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Pharmacology_Katzung. class of channels. Certain centipede toxins appear to selectively inhibit Nav 1.7 channels and may also be useful in the treatment of chronic pain. Genetic polymorphisms of Nav 1.7 are associated with either absence or predisposition to pain, and there may be a direct link between expressed levels of Nav 1.7 and enkephalin in sensory ganglia. Because of the importance of their peripheral sites of action, therapeutic strategies that deliver agents that block peripheral pain transduction or transmission have been introduced in the form of transdermal patches and balms. In addition, products that systemically target peripheral TRPV1, TRPA1, and sodium channel function are in development. Ziconotide, a blocker of voltage-gated N-type calcium channels, is approved for intrathecal analgesia in patients with refractory chronic pain. Ziconotide is a synthetic peptide related to the marine snail toxin Ω-conotoxin, which selec-tively blocks N-type calcium channels. Gabapentin/pregabalin,


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Pharmacology_Katzung. in patients with refractory chronic pain. Ziconotide is a synthetic peptide related to the marine snail toxin Ω-conotoxin, which selec-tively blocks N-type calcium channels. Gabapentin/pregabalin, anticonvulsant analogs of GABA (see Chapter 24) that are effective treatments for neuropathic (nerve injury) pain act at the α2δ1 subunit of voltage-gated calcium channels. N-methyl-D-aspartate (NMDA) receptors appear to play a very important role in central sensitization at both spinal and supraspinal levels. Although certain NMDA antagonists have demonstrated analgesic activity (eg, ketamine), it has been difficult to find agents with an acceptably low profile of adverse effects or neurotoxicity. However, ketamine infused at very small doses improves analgesia and can reduce opioid requirements under conditions of opioid tolerance, eg, after major abdominal and spinal surgery. GABA and acetylcholine (through nicotinic receptors) appear to control the central synaptic release of several


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Pharmacology_Katzung. under conditions of opioid tolerance, eg, after major abdominal and spinal surgery. GABA and acetylcholine (through nicotinic receptors) appear to control the central synaptic release of several transmitters involved in nociception. Nicotine itself and certain nicotine analogs cause analgesia, and their use for postoperative analgesia is under investigation. Use of antibod-ies that bind nerve growth factor (NGF) has been shown to block inflammatory and back pain and is awaiting US Food and Drug Administration (FDA) approval. Finally, work on cannabinoids and vanilloids and their receptors suggest that Δ9-tetrahydrocannabinol, which acts primarily on CB1 canna-binoid receptors, can synergize with μ-receptor analgesics and interact with the TRPV1 capsaicin receptor to produce analgesia under certain circumstances. As our understanding of peripheral and central pain transduction improves, additional therapeutic targets and strategies will become available. Combined with our present


Pharmacology_Katzung

Pharmacology_Katzung. under certain circumstances. As our understanding of peripheral and central pain transduction improves, additional therapeutic targets and strategies will become available. Combined with our present knowledge of opioid analgesics, a “multimodal” approach to pain therapy is emerging. Multimodal analgesia involves the administration of multiple agents (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], gabapentinoids, selective nor-epinephrine receptor inhibitors, etc) with complementary mechanisms of action to provide analgesia that is superior to that provided by an individual compound. Another benefit of multimodal analgesia is reduced opioid requirements with fewer adverse effects.


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Pharmacology_Katzung. 1. Central nervous system effects—The principal effects of opioid analgesics with affinity for μ receptors are on the CNS; the more important ones include analgesia, euphoria, sedation, and respiratory depression. With repeated use, a high degree of tolerance occurs to all of these effects (Table 31–3). a. Analgesia—Pain consists of both sensory and affective (emotional) components. Opioid analgesics are unique in that they can reduce both aspects of the pain experience. In contrast, nonsteroidal anti-inflammatory analgesic drugs, eg, ibuprofen, have no significant effect on the emotional aspects of pain. b. Euphoria—Typically, patients or intravenous drug users who receive intravenous morphine experience a pleasant floating sensation with lessened anxiety and distress. However, dysphoria, an unpleasant state characterized by restlessness and malaise, may also occur. c.


Pharmacology_Katzung

Pharmacology_Katzung. c. Sedation—Drowsiness and clouding of mentation are common effects of opioids. There is little or no amnesia. Sleep is induced by opioids more frequently in the elderly than in young, TABLE 31–3 Degrees of tolerance that may develop to some of the effects of the opioids.


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Pharmacology_Katzung. TABLE 31–3 Degrees of tolerance that may develop to some of the effects of the opioids. healthy individuals. Ordinarily, the patient can be easily aroused from this sleep. However, the combination of morphine with other central depressant drugs such as the sedative-hypnotics may result in very deep sleep. Marked sedation occurs more frequently with compounds closely related to the phenanthrene derivatives and less frequently with the synthetic agents such as meperidine and fentanyl. In standard analgesic doses, morphine (a phenanthrene) disrupts normal rapid eye movement (REM) and non-REM sleep patterns. This disrupting effect is probably characteristic of all opioids. In contrast to humans, a number of other species (cats, horses, cows, pigs) may manifest excitation rather than sedation when given opioids. These paradoxical effects are at least partially dose-dependent. d.


Pharmacology_Katzung

Pharmacology_Katzung. Respiratory depression—All of the opioid analgesics can produce significant respiratory depression by inhibiting brainstem respiratory mechanisms. Alveolar Pco2 may increase, but the most reliable indicator of this depression is a depressed response to a carbon dioxide challenge. The respiratory depression is dose-related and is influenced significantly by the degree of sensory input occurring at the time. For example, it is possible to partially overcome opioid-induced respiratory depression by a variety of stimuli. When strongly painful stimuli that have prevented the depressant action of a large dose of an opioid are relieved, respiratory depression may suddenly become marked. A small to moderate decrease in respiratory function, as measured by Paco2 elevation, may be well tolerated in the patient without prior respiratory impairment. However, in individuals with increased intra-cranial pressure, asthma, chronic obstructive pulmonary disease, or cor pulmonale, this decrease in


Pharmacology_Katzung

Pharmacology_Katzung. in the patient without prior respiratory impairment. However, in individuals with increased intra-cranial pressure, asthma, chronic obstructive pulmonary disease, or cor pulmonale, this decrease in respiratory function may not be tolerated. Opioid-induced respiratory depression remains one of the most difficult clinical challenges in the treatment of severe pain. Ongoing research to overcome this problem is focused on μ-receptor pharmacology and serotonin signaling pathways in the brainstem respiratory control centers.


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Pharmacology_Katzung. e. Cough suppression—Suppression of the cough reflex is a well-recognized action of opioids. Codeine in particular has been used to advantage in persons suffering from pathologic cough. However, cough suppression by opioids may allow accumulation of secretions and thus lead to airway obstruction and atelectasis. f. Miosis—Constriction of the pupils is seen with virtually all opioid agonists. Miosis is a pharmacologic action to which little or no tolerance develops, even in highly tolerant addicts (Table 31–3); thus, it is valuable in the diagnosis of opioid overdose. This action, which can be blocked by opioid antagonists, is mediated by parasympathetic pathways, which, in turn, can be blocked by atropine. g.


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Pharmacology_Katzung. g. Truncal rigidity—Several opioids can intensify tone in the large trunk muscles. It was originally believed that truncal rigidity involved a spinal cord action of these drugs, but a supraspinal action is likely. Truncal rigidity reduces thoracic compliance and thus interferes with ventilation. The effect is most apparent when high doses of the highly lipid-soluble opioids (eg, fentanyl, sufentanil, alfentanil, remifentanil) are rapidly administered intravenously. Truncal rigidity may be overcome by administration of an opioid antagonist, which of course will also antagonize the analgesic action of the opioid. Preventing truncal rigidity while preserving analgesia requires the concomitant use of neuromuscular blocking agents. h. Nausea and vomiting—The opioid analgesics can activate the brainstem chemoreceptor trigger zone to produce nausea and vomiting. As ambulation seems to increase the incidence of nausea and vomiting there may also be a vestibular component in this effect.


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Pharmacology_Katzung. i. Temperature—Homeostatic regulation of body temperature is mediated in part by the action of endogenous opioid peptides in the brain. For example, administration of μ-opioid receptor agonists, such as morphine to the anterior hypothalamus produces hyperthermia, whereas administration of κ agonists induces hypothermia. j. Sleep architecture—Although the mechanism by which opioids interact with circadian rhythm is unclear, they can decrease the percentage of stage 3 and 4 sleep, which may result in fatigue and other sleep disorders, including sleep-disordered breathing and central sleep apnea.


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Pharmacology_Katzung. 2. Peripheral effects a. Cardiovascular system—Most opioids have no significant direct effects on the heart and, other than bradycardia, no major effects on cardiac rhythm. Meperidine is an exception to this generalization because its antimuscarinic action can result in tachycardia. Blood pressure is usually well maintained in subjects receiving opioids unless the cardiovascular system is stressed, in which case hypotension may occur. This hypotensive effect is probably due to peripheral arterial and venous dilation, which has been attributed to a number of mechanisms including central depression of vasomotor-stabilizing mechanisms and release of histamine. No consistent effect on cardiac output is seen, and the electrocardiogram is not significantly affected. However, caution should be exercised in patients with decreased blood volume, because the above mechanisms make these patients susceptible to hypotension. Opioid analgesics affect cerebral circulation minimally except when Pco2


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Pharmacology_Katzung. in patients with decreased blood volume, because the above mechanisms make these patients susceptible to hypotension. Opioid analgesics affect cerebral circulation minimally except when Pco2 rises as a consequence of respiratory depression. Increased Pco2 leads to cerebral vasodilation associated with a decrease in cerebral vascular resistance, an increase in cerebral blood flow, and an increase in intracranial pressure.


Pharmacology_Katzung

b.

Pharmacology_Katzung. b.


Pharmacology_Katzung

Pharmacology_Katzung. Gastrointestinal tract—Constipation has long been recognized as an effect of opioids, an effect that does not diminish with continued use. That is, tolerance does not develop to opioid-induced constipation (Table 31–3). Opioid receptors exist in high density in the gastrointestinal tract, and the constipating effects of the opioids are mediated through an action on the enteric nervous system (see Chapter 6) as well as the CNS. In the stomach, motility (rhythmic contraction and relaxation) may decrease but tone (persistent contraction) may increase—particularly in the central portion; gastric secretion of hydrochloric acid is decreased. Small intestine resting tone is increased, with periodic spasms, but the amplitude of nonpropulsive contractions is markedly decreased. In the large intestine, propulsive peristaltic waves are diminished and tone is increased; this delays passage of the fecal mass and allows increased absorption of water, which leads to constipation. The large bowel


Pharmacology_Katzung

Pharmacology_Katzung. propulsive peristaltic waves are diminished and tone is increased; this delays passage of the fecal mass and allows increased absorption of water, which leads to constipation. The large bowel actions are the basis for the use of opioids in the management of diarrhea, and constipation is a major problem in the use of opioids for control of severe cancer pain. As described later, a new generation of agents designed to block or reverse opioid-induced constipation has been introduced.


