema associated with left ventricular failure, possibly via the vasodilatory effect. This, in effect, decreases cardiac preload and afterload, as well as anxiety experienced by the patient. Opioids are used as preanesthetic medications, for systemic and spinal anesthesia, and for postoperative analgesia. Figure 14.6 Selected clinical uses of opioids. Alfentanil Fentanyl Hydrocodone Meperidine Methadone Morphine Oxycodone Remifentanil Sufentanil Buprenorphine Nalbuphine Pentazocine Codeine Low Moderate High 4. Adverse effects: Many adverse effects are common across the entire opioid class (Figure 14.9). With most μ agonists, severe respiratory depression can occur and may result in death from acute opioid overdose. Respiratory drive may be suppressed in patients with emphysema or cor pulmonale. If opioids are used, respiration must Low Figure 14.7 A comparison of opioid agonist efficacy. High

6 Opioids be closely monitored. Elevation of intracranial pressure, particularly in head injury, can be serious. Morphine should be used with caution in patients with asthma, liver disease, or renal dysfunction. 5. Tolerance and physical dependence: Repeated use produces tolerance to the respiratory depressant, analgesic, euphoric, and sedative effects of morphine. However, tolerance usually does not develop to the pupil-constricting and constipating effects of the drug. Physical and psychological dependence can occur with morphine and with some of the other agonists. Withdrawal produces a series of autonomic, motor, and psychological responses that incapacitate the individual and cause serious symptoms, although it is rare that the effects cause death. Figure 14.8 Characteristic pinpoint pupil associated with morphine use. 6. Drug interactions: Drug interactions with morphine are rare, although the depressant actions of morphine are enhanced by phenothiazines, monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (Figure 14.10). B. Codeine Codeine [KOE-deen] is a naturally occurring opioid that is a weak analgesic compared to morphine. It should be used only for mild to moderate pain. The analgesic actions of codeine are derived from its conversion to morphine by the CYP450 2D6 enzyme system (see Chapter 1). CYP450 2D6 activity varies in patients, and ultrarapid metabolizers may experience higher levels of morphine, leading to possible overdose. Drug interactions associated with the CYP450 2D6 enzyme system may alter the efficacy of codeine or potentially lead to toxicity. Codeine is commonly used in combination with acetaminophen for management of pain. Codeine exhibits good antitussive activity at doses that do not cause analgesia. [Note: In most nonprescription cough preparations, codeine has been replaced by drugs such as dextromethorphan, a synthetic cough depressant that has relatively no analgesic action and a relatively low potential for abuse in usual antitussive doses.] C. Oxycodone and oxymorphone Oxycodone [ok-see-koe-done] is a semisynthetic derivative of morphine. It is orally active and is sometimes formulated with aspirin or acetaminophen. Its oral analgesic effect is approximately twice that of morphine. Oxycodone is metabolized via the CYP450 2D6 and 3A4 enzyme systems and excreted via the kidney. Abuse of the sustained-release preparation (ingestion of crushed tablets) has been implicated in many deaths. It is important that the higher-dosage forms of the latter preparation be used only by patients who are tolerant to opioids. Oxymorphone [ox-ee-mor-fone] is a semisynthetic opioid analgesic. When given parenterally it is approximately ten times more potent than morphine. The oral formulation has a lower relative potency and is about three times more potent than oral morphine. Oxymorphone is available in both immediate-acting and extended-release oral formulations. This agent has no clinically relevant drug drug interactions associated with the CYP450 enzyme system.