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Pharmacology_Katzung. c. Biliary tract—The opioids contract biliary smooth muscle, which can result in biliary colic. The sphincter of Oddi may constrict, resulting in reflux of biliary and pancreatic secretions and elevated plasma amylase and lipase levels. d. Renal—Renal function is depressed by opioids. It is believed that in humans this is chiefly due to decreased renal plasma flow. In addition, μ opioids have an antidiuretic effect in humans. Mechanisms may involve both the CNS and peripheral sites. Opioids also enhance renal tubular sodium reabsorption. The role of opioid-induced changes in antidiuretic hormone (ADH) release is controversial. Ureteral and bladder tone are increased by therapeutic doses of the opioid analgesics. Increased sphincter tone may precipitate urinary retention, especially in postoperative patients. Occasionally, ureteral colic caused by a renal calculus is made worse by opioid-induced increase in ureteral tone. e.


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Pharmacology_Katzung. e. Uterus—The opioid analgesics may prolong labor. Although the mechanism for this action is unclear, both μand κ-opioid receptors are expressed in human uterine muscle. Fentanyl and meperidine (pethidine) inhibit uterine contractility but only at supraclinical concentrations; morphine had no reported effects. In contrast, the κ agonist [3H]-D-ala2,L-met5enkephalinamide (DAMEA) inhibits contractility in human uterine muscle strips. f. Endocrine—Opioids stimulate the release of ADH, prolactin, and somatotropin but inhibit the release of luteinizing hormone (Table 31–1). These effects suggest that endogenous opioid peptides, through effects in the hypothalamus, modulate these systems. Patients receiving chronic opioid therapy can have low testosterone resulting in decreased libido, energy, and mood. Women can experience dysmenorrhea or amenorrhea. g.


Pharmacology_Katzung

Pharmacology_Katzung. g. Pruritus—The opiates, such as morphine and codeine, produce flushing and warming of the skin accompanied sometimes by sweating, urticaria, and itching. Although peripheral histamine release is an important contributor, all opioids can cause pruritus via a central (spinal cord and medullary) action on pruritoceptive neural circuits. When opioids are administered to the neuraxis by the spinal or epidural route, their usefulness may be limited by intense pruritus over the lips and torso. The incidence of opioid-induced pruritus via the neuraxial route is high, estimated at 70–100%. However, the κ agonist/partial μ antagonist nalbuphine and the selective κ agonist nalfurafine have been proven effective and have been approved for the management of itch in some countries. h.


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Pharmacology_Katzung. h. Immune—The opioids modulate the immune system by effects on lymphocyte proliferation, antibody production, angioneogenesis, and chemotaxis. In addition, leukocytes migrate to the site of tissue injury and release opioid peptides, which in turn help counter inflammatory pain. However, natural killer cell cytolytic activity and lymphocyte proliferative responses to mitogens are usually inhibited by opioids, which may play a role in tumor progression. Although the mechanisms involved are complex, activation of central opioid receptors could mediate a significant component of the changes observed in peripheral immune function. These effects are mediated by the sympathetic nervous system in the case of acute administration and by the hypothalamic-pituitary-adrenal system in the case of prolonged administration of opioids.


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Pharmacology_Katzung. Successful management of pain is a challenging task that begins with assessment of and an attempt to understand the source and magnitude of the pain. Pain is an unpleasant sensory and emotional experience with many layers of complexity.


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Pharmacology_Katzung. The amount of pain experienced by the patient is often measured by means of a pain numeric rating scale (NRS) or less frequently by marking a line on a 100-mm visual analog scale (VAS, which is more commonly used in research), as well as the verbal rating scale (VRS) with word descriptors ranging from no pain to excruciating pain. In each case, values indicate the magnitude of pain as mild (1–3), moderate (4–6), or severe (7–10). A similar scale can be used with children (Face, Legs, Activity, Cry, Consolability [FLACC] or Wong-Baker scales) and with patients who cannot speak; the Wong-Baker scale depicts five faces ranging from smiling (no pain) to crying (maximum pain). The Brief Pain Inventory is a series of questions regarding the severity of pain. Functional scales include the Oswestry Disability Index or the World Health Organization Disability Assessment Scale 2.0. There are specialized scales for patients with specific conditions including rheumatoid arthritis and dementia.


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Pharmacology_Katzung. Disability Index or the World Health Organization Disability Assessment Scale 2.0. There are specialized scales for patients with specific conditions including rheumatoid arthritis and dementia. More comprehensive questionnaires such as the McGill Pain Questionnaire address the multiple facets of pain including both the affective and sensory experience.


Pharmacology_Katzung

Pharmacology_Katzung. For a patient in severe pain, administration of an opioid analgesic is usually considered a primary part of the overall management plan. Determining the route of administration (oral, parenteral, neuraxial), duration of drug action, ceiling effect (maximal intrinsic activity), duration of therapy, potential for adverse effects, and the patient’s past experience with opioids, including their genetics, social history, and family history, all should be addressed. One of the principal errors made by physicians in this setting is failure to match the severity of a patient’s pain to his or her analgesic. Just as important is the principle that following delivery of the therapeutic plan, its effectiveness must be monitored and reevaluated and the plan modified if necessary.


Pharmacology_Katzung

Pharmacology_Katzung. Use of opioid drugs in acute situations should be contrasted with their use in chronic pain management, in which a multitude of other factors must be considered, including the development of tolerance, dependence, and the rarer cases of diversion or misuse. Clinical Use of Opioid Analgesics A. Analgesia Severe, constant pain is usually relieved with opioid analgesics having high intrinsic activity (see Table 31–2), whereas sharp, intermittent pain does not appear to be as effectively controlled.


Pharmacology_Katzung

Pharmacology_Katzung. The pain associated with cancer and other terminal illnesses must be treated aggressively and often requires a multidisciplinary approach for effective management. Such conditions may require continuous use of potent opioid analgesics and are associated with some degree of tolerance and dependence. However, this should not be used as a barrier to providing patients with the best possible care and quality of life. The World Health Organization Ladder (see http:// www.who.int/cancer/palliative/painladder/en/) was created in 1986 to promote awareness of the optimal treatment of pain for individuals with cancer and has helped improve pain care for cancer patients worldwide. Research in the hospice setting has also demonstrated that fixed-interval administration of opioid medication (ie, a regular dose at a scheduled time) is more effective in achieving pain relief than dosing on demand. New dosage forms of opioids that allow slower release of the drug are now available, eg,


Pharmacology_Katzung

Pharmacology_Katzung. (ie, a regular dose at a scheduled time) is more effective in achieving pain relief than dosing on demand. New dosage forms of opioids that allow slower release of the drug are now available, eg, sustained-release forms of morphine (MS Contin) and oxycodone (OxyContin). Their purported advantage is a longer and more stable level of analgesia. However, there is little evidence to support long-term (greater than 6 months) use of sustained-release opioids to manage chronic pain in the noncancer patient. Furthermore, attempts to control chronic pain with opioids alone may lead to excessive use and dependence (see Box: Educating Opioid Prescribers).


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Pharmacology_Katzung. If disturbances of gastrointestinal function prevent the use of oral sustained-release morphine, then a fentanyl transdermal system (fentanyl patch) can be used over long periods. Furthermore, buccal transmucosal fentanyl can be used for short episodes of breakthrough pain (see Alternative Routes of Administration). Administration of strong opioids by nasal insufflation is also efficacious, and nasal preparations are now available in some countries. Approval of such formulations in the USA is growing. In addition, stimulant drugs such as the amphetamines can enhance the analgesic actions of opioids and thus may be very useful adjuncts in the patient with chronic pain.


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Pharmacology_Katzung. Opioid analgesics are often used during obstetric labor. Because opioids cross the placental barrier and reach the fetus, care must be taken to minimize neonatal depression. If it occurs, immediate injection of the antagonist naloxone will reverse the depression. The phenylpiperidine drugs (eg, meperidine) appear to produce less depression, particularly respiratory depression, in newborn infants than does morphine; this may justify their use in obstetric practice. The acute, severe pain of renal and biliary colic often requires a strong agonist opioid for adequate relief. However, the drug-induced increase in smooth muscle tone may cause a paradoxical increase in pain secondary to increased spasm. An increase in the dose of opioid is usually successful in providing adequate analgesia. B. Acute Pulmonary Edema


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Pharmacology_Katzung. B. Acute Pulmonary Edema The relief produced by intravenous morphine in patients with dyspnea from pulmonary edema associated with left ventricular heart failure is remarkable. Proposed mechanisms include reduced anxiety (perception of shortness of breath) and reduced cardiac preload (reduced venous tone) and afterload (decreased peripheral resistance). However, if respiratory depression is a problem, furosemide may be preferred for the treatment of pulmonary edema. On the other hand, morphine can be particularly useful when treating painful myocardial ischemia with pulmonary edema. C. Cough Suppression of cough can be obtained at doses lower than those needed for analgesia. However, in recent years, the use of opioid analgesics to allay cough has diminished largely because of the availability of a number of effective synthetic compounds that are neither analgesic nor addictive. These agents are discussed below. D. Diarrhea


Pharmacology_Katzung

Pharmacology_Katzung. D. Diarrhea Diarrhea from almost any cause can be controlled with the opioid analgesics, but if diarrhea is associated with infection such use must not substitute for appropriate chemotherapy. Crude opium preparations (eg, paregoric) were used in the past to control diarrhea, but now synthetic surrogates with more selective gastrointestinal effects and few or no CNS effects, eg, diphenoxylate or loperamide, are used. Several preparations are available specifically for this purpose (see Chapter 62). E. Shivering Although all opioid agonists have some propensity to reduce shivering, meperidine is reported to have the most pronounced anti-shivering properties. Meperidine apparently blocks shivering mainly through an action on subtypes of the α2 adrenoceptor. F. Applications in Anesthesia


Pharmacology_Katzung

Pharmacology_Katzung. F. Applications in Anesthesia The opioids are frequently used as premedicant drugs before anesthesia and surgery because of their sedative, anxiolytic, and analgesic properties. They are also used intraoperatively as a part of induction, maintenance, and preparation for postoperative analgesia. Opioids are most commonly used in cardiovascular surgery and other types of high-risk surgery in which a primary goal is to minimize cardiovascular depression. In such situations, mechanical respiratory assistance must be provided.


Pharmacology_Katzung

Pharmacology_Katzung. Because of their direct action on the neurons of the superficial dorsal horn of the spine, opioids can also be used as regional analgesics, by administration into the epidural or subarachnoid spaces of the spinal column. A number of studies have demonstrated that long-lasting analgesia with minimal adverse effects can be achieved by epidural administration of 3–5 mg of morphine, followed by slow infusion through a catheter placed in the epidural space. It was initially assumed that the epidural application of opioids might selectively produce analgesia without impairment of motor, autonomic, or sensory functions other than pain. However, respiratory depression can occur after the drug is injected into the epidural space and may require reversal with naloxone. Effects such as pruritus and nausea and vomiting are common after epidural and subarachnoid administration of opioids and may also be reversed with naloxone. The use of intrathecal and epidural opioid is common practice for


Pharmacology_Katzung

Pharmacology_Katzung. and nausea and vomiting are common after epidural and subarachnoid administration of opioids and may also be reversed with naloxone. The use of intrathecal and epidural opioid is common practice for postoperative analgesia and can reduce the amount of systemic opioids, thereby reducing other opioid-related side effects such as sedation or constipation. In rare cases, chronic pain management specialists may elect to implant surgically a programmable infusion pump connected to a spinal catheter for continuous infusion of opioids or other analgesic compounds in chronic or cancer pain management.


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G. Alternative Routes of Administration

Pharmacology_Katzung. G. Alternative Routes of Administration


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Pharmacology_Katzung. Patient-controlled analgesia (PCA) is widely used for the management of breakthrough pain. With PCA, the patient controls a parenteral (usually intravenous) infusion device by pressing a button to deliver a preprogrammed dose of the desired opioid analgesic, called the demand dose. A programmable lockout interval prevents administration of another dose for a set period of time. In addition, the pumps can be programmed with a continuous or basal infusion (which should generally be avoided due to safety concerns) and the 1or 4-hour lockout dose (the maximum amount of drug that can be delivered in that time period). Claims of better patient satisfaction are supported by well-designed clinical trials, making this approach very useful in postoperative pain control. However, health care personnel must be very familiar with the use of PCAs to avoid overdosage secondary to misuse or improper programming. There is a proven risk of PCA-associated respiratory depression and hypoxia that requires


Pharmacology_Katzung

Pharmacology_Katzung. must be very familiar with the use of PCAs to avoid overdosage secondary to misuse or improper programming. There is a proven risk of PCA-associated respiratory depression and hypoxia that requires careful monitoring of vital signs and sedation level, and provision of supplemental oxygen. Continuous pulse oximetry is also recommended for patients receiving PCA-administered opioids; this is not a fail-safe method for early detection of hypoventilation or apnea but rather serves as a safety net for an unrecognized adverse event. Monitoring of ventilation is ideal, but is often inadequate. The risk of sedation is increased if medications with sedative properties, such as benzodiazepines and certain types of antiemetics, are concurrently prescribed.


Pharmacology_Katzung

Pharmacology_Katzung. Rectal suppositories of morphine and hydromorphone have been used when oral and parenteral routes are undesirable. The transdermal fentanyl patch provides stable blood levels of drug and better pain control while avoiding the need for repeated parenteral injections. Fentanyl is the most successful opioid in transdermal application and is indicated for the management of persistent unremitting pain. Because of the complication of fentanyl-induced respiratory depression, the FDA recommends that introduction of a transdermal fentanyl patch (25 mcg/h) be reserved for patients with an established oral morphine requirement of at least 60 mg/d for 1 week or more. Extreme caution must be exercised in any patient initiating therapy or undergoing a dose increase because the peak effects may not be realized until 24–48 hours after patch application. The buprenorphine patch (BuTrans) is an example of the transdermal delivery of a mixed agonist-antagonist for the treatment of chronic pain in


Pharmacology_Katzung

Pharmacology_Katzung. be realized until 24–48 hours after patch application. The buprenorphine patch (BuTrans) is an example of the transdermal delivery of a mixed agonist-antagonist for the treatment of chronic pain in addition to opioid maintenance or detoxification. The intranasal route avoids repeated parenteral drug injections and the first-pass metabolism of orally administered drugs. Butorphanol is the only opioid currently available in the USA in a nasal formulation, but more are expected. Another alternative to parenteral administration is the buccal transmucosal route, which uses a fentanyl citrate lozenge or a “lollipop” mounted on a stick.


Pharmacology_Katzung

Pharmacology_Katzung. Direct toxic effects of the opioid analgesics that are extensions of their acute pharmacologic actions include respiratory depression, nausea, vomiting, and constipation (Table 31–4). Tolerance, dependence, diagnosis and treatment of overdosage, and contraindications must be considered. A. Tolerance and Dependence Drug dependence of the opioid type is marked by a relatively specific withdrawal or abstinence syndrome. Just as there are pharmacologic differences between the various opioids, there are also differences in psychological dependence and the severity of withdrawal effects. For example, withdrawal from dependence on a strong agonist is associated with more severe withdrawal signs and symptoms than withdrawal from a mild or moderate agonist. Administration of an opioid antagonist to an opioid-dependent person is followed by brief but severe withdrawal symptoms (see TABLE 31–4 Adverse effects of the opioid analgesics.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 31–4 Adverse effects of the opioid analgesics. antagonist-precipitated withdrawal, below). The potential for physical and psychological dependence of the partial agonistantagonist opioids appears to be less than that of the strong agonist drugs.


Pharmacology_Katzung

Pharmacology_Katzung. antagonist-precipitated withdrawal, below). The potential for physical and psychological dependence of the partial agonistantagonist opioids appears to be less than that of the strong agonist drugs. 1. Opioid tolerance—Opioid tolerance is the phenomenon whereby repeated doses of opioids have a diminishing analgesic effect. Clinically, it has been described as an increasing opioid dose requirement to achieve the analgesia observed at the initiation of opioid administration. Although development of tolerance begins with the first dose of an opioid, tolerance may not become clinically manifest until after 2–3 weeks of frequent exposure to ordinary therapeutic doses. Nevertheless, perioperative and critical care use of ultrapotent opioid analgesics such as remifentanil have been shown to induce opioid tolerance within hours. Tolerance develops most readily when large doses are given at short intervals and is minimized by giving small amounts of drug with longer intervals between doses.


Pharmacology_Katzung

Pharmacology_Katzung. A high degree of tolerance may develop to the analgesic, sedating, and respiratory depressant effects of opioid agonists (Table 31–3). It is possible to produce respiratory arrest in a nontolerant person with a dose of 60 mg of morphine. However, in a patient who is opioid-dependent or requires escalating opioid administration to manage intractable cancer pain, doses such as 2000 mg of morphine taken over a 2or 3-hour period may not produce significant respiratory depression. Tolerance also develops to the antidiuretic, emetic, and hypotensive effects but not to the miotic, convulsant, and constipating actions. Following discontinuation of opioids, loss of tolerance to the sedating and respiratory effects of opioids is variable, and difficult to predict. However, tolerance to the emetic effects may persist for several months after withdrawal of the drug. Therefore, opioid tolerance differs by effect, drug, time, and the individual (genetic-epigenetic factors).


Pharmacology_Katzung

Pharmacology_Katzung. Tolerance also develops to analgesics with mixed receptor effects but to a lesser extent than to the agonists. Adverse effects such as hallucinations, sedation, hypothermia, and respiratory depression are reduced after repeated administration of the mixed receptor drugs. However, tolerance to the latter agents does not generally include cross-tolerance to the agonist opioids. It is also important to note that tolerance does not develop to the antagonist actions of the mixed agents or to those of the pure antagonists.


Pharmacology_Katzung

Pharmacology_Katzung. Cross-tolerance is an extremely important characteristic of the opioids, ie, patients tolerant to morphine often show a reduction in analgesic response to other agonist opioids. This is particularly true of those agents with primarily μ-receptor agonist activity. Morphine and its congeners exhibit cross-tolerance not only with respect to their analgesic actions but also to their euphoriant, sedative, and respiratory effects. However, the cross-tolerance existing among the μ-receptor agonists can often be partial or incomplete. This clinical observation has led to the concept of “opioid rotation,” which has been used for many years in the treatment of cancer pain. A patient who is experiencing decreasing effectiveness of one opioid analgesic regimen is “rotated” to a different opioid analgesic (eg, morphine to hydromorphone; hydromorphone to methadone) and typically experiences significantly improved analgesia at a reduced overall equivalent dosage. Another approach is to recouple


Pharmacology_Katzung

Pharmacology_Katzung. (eg, morphine to hydromorphone; hydromorphone to methadone) and typically experiences significantly improved analgesia at a reduced overall equivalent dosage. Another approach is to recouple opioid receptor function as described previously through the use of adjunctive nonopioid agents. NMDA-receptor antagonists (eg, ketamine) have shown promise in preventing or reversing opioid-induced tolerance in animals and humans. Use of ketamine is increasing because well-controlled studies have shown clinical efficacy in reducing postoperative pain and opioid requirements in opioid-tolerant patients. Agents that independently enhance μ-receptor recycling may also hold promise for improving analgesia in the opioid-tolerant patient.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Dependence—The development of physical dependence is an invariable accompaniment of tolerance to repeated administration of an opioid of the μ type. Failure to continue administering the drug results in a characteristic withdrawal or abstinence syndrome that reflects an exaggerated rebound from the acute pharmacologic effects of the opioid. The signs and symptoms of withdrawal include rhinorrhea, lacrimation, yawning, chills, gooseflesh (piloerection), hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety, and hostility. The number and intensity of the signs and symptoms are largely dependent on the degree of physical dependence that has developed. Administration of an opioid at this time suppresses abstinence signs and symptoms almost immediately.


Pharmacology_Katzung

Pharmacology_Katzung. The time of onset, intensity, and duration of abstinence syndrome depend on the drug previously used and may be related to its biologic half-life. With morphine or heroin, withdrawal signs usually start within 6–10 hours after the last dose. Peak effects are seen at 36–48 hours, after which most of the signs and symptoms gradually subside. By 5 days, most of the effects have disappeared, but some may persist for months. In the case of meperidine, the withdrawal syndrome largely subsides within 24 hours, whereas with methadone several days are required to reach the peak of the abstinence syndrome, and it may last as long as 2 weeks. The slower subsidence of methadone effects is associated with a less intense immediate syndrome, and this is the basis for its use in the detoxification of heroin addicts. However, despite the loss of physical dependence on the opioid, craving for it may persist. In addition to methadone, buprenorphine and the α2 agonist clonidine are FDA-approved


Pharmacology_Katzung

Pharmacology_Katzung. of heroin addicts. However, despite the loss of physical dependence on the opioid, craving for it may persist. In addition to methadone, buprenorphine and the α2 agonist clonidine are FDA-approved treatments for opioid analgesic detoxification (see Chapter 32).