7 III. Opioid s 197 D. Hydromorphone and hydrocodone Hydromorphone [hye-droe-more-fone] and hydrocodone [hye-droe-koe-done] are orally active, semisynthetic analogs of morphine and codeine, respectively. Oral hydromorphone is approximately 8 to 10 times more potent than morphine. It is preferred over morphine in patients with renal dysfunction due to less accumulation of active metabolites. Hydrocodone is the methyl ether of hydromorphone, but is a weaker analgesic than hydromorphone, with oral analgesic efficacy comparable to that of morphine. This agent is often combined with acetaminophen or ibuprofen to treat moderate to severe pain. It is also used as an antitussive. Hydrocodone is metabolized in the liver to several metabolites, one of which is hydromorphone via the actions of CYP450 2D6. Metabolism to hydromorphone can be affected by drug drug interactions. E. Fentanyl Hypotension Dysphoria (anxiety, depression, or unease) Sedation BP Z Z Z Fentanyl [FEN-ta-nil], a synthetic opioid chemically related to meperidine, has 100-fold the analgesic potency of morphine and is used for anesthesia. The drug is highly lipophilic and has a rapid onset and short duration of action (15 to 30 minutes). It is usually administered IV, epidurally, or intrathecally. Fentanyl is combined with local anesthetics to provide epidural analgesia for labor and postoperative pain. IV fentanyl is used in anesthesia for its analgesic and sedative effects. An oral transmucosal preparation and a transdermal patch are also available. The oral transmucosal preparation is used in the treatment of cancer patients with breakthrough pain who are tolerant to opioids. The transdermal patch must be used with caution because death resulting from hypoventilation has been known to occur. Use is contraindicated in opioid-naïve patients, and patches should not be used in managing acute and postoperative pain. [Note: The transdermal patch creates a reservoir of the drug in the skin. Hence, the onset is delayed at least 12 hours, and the offset is prolonged.] Fentanyl is metabolized to inactive metabolites by the CYP450 3A4 system, and drugs that inhibit this isoenzyme can potentiate the effect of fentanyl. The drug and inactive metabolites are eliminated through the urine. Constipation Urinary retention Nausea F. Sufentanil, alfentanil, and remifentanil Sufentanil [soo-fen-ta-nil], alfentanil [al-fen-ta-nil], and remifentanil [rem-ih-fen-ta-nil] are three synthetic opioid agonists related to fentanyl. They differ in potency and metabolic disposition. Sufentanil is even more potent than fentanyl, whereas the other two are less potent and shorter acting. These agents are mainly used for their analgesic and sedative properties during surgical procedures requiring anesthesia. Potential for addiction G. Methadone Methadone [METH-a-done] is a synthetic, orally effective opioid that has variable equianalgesic potency compared to that of morphine, and the conversion between the two products is not linear. Methadone induces less euphoria and has a longer duration of action. The actions of methadone are mediated by μ receptors. In addition, methadone is an antagonist of the N-methyl-D-aspartate (NMDA) Respiratory depression Figure 14.9 Adverse effects commonly observed in individuals treated with opioids.

8 Opioids Absolute contraindication to meperidine and relative contraindication to other opioids because of high incidence of hyperpyrexic coma MAO inhibitors Tricyclic antidepressants Opioids Increased CNS depression, particularly respiratory depression Sedative hypnotics Antipsychotic drugs Increased sedation; variable effects on respiratory depression Figure Drugs interacting with opioids. CNS = central nervous system; MAO = monoamine oxidase. receptor and a norepinephrine and serotonin reuptake inhibitor. Thus, it has efficacy in the treatment of both nociceptive and neuropathic pain. Methadone is also used in the controlled withdrawal of dependent abusers from opioids and heroin. Oral methadone is administered as a substitute for the opioid of abuse, and the patient is then slowly weaned from methadone. The withdrawal syndrome with methadone is milder but more protracted (days to weeks) than that with other opioids. Unlike morphine, methadone is well absorbed after oral administration. It increases biliary pressure and is also constipating, but less so than morphine. An understanding of the pharmacokinetics of methadone is important for proper use of this medication. Methadone is readily absorbed following oral administration, is biotransformed in the liver, and is excreted almost exclusively in feces. Methadone is very lipophilic, leading to accumulation in the fat tissues. The half-life of methadone ranges from 12 to 40 hours. It may extend up to 150 hours, although the actual duration of analgesia ranges from 4 to 8 hours. Consequently, the time frame it takes for an individual patient to reach steady state can vary dramatically, from 35 hours to 2 weeks. Upon repeated dosing, methadone can accumulate due to the long terminal half-life, thereby leading to toxicity. Overdose is possible when prescribers are unaware of the long half-life of methadone, the incomplete cross-tolerance between methadone and other opioids, and the proper titration guidelines to avoid its accumulation. The metabolism is variable