Pharmacology_Katzung

Pharmacology_Katzung. A transient, explosive abstinence syndrome—antagonistprecipitated withdrawal—can be induced in a subject physically dependent on opioids by administering naloxone or another antagonist. Within 3 minutes after injection of the antagonist, signs and symptoms similar to those seen after abrupt discontinuance appear, peaking in 10–20 minutes and largely subsiding after 1 hour. Even in the case of methadone, withdrawal of which results in a relatively mild abstinence syndrome, the antagonist-precipitated abstinence syndrome may be very severe. In the case of agents with mixed effects, withdrawal signs and symptoms can be induced after repeated administration followed by abrupt discontinuance of pentazocine, cyclazocine, or nalorphine, but the syndrome appears to be somewhat different from that produced by morphine and other agonists. Anxiety, loss of appetite and body weight, tachycardia, chills, increase in body temperature, and abdominal cramps have been noted.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Addiction—As defined by the American Society of Addiction Medicine, addiction is a primary, chronic disease of brain reward, motivation, memory, and related circuitry. Dysfunction in these circuits leads to characteristic biologic, psychological, and social manifestations. This is reflected in an individual’s pathologic pursuit of reward and relief through substance use and other behaviors. Addiction is characterized by inability to abstain consistently, impairment in behavioral control, craving, diminished recognition of significant problems with one’s behaviors and interpersonal relationships, and a dysfunctional emotional response (see Chapter 32).


Pharmacology_Katzung

Pharmacology_Katzung. The risk of inducing dependence and, potentially, addiction is clearly an important consideration in the therapeutic use of opioid drugs. Despite that risk, under no circumstances should adequate pain relief ever be withheld simply because an opioid exhibits potential for misuse or because legislative controls complicate the process of prescribing controlled substances. Furthermore, certain principles can be observed by the clinician to minimize problems presented by tolerance and dependence when using opioid analgesics: therapeutic goals before starting opioid therapy. This tends to limit the potential for physical dependence. The patient and his or her family should be included in this process. an effective dose is established, attempt to limit dosage to this level. This goal is facilitated by use of a written treatment contract that specifically prohibits early refills and having multiple prescribing physicians.


Pharmacology_Katzung

Pharmacology_Katzung. using nonopioid analgesics whenever possible. Especially in chronic management, consider using other types of analgesics or compounds exhibiting less pronounced withdrawal symptoms on discontinuance. evaluate continuing analgesic therapy and the patient’s need for opioids. the rights, responsibilities, and roles of patients and providers regarding controlled substances. If there are concerns about the patient’s safety, difficult decisions may need to be made. B. Diagnosis and Treatment of Opioid Overdosage


Pharmacology_Katzung

Pharmacology_Katzung. B. Diagnosis and Treatment of Opioid Overdosage Intravenous injection of naloxone dramatically reverses coma due to opioid overdose but not that due to other CNS depressants. Use of the antagonist should not, of course, delay the institution of other therapeutic measures, especially respiratory support. (See also The Opioid Antagonists, below, and Chapter 58.) The growing epidemic of prescription opioid use and opioid-related adverse drug reactions has been accompanied by an even greater increase in heroin-related deaths in the United States from 2010 to 2014. For this reason, attention is being directed to make naloxone via intramuscular and intranasal routes widely available, including as over-the-counter formulations.


Pharmacology_Katzung

Pharmacology_Katzung. C. Contraindications and Cautions in Therapy 1. Use of pure agonists with weak partial agonists—When a weak partial agonist such as pentazocine is given to a patient also receiving a full agonist (eg, morphine), there is a risk of diminishing analgesia or even inducing a state of withdrawal; thus combining a full agonist with partial agonist opioids should be avoided. 2. Use in patients with head injuries—Carbon dioxide retention caused by respiratory depression results in cerebral vasodilation. In patients with elevated intracranial pressure, this may lead to lethal alterations in brain function. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Use during pregnancy—In pregnant women who are chronically using opioids, the fetus may become physically dependent in utero and manifest withdrawal symptoms in the early postpartum period. A daily dose as small as 6 mg of heroin (or equivalent) taken by the mother can result in a mild withdrawal syndrome in the infant, and twice that much may result in severe signs and symptoms, including irritability, shrill crying, diarrhea, or even seizures. Recognition of the problem is aided by a careful history and physical examination. When withdrawal symptoms are judged to be relatively mild, treatment is aimed at control of these symptoms using such drugs as diazepam; with more severe withdrawal, camphorated tincture of opium (paregoric; 0.4 mg of morphine/mL) in an oral dose of 0.12–0.24 mL/kg is used. Oral doses of methadone (0.1–0.5 mg/kg) have also been used. 4. Use in patients with impaired pulmonary function—


Pharmacology_Katzung

Pharmacology_Katzung. 4. Use in patients with impaired pulmonary function— In patients with borderline respiratory reserve, the depressant properties of the opioid analgesics may lead to acute respiratory failure. 5. Use in patients with impaired hepatic or renal function— Because morphine and its congeners are metabolized primarily in the liver, their use in patients in prehepatic coma may be questioned. Half-life is prolonged in patients with impaired renal function, and morphine and its active glucuronide metabolite may accumulate; dosage can often be reduced in such patients. 6. Use in patients with endocrine disease—Patients with adrenal insufficiency (Addison’s disease) and those with hypothyroidism (myxedema) may have prolonged and exaggerated responses to opioids. Because seriously ill or hospitalized patients may require a large number of drugs, there is always a possibility of drug interactions when the opioid analgesics are administered. Table 31–5 lists


Pharmacology_Katzung

Pharmacology_Katzung. Because seriously ill or hospitalized patients may require a large number of drugs, there is always a possibility of drug interactions when the opioid analgesics are administered. Table 31–5 lists TABLE 31–5 Opioid drug interactions. some of these drug interactions and the reasons for not combining the named drugs with opioids. The following section describes the most important and widely used opioid analgesics, along with features peculiar to specific agents. Data about doses approximately equivalent to 10 mg of intramuscular morphine, oral versus parenteral efficacy, duration of analgesia, and intrinsic activity (maximum efficacy) are presented in Table 31–2. Morphine, hydromorphone, and oxymorphone are strong agonists useful in treating severe pain. These prototypic agents have been described in detail above.


Pharmacology_Katzung

Pharmacology_Katzung. Morphine, hydromorphone, and oxymorphone are strong agonists useful in treating severe pain. These prototypic agents have been described in detail above. Heroin (diamorphine, diacetylmorphine) is potent and fast-acting, but its use is prohibited in the USA and Canada. In recent years, there has been considerable agitation to revive its use. However, double-blind studies have not supported the claim that heroin is more effective than morphine in relieving severe chronic pain, at least when given by the intramuscular route. Methadone has undergone a dramatic revival as a potent and clinically useful analgesic. It can be administered by the oral, intravenous, subcutaneous, spinal, and rectal routes. It is well absorbed from the gastrointestinal tract, and its bioavailability far exceeds that of oral morphine.


Pharmacology_Katzung

Pharmacology_Katzung. Methadone is not only a potent μ-receptor agonist but its racemic mixture of dand l-methadone isomers can also block both NMDA receptors and monoaminergic reuptake transporters. These nonopioid receptor properties may help explain its ability to relieve difficult-to-treat pain (neuropathic, cancer pain), especially when a previous trial of morphine has failed. In this regard, when analgesic tolerance or intolerable side effects have developed with the use of increasing doses of morphine or hydromorphone, “opioid rotation” to methadone has provided superior analgesia at 10–20% of the morphine-equivalent daily dose. In contrast to its use in suppressing symptoms of opioid withdrawal, use of methadone as an analgesic typically requires administration at intervals of no more than 8 hours. However, given methadone’s highly variable pharmacokinetics and long half-life (25–52 hours), initial administration should be closely monitored to avoid potentially harmful adverse effects, especially


Pharmacology_Katzung

Pharmacology_Katzung. given methadone’s highly variable pharmacokinetics and long half-life (25–52 hours), initial administration should be closely monitored to avoid potentially harmful adverse effects, especially respiratory depression. Because methadone is metabolized by CYP2B6 and CYP3A4 isoforms in the liver, inhibition of its metabolic pathway or hepatic dysfunction has also been associated with overdose effects, including respiratory depression or, more rarely, prolonged QT-based cardiac arrhythmias.


Pharmacology_Katzung

Pharmacology_Katzung. Methadone is widely used in the treatment of opioid misuse. Tolerance and physical dependence develop more slowly with methadone than with morphine. The withdrawal signs and symptoms occurring after abrupt discontinuance of methadone are milder, although more prolonged, than those of morphine. These properties make methadone a useful drug for detoxification and for maintenance of the chronic relapsing heroin addict. For detoxification of a heroin-dependent addict, low doses of methadone (5–10 mg orally) are given two or three times daily for 2 or 3 days. Upon discontinuing methadone, most addicts experience a mild but endurable withdrawal syndrome.


Pharmacology_Katzung

Pharmacology_Katzung. For maintenance therapy of the opioid recidivist, tolerance to 50–100 mg/d of oral methadone may be deliberately produced; in this state, the addict experiences cross-tolerance to heroin, which prevents most of the addiction-reinforcing effects of heroin. One rationale of maintenance programs is that blocking the reinforcement obtained from misuse of illicit opioids removes the drive to obtain them, thereby reducing criminal activity and making the addict more amenable to psychiatric and rehabilitative therapy. The pharmacologic basis for the use of methadone in maintenance programs is sound and the sociologic basis is rational, but some methadone programs fail because nonpharmacologic management is inadequate.


Pharmacology_Katzung

Pharmacology_Katzung. The concurrent administration of methadone to heroin addicts known to be recidivists has been questioned because of the increased risk of overdose death secondary to respiratory arrest. As the number of patients prescribed methadone for persistent pain has increased, so, too, has the incidence of accidental overdose and complications related to respiratory depression. Variability in methadone metabolism, protein binding, distribution, and nonlinear opioid dose conversion all play a role in adverse events. Buprenorphine, a partial μ-receptor agonist with long-acting properties, has been found to be effective in opioid detoxification and maintenance programs and is presumably associated with a lower risk of such overdose fatalities.


Pharmacology_Katzung

Pharmacology_Katzung. Fentanyl is one of the most widely used agents in the family of synthetic opioids. The fentanyl subgroup now includes sufentanil, alfentanil, and remifentanil in addition to the parent compound, fentanyl. An extremely potent analog, carfentanil, is used in veterinary medicine for sedating large mammals, eg, elephants. Adulteration of street heroin with carfentanil has been responsible for many deaths in humans.


Pharmacology_Katzung

Pharmacology_Katzung. These opioids differ mainly in their potency and biodisposition. Sufentanil is five to seven times more potent than fentanyl. Alfentanil is considerably less potent than fentanyl, but acts more rapidly and has a markedly shorter duration of action. Remifentanil is metabolized very rapidly by blood and nonspecific tissue esterases, making its pharmacokinetic and pharmacodynamic half-lives extremely short. Such properties are useful when these compounds are used in anesthesia practice. Although fentanyl is now the predominant analgesic in the phenylpiperidine class, meperidine continues to be used. This older opioid has significant antimuscarinic effects, which may be a contraindication if tachycardia would be a problem. Meperidine is also reported to have a negative inotropic action on the heart. In addition, it has the potential for producing seizures secondary to accumulation of its metabolite, normeperidine, in patients receiving high doses or with concurrent renal failure. Given


Pharmacology_Katzung

Pharmacology_Katzung. heart. In addition, it has the potential for producing seizures secondary to accumulation of its metabolite, normeperidine, in patients receiving high doses or with concurrent renal failure. Given this undesirable profile, use of meperidine as a first-line analgesic is becoming increasingly rare.


Pharmacology_Katzung

Pharmacology_Katzung. Levorphanol is a synthetic opioid analgesic closely resembling morphine that has μ-, δ-, and κ-opioid agonist actions, serotoninnorepinephrine reuptake inhibition, and NMDA receptor antagonist properties. Codeine, dihydrocodeine, and hydrocodone have lower binding affinity to μ-opioid receptors than morphine and often have adverse effects that limit the maximum tolerated dose when one attempts to achieve analgesia comparable to that of morphine. Oxycodone is more potent and is prescribed alone in higher doses as immediate-release or controlled-release forms for the treatment of moderate to severe pain. Combinations of hydrocodone or oxycodone with acetaminophen are the predominant formulations of orally administered analgesics in the United States for the treatment of mild to moderate pain. However, there has been a large increase in the use of controlled-release oxycodone at the highest dose range. An intravenous formulation of oxycodone is available outside the United States.


Pharmacology_Katzung

Pharmacology_Katzung. Since each controlled-release tablet of oxycodone contains a large quantity of oxycodone to allow for prolonged action, those intent on abusing the old formulation have extracted crushed tablets and injected high doses, resulting in misuse and possible fatal overdose. In 2010, the FDA approved a new formulation of the controlled-release form of oxycodone that reportedly prevents the tablets from being cut, broken, chewed, crushed, or dissolved to release more oxycodone. It is hoped that this new formulation will lead to less misuse by snorting or injection. The FDA is now requiring a Risk Evaluation and Mitigation Strategy (REMS) that will include the issuance of a medication guide to patients and a requirement for prescriber education regarding the appropriate use of opioid analgesics in the treatment of pain. (See Box: Educating Opioid Prescribers.)


Pharmacology_Katzung

Pharmacology_Katzung. Propoxyphene is chemically related to methadone but has extremely low analgesic activity. Its low efficacy makes it unsuitable, even in combination with aspirin, for severe pain. The increasing incidence of deaths associated with its use and misuse caused it to be withdrawn in the United States. Diphenoxylate and its metabolite, difenoxin, are not used for analgesia but for the treatment of diarrhea. They are scheduled for minimal control (difenoxin is Schedule IV, diphenoxylate Schedule V; see inside front cover) because the likelihood of their misuse is remote. The poor solubility of the compounds limits their use for parenteral injection. As antidiarrheal drugs, they are used in combination with atropine. The atropine is added in a concentration too low to have a significant antidiarrheal effect but is presumed to further reduce the likelihood of misuse.


Pharmacology_Katzung

Pharmacology_Katzung. Loperamide is a phenylpiperidine derivative used to control diarrhea. Due to action on peripheral μ-opioid receptors and lack of effect on CNS receptors, investigations are ongoing as to whether it could be an effective analgesic. Its potential for misuse is considered very low because of its limited access to the brain. It is therefore available without a prescription. The usual dose with all of these antidiarrheal agents is two tablets to start and then one tablet after each diarrheal stool. Care should be taken not to administer any partial agonist or drug with mixed opioid receptor actions to patients receiving pure agonist drugs because of the unpredictability of both drugs’ effects; reduction of analgesia or precipitation of an explosive abstinence syndrome may result.


Pharmacology_Katzung

Pharmacology_Katzung. The treatment of pain is a difficult clinical-pharmacologic prob-lem, and prescribers of opioids have been caught between a number of competing forces in their attempt to relieve suffering. These forces include evolving opioid outcome data, regulations, advertising, and potential misinterpretation of recommenda-tions and guidelines. Together with opioid misuse and diversion, an “opioid epidemic” has emerged in multiple countries. In 2014, the United States recorded the highest death rate related to opioids (greater than 9/100,000) since the Centers for Disease Control and Prevention (CDC) began tracking these data. These statistics have prompted the FDA to formulate plans for opioid manufacturers to provide training for all opioid prescribers and the CDC to create the first Opioid Prescribing Guidelines for Pre-scribers caring for patients with chronic pain. The FDA has insti-tuted training programs such as the Transmucosal Immediate Release Fentanyl Risk Evaluation and Mitigation


Pharmacology_Katzung

Pharmacology_Katzung. Guidelines for Pre-scribers caring for patients with chronic pain. The FDA has insti-tuted training programs such as the Transmucosal Immediate Release Fentanyl Risk Evaluation and Mitigation Strategy (TIRF-REMS) program to curb the misuse of these products. More recently, the FDA has worked to educate providers on the risks of extended-release/long-acting (ER/LA) opioids. Better data regarding the effectiveness of opioids ver-sus their adverse effects in the treatment of chronic pain are critically needed. Attempts to link the public health problem of opioid misuse to basic science findings, such as opioid-induced hyperalgesia, must be approached cau-tiously. Nevertheless, it is estimated that the United States, which constitutes 4.6% of the world’s population, consumes approximately 80% of the world’s opioids. In contrast, there are several countries in which the medical use of opioids is prohibited, resulting in unmanaged pain after surgery or trauma and near the end of life.


Pharmacology_Katzung

Pharmacology_Katzung. As noted above, buprenorphine is a potent and long-acting phenanthrene derivative that is a partial μ-receptor agonist (low intrinsic activity) and an antagonist at the δ and κ receptors and is therefore referred to as a mixed agonist-antagonist. Although buprenorphine is used as an analgesic, it can antagonize the action of more potent μ agonists such as morphine. Buprenorphine also binds to ORL1, the orphanin receptor. Whether this property also participates in opposing μ receptor function is under study. Administration by the sublingual route is preferred to avoid significant first-pass effect. Buprenorphine’s long duration of action is due to its slow dissociation from μ receptors. This property renders its effects resistant to naloxone reversal. Buprenorphine was approved by the FDA in 2002 for the management of opioid dependence, and studies suggest it is as effective as methadone for the management of opioid withdrawal and detoxification in programs that include counseling,


Pharmacology_Katzung

Pharmacology_Katzung. in 2002 for the management of opioid dependence, and studies suggest it is as effective as methadone for the management of opioid withdrawal and detoxification in programs that include counseling, psychosocial support, and direction by physicians qualified under the Drug Addiction Treatment Act. In the USA, a special Drug Enforcement Administration (DEA) license and training are needed to legally prescribe buprenorphine for addiction. In contrast to methadone, high-dose administration of buprenorphine results in a μ-opioid antagonist action, limiting its properties of analgesia and respiratory depression. However, buprenorphine formulations can still cause serious respiratory depression and death, particularly when extracted and injected intravenously in combination with benzodiazepines or used with other CNS depressants (ie, sedatives, antipsychotics, or alcohol). Buprenorphine is also available combined with naloxone, a pure μ-opioid antagonist (as Suboxone), to help prevent its


Pharmacology_Katzung

Pharmacology_Katzung. or used with other CNS depressants (ie, sedatives, antipsychotics, or alcohol). Buprenorphine is also available combined with naloxone, a pure μ-opioid antagonist (as Suboxone), to help prevent its diversion for illicit intravenous misuse. A slow-release transdermal patch preparation that releases drug over a 1-week period is also available (Butrans). Most recently, the FDA approved an implanted buprenorphine rod (Probuphine) that lasts for 6 months and is meant to deter misuse. Psychotomimetic effects, with hallucinations, nightmares, and anxiety, have been reported after use of drugs with mixed agonist-antagonist actions.


Pharmacology_Katzung

Pharmacology_Katzung. Pentazocine (a benzomorphan) and nalbuphine are other examples of opioid analgesics with mixed agonist-antagonist properties. Nalbuphine is a strong κ-receptor agonist and a partial μ-receptor antagonist; it is given parenterally. At higher doses there seems to be a definite ceiling—not noted with morphine—to the respiratory depressant effect. Unfortunately, when respiratory depression does occur, it may be relatively resistant to naloxone reversal due to its greater affinity for the receptor than naloxone. Nalbuphine is equipotent to morphine for analgesia and, at lower doses, can be effective for pruritus for opioid and nonopioid etiologies. Butorphanol produces analgesia equivalent to nalbuphine but appears to produce more sedation at equianalgesic doses. Butorphanol is considered to be predominantly a κ agonist. However, it may also act as a partial agonist or antagonist at the μ receptor.


Pharmacology_Katzung

Pharmacology_Katzung. Pentazocine is a κ agonist with weak μ-antagonist or partial agonist properties. It is the oldest mixed agent available. It may be used orally or parenterally. However, because of its irritant properties, the injection of pentazocine subcutaneously is not recommended.