because it relies on multiple CYP450 isoenzymes, some of which are affected by known genetic polymorphisms and are susceptible to many drug drug interactions. Methadone can produce physical dependence like that of morphine, but has less neurotoxicity than morphine due to the lack of active metabolites. Methadone can prolong the QT interval and cause torsades de pointes, possibly by interacting with cardiac potassium channels. It should be used with caution in patients with a family or personal history of QT prolongation or those taking other medications that can prolong the QT interval. H. Meperidine Meperidine [me-per-i-deen] is a lower-potency synthetic opioid structurally unrelated to morphine. It is used for acute pain and acts primarily as a κ agonist, with some μ agonist activity also. Meperidine is very lipophilic and has anticholinergic effects, resulting in an increased incidence of delirium as compared to other opioids. The duration of action is slightly shorter than that of morphine and other opioids. Meperidine also has an active metabolite (normeperidine) that is renally excreted. Normeperidine has significant neurotoxic actions that can lead to delirium, hyperreflexia, myoclonus, and possibly seizures. Due to the short duration of action and the potential for toxicity, meperidine should only be used for short-term ( 48 hours) management of pain. Other agents are generally preferred. Meperidine should not be used in elderly patients or those with renal insufficiency, hepatic insufficiency, preexisting respiratory compromise, or concomitant or recent administration of MAOIs. Serotonin syndrome has also been reported in patients receiving both meperidine and selective serotonin reuptake inhibitors (SSRIs).

9 IV. Partial s and Mixed Antagonists 199 IV. PARTIAL AGONISTS AND MIXED AGONIST ANTAGONISTS Partial agonists bind to the opioid receptor, but have less intrinsic activity than full agonists (see Chapter 2). There is a ceiling to the pharmacologic effects of these agents. Drugs that stimulate one receptor but block another are termed mixed agonist antagonists. The effects of these drugs depend on previous exposure to opioids. In individuals who have not received opioids (naïve patients), mixed agonist antagonists show agonist activity and are used to relieve pain. In the patient with opioid dependence, the agonist antagonist drugs may show primarily blocking effects (that is, produce withdrawal symptoms). A. Buprenorphine Buprenorphine [byoo-pre-nor-feen] is classified as a partial agonist, acting at the μ receptor. It acts like morphine in naïve patients, but it can also precipitate withdrawal in users of morphine or other full opioid agonists. A major use is in opioid detoxification, because it has shorter and less severe withdrawal symptoms compared to methadone (Figure 14.11). It causes little sedation, respiratory depression, or hypotension, even at high doses. In contrast to methadone, which is available only at specialized clinics when used for detoxification or maintenance, buprenorphine is approved for officebased detoxification or maintenance. Buprenorphine is administered sublingually, parenterally, or transdermally and has a long duration of action because of its tight binding to the μ receptor. Buprenorphine tablets are indicated for the treatment of opioid dependence and are also available in a combination product containing buprenorphine and naloxone. Naloxone was added to prevent the abuse of buprenorphine via IV administration. The injectable form and the once-weekly transdermal patch are indicated for the relief of moderate to severe pain. Buprenorphine is metabolized by the liver and excreted in bile and urine. Adverse effects include respiratory depression that cannot easily be reversed by naloxone and decreased (or, rarely, increased) blood pressure, nausea, and dizziness. Severity of withdrawal Buprenorphine is used in opiate detoxification, because it has a less severe and shorter duration of withdrawal symptoms compared to methadone. Heroin Buprenorphine Methadone Days since last drug dose Symptoms last longest with methadone, but are less severe than those of heroin withdrawal. Figure Severity of opioid withdrawal symptoms after abrupt withdrawal of equivalent doses of heroin, buprenorphine, and methadone. B. Pentazocine Pentazocine [pen-taz-oh-seen] acts as an agonist on κ receptors and is a weak antagonist at μ and δ receptors. Pentazocine promotes analgesia by activating receptors in the spinal cord, and it is used to relieve moderate pain. It may be administered either orally or parenterally. Pentazocine produces less euphoria compared to morphine. In higher doses, the drug causes respiratory depression and decreases the activity of the GI tract. High doses increase blood pressure and can cause hallucinations, nightmares, dysphoria, tachycardia, and dizziness. The latter properties have led to its decreased use. Despite its antagonist action, pentazocine does not antagonize the respiratory depression of morphine, but it can precipitate a withdrawal syndrome in a morphine abuser. Tolerance and dependence develop with repeated use. Pentazocine should be used with caution in patients with angina or coronary artery disease, since it can increase systemic and pulmonary arterial pressure and, thus, increase the work of the heart.