Pharmacology_Katzung

Pharmacology_Katzung. Tramadol is a centrally acting analgesic whose mechanism of action is complex and dependent on ability of the parent drug and its metabolites to block serotonin and norepinephrine reuptake. Because its analgesic effect is only partially antagonized by naloxone, it is thought to depend less on its low-affinity binding to the μ receptor for therapeutic activity. The recommended dosage is 50–100 mg orally four times daily; however, its systemic concentration and analgesic effect are dependent on the enzymatic activity of CYP2D6 polymorphisms. Toxicity includes association with seizures; the drug is relatively contraindicated in patients with a history of epilepsy and for use with other drugs that lower the seizure threshold. Another serious risk is the development of serotonin syndrome, especially if selective serotonin reuptake inhibitor antidepressants are being administered (see Chapter 16). Other adverse effects include nausea and dizziness, but these symptoms typically abate after


Pharmacology_Katzung

Pharmacology_Katzung. if selective serotonin reuptake inhibitor antidepressants are being administered (see Chapter 16). Other adverse effects include nausea and dizziness, but these symptoms typically abate after several days of therapy. No clinically significant effects on respiration or the cardiovascular system have thus far been reported when used as monotherapy. Given the fact that the analgesic action of tramadol is largely independent of μ-receptor action, tramadol may serve as an adjunct with pure opioid agonists in the treatment of chronic neuropathic pain.


Pharmacology_Katzung

Pharmacology_Katzung. Tapentadol is an analgesic with modest μ-opioid receptor affinity and significant norepinephrine reuptake-inhibiting action. In animal models, its analgesic effects were only moderately reduced by naloxone but strongly reduced by an α2-adrenoceptor antagonist. Furthermore, its binding to the norepinephrine transporter (NET, see Chapter 6) was stronger than that of tramadol, whereas its binding to the serotonin transporter (SERT) was less than that of tramadol. Tapentadol was approved in 2008 and has been shown to be as effective as oxycodone in the treatment of moderate to severe pain but with a reduced profile of gastrointestinal complaints such as nausea. Tapentadol carries risk for seizures in patients with seizure disorders and for the development of serotonin syndrome. It is unknown how tapentadol compares in clinical utility to tramadol or other analgesics whose mechanism of action is not based


Pharmacology_Katzung

Pharmacology_Katzung. The opioid analgesics are among the most effective drugs available for the suppression of cough. This effect is often achieved at doses below those necessary to produce analgesia. The receptors involved in the antitussive effect appear to differ from those associated with the other actions of opioids. For example, the antitussive effect is also produced by stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability (see below). The physiologic mechanism of cough is complex, and little is known about the specific mechanism of action of the opioid antitussive drugs. It appears likely that both central and peripheral effects play a role.


Pharmacology_Katzung

Pharmacology_Katzung. The opioid derivatives most commonly used as antitussives are dextromethorphan, codeine, levopropoxyphene, and noscapine (levopropoxyphene and noscapine are not available in the USA). They should be used with caution in patients taking monoamine oxidase inhibitors (Table 31–5). Antitussive preparations usually also contain expectorants to thin and liquefy respiratory secretions. Importantly, due to increasing reports of death in young children taking dextromethorphan in formulations of over-the-counter “cold/cough” medications, its use in children younger than 6 years of age has been banned by the FDA. Moreover, because of variations in the metabolism of codeine, its use for any purpose in young children is being reconsidered.


Pharmacology_Katzung

Pharmacology_Katzung. Dextromethorphan is the dextrorotatory stereoisomer of a methylated derivative of levorphanol. It is purported to be free of addictive properties and produces less constipation than codeine. The usual antitussive dose is 15–30 mg three or four times daily. It is available in many over-the-counter products. Dextromethorphan has also been found to enhance the analgesic action of morphine and presumably other μ-receptor agonists. However, misuse of its purified (powdered) form has been reported to lead to serious adverse events including death. Codeine, as noted, has a useful antitussive action at doses lower than those required for analgesia. Thus, 15 mg is usually sufficient to relieve cough. Levopropoxyphene is the stereoisomer of the weak opioid agonist dextropropoxyphene. It is devoid of opioid effects, although sedation has been described as a side effect. The usual antitussive dose is 50–100 mg every 4 hours.


Pharmacology_Katzung

Pharmacology_Katzung. primarily on opioid receptor pharmacology. ANTITUSSIVES The pure opioid antagonist drugs naloxone, naltrexone, and nalmefene are morphine derivatives with bulkier substituents at the N17 position. These agents have a relatively high affinity for μ-opioid binding sites. They have lower affinity for the other receptors but can also reverse agonists at δ and κ sites. HOOCH2CH2ONCH2CH2CHHONaloxonePharmacokinetics Naloxone is usually given by injection and has a short duration of action (1–2 hours) when given by this route. Metabolic dis-position is chiefly by glucuronide conjugation like that of the agonist opioids with free hydroxyl groups. Naltrexone is well absorbed after oral administration but may undergo rapid first-pass metabolism. It has a half-life of 10 hours, and a single oral dose of 100 mg blocks the effects of injected heroin for up to 48 hours. Nalmefene, the newest of these agents, is a derivative of naltrexone but is available only for intravenous administration. Like


Pharmacology_Katzung

Pharmacology_Katzung. of 100 mg blocks the effects of injected heroin for up to 48 hours. Nalmefene, the newest of these agents, is a derivative of naltrexone but is available only for intravenous administration. Like naloxone, nalmefene is used for opioid overdose but has a longer half-life (8–10 hours).


Pharmacology_Katzung

Pharmacology_Katzung. When given in the absence of an agonist drug, these antagonists are almost inert at doses that produce marked antagonism of agonist opioid effects. When given intravenously to a morphine-treated subject, the antagonist completely and dramatically reverses the opioid effects within 1–3 minutes. In individuals who are acutely depressed by an overdose of an opioid, the antagonist effectively normalizes respiration, level of consciousness, pupil size, bowel activity, and awareness of pain. In dependent subjects who appear normal while taking opioids, naloxone or naltrexone almost instantaneously precipitates an abstinence syndrome. There is no tolerance to the antagonistic action of these agents, nor does withdrawal after chronic administration precipitate an abstinence syndrome. Naloxone is a pure antagonist and is preferred over older weak agonist-antagonist agents that had been used primarily as antagonists, eg, nalorphine and levallorphan.


Pharmacology_Katzung

Pharmacology_Katzung. Naloxone is a pure antagonist and is preferred over older weak agonist-antagonist agents that had been used primarily as antagonists, eg, nalorphine and levallorphan. The major application of naloxone is in the treatment of acute opioid overdose (see also Chapter 58). It is very important that the relatively short duration of action of naloxone be borne in mind, because a severely depressed patient may recover after a single dose of naloxone and appear normal, only to relapse into coma after 1–2 hours. The usual initial dose of naloxone is 0.1–0.4 mg intravenously for life-threatening respiratory and CNS depression. Maintenance is with the same drug, 0.4–0.8 mg given intravenously, and repeated whenever necessary. In using naloxone in the severely opioid-depressed newborn, it is important to start with doses of 5–10 mcg/kg and to consider a second dose of up to a total of 25 mcg/kg if no response is noted.


Pharmacology_Katzung

Pharmacology_Katzung. Low-dose naloxone (0.04 mg) has an increasing role in the treatment of adverse effects that are commonly associated with intravenous or epidural opioids. Careful titration of the naloxone dosage can often eliminate the itching, nausea, and vomiting while sparing the analgesia. For this purpose, oral naloxone, and modified analogs of naloxone and naltrexone, have been approved by the FDA. These include methylnaltrexone bromide for the treatment of constipation in patients with opioid-induced constipation (OIC) with chronic noncancer pain and late-stage advanced illness and naloxegol and alvimopan for the treatment of postoperative ileus following bowel resection surgery. Methylnaltrexone has a quaternary amine preventing it from crossing the blood-brain barrier. Naloxegol is pegylated naloxone, which limits penetration into the CNS and through peripheral μ-antagonism mitigates constipation. Alvimopan has a high affinity for peripheral μ receptors and does not impair the central effects


Pharmacology_Katzung

Pharmacology_Katzung. which limits penetration into the CNS and through peripheral μ-antagonism mitigates constipation. Alvimopan has a high affinity for peripheral μ receptors and does not impair the central effects of μ-opioid agonists. The principal mechanism for the selective therapeutic effect of these agents is peripheral enteric μ-receptor antagonism with minimal CNS penetration.


Pharmacology_Katzung

Pharmacology_Katzung. Because of its long duration of action, naltrexone has been proposed as a maintenance drug for addicts in treatment programs. A single dose given on alternate days blocks virtually all of the effects of a dose of heroin. It might be predicted that this approach to rehabilitation would not be popular with a large percentage of drug users unless they are motivated to become drug-free. A related use is in combination with morphine sulfate in a controlled-release formulation (Embeda) in which 20–100 mg of morphine is slowly released over 8–12 hours or longer for the control of prolonged postoperative pain. Naltrexone, 0.4–4 mg, is sequestered in the center of the formulation pellets and is present to prevent the misuse of the morphine (by grinding and extraction of the morphine from the capsules).


Pharmacology_Katzung

Pharmacology_Katzung. There is evidence that naltrexone decreases the craving for alcohol in chronic alcoholics by increasing baseline β-endorphin release, and it has been approved by the FDA for this purpose (see Chapter 23). Naltrexone also facilitates abstinence from nicotine (cigarette smoking) with reduced weight gain. In fact, a combination of naltrexone plus bupropion (Chapter 16) may also offer an effective and synergistic strategy for weight loss. • Hydromorphone, oxymorphone: Like morphine in efficacy, but higher potency • Meperidine: Strong agonist with anticholinergic effects • Oxycodone: • Sufentanil, alfentanil, remifentanil: Like fentanyl but shorter durations of action anesthesia (fentanyl, morphine) except methadone, 4–6 h Toxicity: Respiratory depression Poorly understood but strong and partial μ agonists are also effective antitussives


Pharmacology_Katzung

Pharmacology_Katzung. Codeine, levopropoxyphene: Similar to dextromethorphan • Naltrexone, nalmefene: Like naloxone but longer durations of action (10 h); naltrexone is used in maintenance programs and can block heroin effects for up to 48 h; naltrexone is also used for alcohol and nicotine dependence; when combined with bupropion, may be effective in weight-loss programs • Alvimopan, methylnaltrexone bromide: Potent μ antagonists with poor entry into the central nervous system; can be used to treat severe opioid-induced constipation without precipitating an abstinence syndrome •TapentadolModerate μ agonist, strong NET inhibitor Analgesia Moderate pain Duration4–6h•Toxicity:Headache; nausea and vomiting; possible dependence •TramadolMixed effects: weak μagonist, moderate SERT inhibitor, weak NET inhibitor Analgesia Moderatepain•adjuncttoopioids in chronic pain syndromes Duration4–6h•Toxicity: Seizures •riskofserotoninsyndromeOTHER ANALGESICS USED IN MODERATE PAIN


Pharmacology_Katzung

Pharmacology_Katzung. NET, norepinephrine reuptake transporter; SERT, serotonin reuptake transporter. Buprenorphine Buprenex, others, Butrans (transdermal) Fentanyl Generic, Duragesic (transdermal). Fentanyl Buccal, Fentanyl Actiq (lozenge) Hydromorphone Generic, Dilaudid, others Oral, rectal, parenteral Generic Oral sustained-release capsules Avinza, Kadian Nalbuphine Generic, Nubain Oxycodone Generic, OxyContin (sustained release) Pentazocine Talwin Sufentanil Generic, Sufenta Oxymorphone Generic, Numorphan, others Remifentanil Generic, Ultiva Codeine/aspirin Generic, Empirin Compound, others Naloxone Generic, Narcan *Antidiarrheal opioid preparations are listed in Chapter 62. †Orphan drug approved only for the treatment of narcotic addiction.


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Pharmacology_Katzung. Naloxone Generic, Narcan *Antidiarrheal opioid preparations are listed in Chapter 62. †Orphan drug approved only for the treatment of narcotic addiction. ‡Dozens of combination products are available; only a few of the most commonly prescribed are listed here. Codeine combination products available in several strengths are usually denoted No. 2 (15 mg codeine), No. 3 (30 mg codeine), and No. 4 (60 mg codeine). Prescribers should be aware of the possible danger of renal and hepatic injury with acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs contained in these analgesic combinations. Angst MS, Clark JD: Opioid-induced hyperalgesia. Anesthesiology 2006;104:570. Anton RF: Naltrexone for the management of alcohol dependence. N Engl J Med 2008;359:715. Basbaum AI et al: Cellular and molecular mechanisms of pain. Cell 2009;139:267. Basbaum AI, Jessel T: The perception of pain. In: Kandel ER et al (editors): Prin ciples of Neural Science, 4th ed. McGraw-Hill, 2000.


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Pharmacology_Katzung. Basbaum AI, Jessel T: The perception of pain. In: Kandel ER et al (editors): Prin ciples of Neural Science, 4th ed. McGraw-Hill, 2000. Benedetti C, Premuda L: The history of opium and its derivatives. In: Benedetti C et al (editors): Advances in Pain Research and Therapy, vol 14. Raven Press, 1990. Bolan EA, Tallarida RJ, Pasternak GW: Synergy between mu opioid ligands: Evidence for functional interactions among mu opioid receptor subtypes. J Pharmacol Exp Ther 2002;303:557. Chu LF, Angst MS, Clark D: Opioid-induced hyperalgesia in humans: Molecular mechanisms and clinical considerations. Clin J Pain 2008;24:479. Curran MP et al: Alvimopan. Drugs 2008;68:2011. Dahan A et al: Sex-specific responses to opiates: Animal and human studies. Anesth Analg 2008;107:83. Davis MP, Walsh D: Methadone for relief of cancer pain: A review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer 2001;9:73.


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Pharmacology_Katzung. Davis MP, Walsh D: Methadone for relief of cancer pain: A review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer 2001;9:73. Ferner RE, Daniels AM: Office-based treatment of opioid-dependent patients. N Engl J Med 2003;348:81. Ferrante FM: Principles of opioid pharmacotherapy: Practical implications of basic mechanisms. J Pain Symptom Manage 1996;11:265. Fields HL, Basbaum AI: Central nervous system mechanisms of pain modulation. In: Wall PD, Melzack R (editors): Textbook of Pain. Churchill Livingstone, 1999. Fillingim RB, Gear RW: Sex differences in opioid analgesia: Clinical and experimental findings. Eur J Pain 2004;8:413. Fischer BD, Carrigan KA, Dykstra LA: Effects of N-methyl-d-aspartate receptor antagonists on acute morphine-induced and l-methadone-induced antinociception in mice. J Pain 2005;6:425. Goldman D, Barr CS: Restoring the addicted brain. N Engl J Med 2002;347:843.


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Pharmacology_Katzung. Goldman D, Barr CS: Restoring the addicted brain. N Engl J Med 2002;347:843. Inui S: Nalfurafine hydrochloride for the treatment of pruritus. Expert Opin Pharmacother 2012;13:1507. Joly V et al: Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 2005;103:147. Julius D, Basbaum AI: Molecular mechanisms of nociception. Nature 2001;413:203. Kalso E et al: No pain, no gain: Clinical excellence and scientific rigour—Lessons learned from IA morphine. Pain 2002;98:269. Kharasch ED et al: Methadone pharmacogenetics: CYP2B6 polymorphisms determine plasma concentrations, clearance, and metabolism. Anesthesiology 2015;123:1142. Kiefer BL: Opioids: First lessons from knockout mice. Trends Pharmacol Sci 1999;20:19. Kim JA et al: Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence. Curr Biol 2008;18:129.


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Pharmacology_Katzung. Kim JA et al: Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence. Curr Biol 2008;18:129. Lai J et al: Pronociceptive actions of dynorphin via bradykinin receptors. Neurosci Lett 2008;437:175. Lambert DG: The nociceptin/orphanin FQ receptor: A target with broad therapeutic potential. Nat Rev Drug Discov 2008;7:694. Laughlin TM, Larson AA, Wilcox GL: Mechanisms of induction of persistent nociception by dynorphin. J Pharmacol Exp Ther 2001;299:6. Liaw WI et al: Distinct expression of synaptic NR2A and NR2B in the central nervous system and impaired morphine tolerance and physical dependence in mice deficient in postsynaptic density-93 protein. Mol Pain 2008;4:45. Liu XY et al: Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell 2011;147:447.


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Pharmacology_Katzung. Liu XY et al: Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell 2011;147:447. McGaraughty S, Heinricher MM: Microinjection of morphine into various amygdaloid nuclei differentially affects nociceptive responsiveness and RVM neuronal activity. Pain 2002;96:153. Mercadante S, Arcuri E: Opioids and renal function. J Pain 2004;5:2. Meunier J, Mouledous L, Topham CM: The nociceptin (ORL1) receptor: Molecular cloning and functional architecture. Peptides 2000;21:893. Mitchell JM, Basbaum AI, Fields HL: A locus and mechanism of action for associative morphine tolerance. Nat Neurosci 2000;3:47. Pan YX: Diversity and complexity of the mu opioid receptor gene: Alternate premRNA splicing and promoters. DNA Cell Biol 2005;24:736. Reimann F et al: Pain perception is altered by a nucleotide polymorphism in SCN9A. Proc Natl Acad Sci USA 2010;107:5148. Reynolds SM et al: The pharmacology of cough. Trends Pharmacol Sci 2004;25:569.


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Pharmacology_Katzung. Reynolds SM et al: The pharmacology of cough. Trends Pharmacol Sci 2004;25:569. Rittner HL, Brack A, Stein C: Pain and the immune system. Br J Anaesth 2008;101:40. Roeckel LA et al: Opioid-induced hyperalgesia: Cellular and molecular mechanisms. Neuroscience 2016;338:160. Scherrer G et al: Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell 2009;137:1148. Schuckit MA: Treatment of opioid use disorders. N Engl J Med 2016;375:357. Skarke C, Geisslinger G, Lotsch J: Is morphine-3-glucuronide of therapeutic relevance? Pain 2005;116:177. Smith MT: Differences between and combinations of opioids revisited. Curr Opin Anaesthesiol 2008;21:596. Smith MT: Neuroexcitatory effects of morphine and hydromorphone: Evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol 2000;27:524. Spahn V et al: A nontoxic pain killer designed by modeling of pathological receptor conformations. Science 2017;355:966.


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Pharmacology_Katzung. Spahn V et al: A nontoxic pain killer designed by modeling of pathological receptor conformations. Science 2017;355:966. Stein C: Opioid receptors Annu Rev Med 2016;67:433. Vanderah TW et al: Mechanisms of opioid-induced pain and antinociceptive tolerance: Descending facilitation and spinal dynorphin. Pain 2001;92:5. Volkow ND, McLellan AT: Opioid abuse in chronic pain: Misconceptions and mitigation strategies. N Engl J Med 2016;374:1253. Waldhoer M et al: A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. Proc Natl Acad Sci USA 2005;102:9050. Wang Z et al: Pronociceptive actions of dynorphin maintain chronic neuropathic pain. J Neurosci 2001;21:1779. Wild JE et al: Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Pract 2010;10:416.


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Pharmacology_Katzung. Wild JE et al: Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Pract 2010;10:416. Williams JT, Christie MJ, Manzoni O: Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev 2001;81:299. Woolf CJ, Salter MW: Neuronal plasticity: Increasing the gain in pain. Science 2000;288:1765. Zhao GM et al: Profound spinal tolerance after repeated exposure to a highly selective mu-opioid peptide agonist: Role of delta-opioid receptors. J Pharmacol Exp Ther 2002;302:188. Zubieta JK et al: Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science 2001;293:311.


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Pharmacology_Katzung. In this case, the treatment of severe pain should be managed with the administration of a potent intravenous opioid anal-gesic such as morphine, hydromorphone, or fentanyl. Before an additional dose of an opioid analgesic is administered, it is expected that the patient will require frequent reevaluation of both the severity of his pain and the presence of potential adverse effects. Given his history of pulmonary disease, he is also at increased risk of developing respiratory depression. Concurrent use of nonopioid analgesics including nerve blocks with a local anesthetic can reduce opioid require-ments and risk of respiratory failure. Reevaluation of his level of consciousness, respiratory rate, fractional oxygen satura-tion, and other vital parameters can help achieve the goal of pain relief and minimize respiratory depression. Concurrent use of sedative agents such as benzodiazepines should be avoided if possible and proceed only with great caution. Drugs of Abuse


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Drugs of Abuse Christian Lüscher, MD

Pharmacology_Katzung. Drugs of Abuse Christian Lüscher, MD


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Pharmacology_Katzung. Christian Lüscher, MD A 15-year-old high school student is brought to the emergency department after his parents found him in his room staring at the ceiling and visibly frightened. Earlier that evening, he attended a party but was depressed because his girlfriend just broke up with him. Jerry is failing this year at school and has stopped playing soccer. His parents are also worried about a change in his behavior over the last few months. He has lost interest in school, at times seems depressed, and tells his par-ents that his pocket money is not sufficient. When questioned by the intern, he reports that space-cookies were served at the party. He also says that smoking marijuana has become a habit (three to four joints a week) but denies consumption of alcohol and other drugs. How do you explain the state he was found in? What is the difference between hashish and marijuana? What may be the link to his poor performance at school? Are all drug users necessarily using several drugs?