10 Opioids C. Nalbuphine and butorphanol Nalbuphine [NAL-byoo-feen] and butorphanol [byoo-tor-fa-nole] are mixed opioid agonist antagonists. Like pentazocine, they play a limited role in the treatment of chronic pain. Butorphanol is available in a nasal formulation that has been used for severe headaches, but has also been associated with abuse. Neither agent is available for oral use. Their propensity to cause psychotomimetic effects (actions mimicking the symptoms of psychosis) is less than that of pentazocine. Nalbuphine does not affect the heart or increase blood pressure, in contrast to pentazocine and butorphanol. A benefit of all three medications is that they exhibit a ceiling effect for respiratory depression. V. OTHER ANALGESICS A. Tapentadol Tapentadol [ta-pen-ta-dol], a centrally acting analgesic, is an agonist at the μ opioid receptor and an inhibitor of norepinephrine reuptake. It has been used to manage moderate to severe pain, both chronic and acute. Tapentadol is mainly metabolized to inactive metabolites via glucuronidation, and it does not inhibit or induce the CYP450 enzyme system. Because tapentadol does not produce active metabolites, dosing adjustment is not necessary in mild to moderate renal impairment. Tapentadol should be avoided in patients who have received MAOIs within the last 14 days. It is available in an immediate-release and extended-release formulation. B. Tramadol Tramadol [TRA-ma-dole] is a centrally acting analgesic that binds to the μ opioid receptor. The drug undergoes extensive metabolism via CYP450 2D6, leading to an active metabolite with a much higher affinity for the μ receptor than the parent compound. In addition, it weakly inhibits reuptake of norepinephrine and serotonin. It is used to manage moderate to moderately severe pain. Its respiratorydepressant activity is less than that of morphine. Naloxone can only partially reverse the analgesia produced by tramadol or its active metabolite. Anaphylactoid reactions have been reported. Overdose or drug drug interactions with medications, such as SSRIs, MAOIs, and tricyclic antidepressants, can lead to toxicity manifested by CNS excitation and seizures. As with other agents that bind the μ opioid receptor, tramadol has been associated with misuse and abuse. VI. ANTAGONISTS The opioid antagonists bind with high affinity to opioid receptors, but fail to activate the receptor-mediated response. Administration of opioid antagonists produces no profound effects in normal individuals. However, in patients dependent on opioids, antagonists rapidly reverse the effect of agonists, such as morphine or any full μ agonist, and precipitate the symptoms of opioid withdrawal. Figure summarizes some of the signs and symptoms of opioid withdrawal.

11 VI. Antagonists 201 Stage I: Up to 8 hours Stage II: 8 24 hours Anxiety Drug craving Anxiety Insomnia GI disturbance Rhinorrhea Mydriasis Diaphoresis Stage III: Up to 3 days BP 98.6 Tachycardia Nausea, vomiting Hypertension Diarrhea Fever Chills Tremors Seizure Muscle spasms Figure Opiate withdrawal syndrome. GI = gastrointestinal. A. Naloxone Naloxone [nal-ox-own] is used to reverse the coma and respiratory depression of opioid overdose. It rapidly displaces all receptor-bound opioid molecules and, therefore, is able to reverse the effect of a morphine overdose. Within 30 seconds of IV injection of naloxone, the respiratory depression and coma characteristic of high doses of morphine are reversed, causing the patient to be revived and alert. Naloxone has a half-life of 30 to 81 minutes; therefore, a patient who has been treated and recovered may lapse back into respiratory depression. Naloxone is a competitive antagonist at μ, κ, and δ receptors, with a 10-fold higher affinity for μ than for κ receptors. This may explain why naloxone readily reverses respiratory depression with only minimal reversal of the analgesia that results from

12 Opioids agonist stimulation of κ receptors in the spinal cord. There is little to no clinical effect seen with oral naloxone, but, upon IV administration, opioid antagonism occurs, and the patient experiences withdrawal. This is why naloxone has been combined with oral opioids to deter IV drug abuse. B. Naltrexone Naltrexone [nal-trex-own] has actions similar to those of naloxone. It has a longer duration of action than naloxone, and a single oral dose of naltrexone blocks the effect of injected heroin for up to 24 hours. Naltrexone in combination with clonidine (and, sometimes, with buprenorphine) is used for rapid opioid detoxification. Although it may also be beneficial in treating chronic alcoholism by an unknown mechanism, benzodiazepines and clonidine are preferred. Naltrexone can lead to hepatotoxicity. Study Questions Choose the ONE best answer A young woman is brought into the emergency room. She is unconscious, and she has pupillary constriction and depressed respiration. Based on reports, an opioid overdose is almost certain. Which of the listed phenanthrene opioids will exhibit a full and immediate response to treatment with naloxone? A. Meperidine. B. Morphine. C. Buprenorphine. D. Fentanyl A 76-year-old female with renal insufficiency presents to the clinic with severe pain secondary to a compression fracture in the lumbar spine. She reports that the pain has been uncontrolled with tramadol, and it is decided to start treatment with an opioid. Which of the following is the best opioid for this patient? A. Meperidine. B. Fentanyl transdermal patch. C. Hydrocodone. D. Morphine Which of the following statements about fentanyl is correct? A. Fentanyl is 100 times more potent than morphine. B. Its withdrawal symptoms can be relieved by naloxone. C. The active metabolites of fentanyl can cause seizures. D. It is most effective by oral administration. Correct answer = B. A morphine overdose can be effectively treated with naloxone, and morphine is a phenanthrene. Naloxone antagonizes the opioid by displacing it from the receptor, but there are cases in which naloxone is not effective. Meperidine is a phenylpiperidine, not a phenanthrene, and the active metabolite, normeperidine, is not reversible by naloxone. The effects of buprenorphine are only partially reversible by naloxone. Naloxone is effective for fentanyl overdoses; however, fentanyl is a phenylpiperidine, and not a phenanthrene. Correct answer = C. Hydrocodone would be the best choice of the opioid given in this case. It will be very important to use a low dose and monitor closely for proper pain control and any side effects. Meperidine should not be used for chronic pain, nor should it be used in a patient with renal insufficiency. The transdermal patch is not a good option, since at this time, her pain would be considered acute and she is opioid naïve. Morphine also is not the best choice in this case due to the active metabolites that can accumulate in renal insufficiency. Correct answer = A. Fentanyl is very selective for the μ receptor and is a very potent opioid. Naloxone is an opioid antagonist and can precipitate withdrawal symptoms in patients currently taking opioids. Meperidine is the opioid whose active metabolite, normeperidine, can cause seizures. Fentanyl undergoes hepatic first-pass metabolism and is not effective via oral administration. Due to high lipid solubility, fentanyl has been developed for many routes of administration such as buccal, transmucosal, and transdermal.