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Pharmacology_Katzung. Drugs are abused (used in ways that are not medically approved) because they cause strong feelings of euphoria or alter perception. However, repetitive exposure induces widespread adaptive changes in the brain. As a consequence, drug use may become compulsive—the hallmark of addiction. There is a conceptual and mechanistic separation of “dependence” and “addiction.” The older term “physical dependence” is now denoted as dependence, whereas “psychological dependence” is more simply called addiction.


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Pharmacology_Katzung. Every addictive drug causes its own characteristic spectrum of acute effects, but all have in common the characteristic that they induce strong feelings of euphoria and reward. With repetitive exposure, addictive drugs induce adaptive changes such as tolerance (ie, escalation of dose to maintain effect). Once the abused drug is no longer available, signs of withdrawal become apparent. A combination of such signs, referred to as the withdrawal syndrome, defines dependence. Dependence is not always a correlate of drug abuse—it can also occur with many classes of non-psychoactive drugs, eg, sympathomimetic vasoconstrictors and bronchodilators, and organic nitrate vasodilators. Addiction, on the other hand, consists of compulsive, relapsing drug use despite negative consequences, at times triggered by cravings that occur in response to contextual cues (see Box: Animal Models in Addiction Research). Although dependence invariably occurs with chronic exposure, only a small percentage of


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Pharmacology_Katzung. triggered by cravings that occur in response to contextual cues (see Box: Animal Models in Addiction Research). Although dependence invariably occurs with chronic exposure, only a small percentage of subjects develop a habit, lose control, and become addicted. For example, very few patients who receive opioids as analgesics desire the drug after withdrawal. And only one person out of six becomes addicted within 10 years of first use of cocaine. Conversely, relapse is very common in addicts after a successful withdrawal when, by definition, they are no longer dependent.


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Pharmacology_Katzung. ADDICTIVE DRUGS INCREASE THE LEVEL OF DOPAMINE: REINFORCEMENT


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Pharmacology_Katzung. To understand the long-term changes induced by drugs of abuse, their initial molecular and cellular targets must be identified. A combination of approaches in animals and humans, including functional imaging, has revealed the mesolimbic dopamine system as the prime target of addictive drugs. This system originates in the ventral tegmental area (VTA), a tiny structure at the tip of the brainstem, which projects to the nucleus accumbens, the amygdala, the hippocampus, and the prefrontal cortex (Figure 32–1). Most projection neurons of the VTA are dopamine-producing neurons. When the dopamine neurons of the VTA begin to fire in bursts, large quantities of dopamine are released in the nucleus accumbens and the prefrontal cortex. Early animal studies pairing electrical stimulation of the VTA with operant responses (eg, lever pressing) that result in strong reinforcement established the central role of the mesolimbic dopamine system in reward processing. Direct application of drugs into the


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Pharmacology_Katzung. operant responses (eg, lever pressing) that result in strong reinforcement established the central role of the mesolimbic dopamine system in reward processing. Direct application of drugs into the VTA also acts as a strong reinforcer, and systemic administration of drugs of abuse causes release of dopamine. Even selective activation of dopamine neurons is sufficient to drive reinforcement and elicit adaptive behavioral changes typically observed with addictive drugs. These very selective interventions use optogenetic methods. Blue light is delivered in a freely moving mouse through light guides to activate channelrhodopsin, a light-gated cation channel that is artificially expressed in dopamine neurons. As a result, mice will self-administer light to activate VTA dopamine neurons. After several pairings with a specific environment, a long-lasting place preference is established. Once the light is no longer available, a seeking behavior is observed. Finally some mice will


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Pharmacology_Katzung. After several pairings with a specific environment, a long-lasting place preference is established. Once the light is no longer available, a seeking behavior is observed. Finally some mice will self-stimulate even if they have to endure a punishment (light electric shock). Conversely, using inhibitory optogenetic effectors or activation of inhibitory neurons upstream causes aversion.


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Pharmacology_Katzung. FIGURE 32–1 Major connections of the mesolimbic dopamine system in the brain. Schematic diagram of the brain illustrating that the dopamine projections (red) originate in the ventral tegmental area (VTA) and target the nucleus accumbens (NAc), prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral pallidum (VP). Neurons in the NAc fall into two classes, one expressing type 1 dopamine receptors (D1s) and the other expressing type 2 receptors (D2s). Both classes contain GABAergic projection neurons (green); the D1R neurons send their axons to both the VP and the VTA (where they target primarily the GABA interneurons), whereas the D2R neurons send their axons selectively to the VP. The NAc is also a site of convergence of excitatory projections from the mPFC, the ventral hippocampus (vHippo), and the BLA. The midbrain dopamine neurons receive a direct excitatory input (blue) from the lateral dorsal tegmentum (LDT), while the GABA neurons of the rostromedial tegmentum (RMTg) at


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Pharmacology_Katzung. (vHippo), and the BLA. The midbrain dopamine neurons receive a direct excitatory input (blue) from the lateral dorsal tegmentum (LDT), while the GABA neurons of the rostromedial tegmentum (RMTg) at the tail of the VTA are excited by neurons from the lateral habenula (LHb), typically when an aversive stimulus occurs. (Modified with permission from Lüscher C: Emergence of circuit model for addiction. Ann Rev Neurosci 2016;39:257.)


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Pharmacology_Katzung. As a general rule, all addictive drugs activate the mesolimbic dopamine system. The behavioral significance of this increase of dopamine is still debated. An appealing hypothesis is that mesolimbic dopamine codes for the difference between expected and actual reward and thus constitutes a strong learning signal (see Box: The Dopamine Hypothesis of Addiction).


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Pharmacology_Katzung. Since each addictive drug has a specific molecular target that engages distinct cellular mechanisms to activate the mesolimbic system, three classes can be distinguished: A first group binds to Gio protein-coupled receptors, a second group interacts with ionotropic receptors or ion channels, and a third group targets the dopamine transporter (Table 32–1 and Figure 32–2). G protein-coupled receptors (GPCRs) of the Gio family inhibit neurons through postsynaptic hyperpolarization and presynaptic regulation of transmitter release. These three classes of drugs loosely map onto three distinct cellular mechanisms to increase dopamine levels. The first is a direct stimulation of the dopamine neurons (eg, nicotine). The second mechanism is the interference with the reuptake of dopamine or the promotion of nonvesicular release (eg, amphetamines). This happens in the target regions as well as the VTA itself, because dopamine neurons also express somatodendritic transporters, which normally


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Pharmacology_Katzung. promotion of nonvesicular release (eg, amphetamines). This happens in the target regions as well as the VTA itself, because dopamine neurons also express somatodendritic transporters, which normally clear dopamine released by the dendrites. Although drugs of this class also affect transporters of other monoamines (norepinephrine, serotonin), action on the dopamine transporter remains central for addiction. This is consistent with the observations that antidepressants that block serotonin and norepinephrine uptake, but not dopamine uptake, do not cause addiction even after prolonged use. The third mechanism is indirect, whereby the drugs inhibit γ-aminobutyric acid (GABA) neurons that act as local inhibitory interneurons (eg, opioids).


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Pharmacology_Katzung. DEPENDENCE: TOLERANCE & WITHDRAWAL With chronic exposure to addictive drugs, the brain shows signs of adaptation. For example, if morphine is used at short intervals, the dose has to be progressively increased over the course of several days to maintain rewarding or analgesic effects. This phenomenon is called tolerance. It may become a serious problem because of increasing side effects—eg, respiratory depression—that do not show as much tolerance and may lead to fatalities associated with overdose.


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Pharmacology_Katzung. Tolerance to opioids may be due to a reduction of the concentration of a drug or a shorter duration of action in a target system (pharmacokinetic tolerance). Alternatively, it may involve changes of μ-opioid receptor function (pharmacodynamic tolerance). In fact, many μ-opioid receptor agonists promote strong receptor phosphorylation that triggers the recruitment of the adaptor protein β-arrestin, causing G proteins to uncouple from the receptor and to internalize within minutes (see Chapter 2). Since this decreases signaling, it is tempting to explain tolerance by such a mechanism. However, morphine, which strongly induces tolerance, does not recruit β-arrestins and fails to promote receptor internalization (see Chapter 31). Conversely, other agonists that


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Pharmacology_Katzung. TABLE 32–1 The mechanistic classification of drugs of abuse.1 5-HTxR, serotonin receptor; CB1R, cannabinoid-1 receptor; DAT, dopamine transporter; GABA, γ-aminobutyric acid; Kir3 channels, G protein-coupled inwardly rectifying potassium channels; LSD, lysergic acid diethylamide; μ-OR, μ-opioid receptor; nAChR, nicotinic acetylcholine receptor; NET, norepinephrine transporter; NMDAR, N-methyl-D-aspartate receptor; R, receptor; SERT, serotonin transporter; VMAT, vesicular monoamine transporter; ? indicates data not available. 1Drugs fall into one of three categories, targeting either G protein-coupled receptors, ionotropic receptors or ion channels, or biogenic amine transporters. 2RR, relative risk of addiction; 1 = nonaddictive; 5 = highly addictive.


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Pharmacology_Katzung. drive receptor internalization very efficiently induce only modest Adaptive changes become fully apparent once drug exposure tolerance. Based on these observations, it has been hypothesized is terminated. This state is called withdrawal and is observed to that desensitization and receptor internalization actually protect varying degrees after chronic exposure to most drugs of abuse. the cell from overstimulation. In this model, morphine, by fail-Withdrawal from opioids in humans is particularly strong ing to trigger receptor endocytosis, disproportionally stimulates (described below). Studies in rodents have added significantly to adaptive processes, which eventually cause tolerance. Although our understanding of the neural and molecular mechanisms that the molecular identity of these processes is still under investiga-underlie dependence. For example, signs of dependence, as well tion, they may be similar to the ones involved in withdrawal as analgesia and reward, are abolished in


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Pharmacology_Katzung. is still under investiga-underlie dependence. For example, signs of dependence, as well tion, they may be similar to the ones involved in withdrawal as analgesia and reward, are abolished in knockout mice lack(see below). ing the μ-opioid receptor, but not in mice lacking other opioid


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Pharmacology_Katzung. Class 2 (benzodiazepines, nicotine, ethanol): channels Class 3 (cocaine, amphetamine, ecstasy): transporters (opioids, THC, GHB): GPCRs Glutamate GABA GABA DA Increased dopamine (all addictive drugs) FIGURE 32–2 Neuropharmacologic classification of addictive drugs by primary target (see text and Table 32–1). DA, dopamine; GABA, γ-aminobutyric acid; GHB, γ-hydroxybutyric acid; GPCRs, G protein-coupled receptors; THC, Δ9-tetrahydrocannabinol.