13 Study Questions A 56-year-old patient who has suffered with severe chronic pain with radiculopathy secondary to spinal stenosis for years presents to the clinic for pain management. Over the years, this patient has failed to receive relief from the neuropathic pain from the radiculopathy with traditional agents such as tricyclics or anticonvulsants. Based on the mechanism of action, which opioid might be beneficial in this patient to treat both nociceptive and neuropathic pain? A. Meperidine. B. Oxymorphone. C. Morphine. D. Methadone Which of the following statements regarding methadone is correct? A. Methadone is an excellent choice for analgesia in most patients since there are limited drug drug interactions. B. The equianalgesic potency of methadone is similar to that of morphine. C. The duration of analgesia for methadone is much shorter than the elimination half-life. D. The active metabolites of methadone accumulate in patients with renal dysfunction Which of the following opioids is the LEAST lipophilic? A. Fentanyl. B. Methadone. C. Meperidine. D. Morphine A 64-year-old male is preparing for a total knee replacement. He is taking many medications that are metabolized by the CYP450 enzyme system and is worried about drug interactions with the pain medication that will be used following his surgery. Which of the following opioids would have the lowest chance of interacting with his medications that are metabolized by the CYP450 enzyme system? A. Methadone. B. Oxymorphone. C. Oxycodone. D. Hydrocodone Which of the following opioids is the best choice for treating pain associated with diabetic peripheral neuropathy? A. Morphine. B. Tapentadol. C. Codeine. D. Buprenorphine. Correct answer = D. Methadone has a unique mechanism of action in comparison to the other choices given. Methadone is a μ agonist, but it also exhibits NMDA receptor antagonism that is thought to aid in the treatment of neuropathic pain and could also aid in prevention of opioid tolerance. All other μ agonists could help manage neuropathic pain, but in some situations, higher doses of opioids are needed to achieve efficacy. It is much better to consider adjuvants such as tricyclics or certain anticonvulsants in the treatment of neuropathic pain. Correct Answer = C. The duration of analgesia is much shorter than the elimination half-life, leading to dangers of accumulation and increased potential for respiratory depression and death. Methadone s equianalgesic potency is extremely variable based on many factors, and it is highly recommended that only prescribers very familiar with methadone should prescribe this agent. The drug interactions associated with methadone are numerous due to the multiple enzymes in the liver that metabolize this drug. Methadone does not have active metabolites, which does make it an option in patients with renal dysfunction. Correct answer = D. Morphine is the least lipophilic of the opioids listed. Fentanyl, methadone, and meperidine are all very lipophilic opioids. Correct answer = B. Oxymorphone is metabolized via glucuronidation and has not been shown to have any drug interactions associated with the CYP enzyme family. All other opioids listed are metabolized by one or more CYP enzymes and increase the risk of drug interactions. Correct answer = B. Tapentadol has a dual mechanism of action (μ agonist and norepinephrine reuptake inhibition) that has demonstrated effectiveness in treating neuropathic pain. Morphine and buprenorphine could decrease some of the pain associated with neuropathic pain, but are not the best choices. Codeine should not be used in chronic pain management.

14 Opioids 14.9 KM is a 64-year-old male who has been hospitalized following a car accident in which he sustained a broken leg and broken arm. He has been converted to oral morphine in anticipation of his discharge. What other medication should he receive with his morphine upon discharge? A. Diphenhydramine. B. Methylphenidate. C. Docusate sodium with senna. D. Docusate sodium. Correct answer = C. A bowel regimen should be prescribed with the initiation of the opioid. Docusate and senna include both a stool softener and a stimulant, which is recommended for opioid-induced constipation. Treatment with docusate sodium only is ineffective. Constipation is very common with all opioids, and tolerance does not occur. Diphenhydramine can be used for urticaria that might occur with the initiation of an opioid, but this is not reported in this case. Methylphenidate has been used for opioid-induced sedation in certain situations, but is not an issue in this case AN is a 57-year-old male who has been treated with oxycodone for chronic nonmalignant pain for over 2 years. He is now reporting increased pain in the afternoon while at work. Which of the following opioids is a short-acting opioid and is the best choice for this patient s breakthrough pain? A. Methadone. B. Pentazocine. C. Hydrocodone. D. Nalbuphine. Correct answer = C. Hydrocodone is a commonly used short-acting agent that is commercially available in combination form with either acetaminophen or ibuprofen. Methadone should not routinely be used for breakthrough pain due to the unique pharmacokinetics and should be reserved for practitioners who have experience with this agent and understand the variables associated with this drug. Pentazocine and nalbuphine are mixed agonist/antagonist analgesics that could precipitate withdrawal in patients who are currently taking a full μ agonist such as oxycodone.