Abbreviations
CNS	Central nervous system
COX	Cyclooxygenase
GI	Gastrointestinal
5-HT	Serotonin
IV	Intravenous
MAO	Monoamine oxidase
NAPQI	N-acetyl-p-benzoquinoneimine
NE	Norepinephrine
NSAID	Nonsteroidal antiinflammatory drug
PG	Prostaglandin
PGI₂	Prostacyclin
TX	Thromboxane

Therapeutic Overview

In Paradise Lost, John Milton wrote that “Pain is perfect misery, the worst of evils, and excessive, overturns all patience.” Pain is a subjective symptom, an unpleasant sensory or emotional experience that is associated typically with actual or potential tissue damage and is the most common reason for seeking medical care. Analgesia is a state in which no pain is felt despite the presence of normally painful stimuli. Drugs that alleviate pain without major impairment of other sensory modalities are termed analgesics and fall into three major categories: the opioid analgesics, the non-opioid analgesics, and analgesics used to treat specific pain syndromes.

The opioid analgesics include compounds that relieve moderate to severe pain through actions mediated by a specific family of cell-surface receptors. Morphine is the prototypical opioid and is one of two analgesics (codeine is the other) found in opium, the milky exudate of the poppy plant (Papaver somniferum). It was the first alkaloid to be isolated in 1806 by Sertürner, who named the substance after the Greek god of dreams, Morpheus.

Narcotic is a term still used to refer to opioids and has its origins in Federal legislation (1914 Harrison Narcotic Act). Medically, a narcotic is a drug that produces a stuporous, sleeplike state and may or may not relieve pain; thus it is not a precise term. In addition, the term opiate is also used sometimes to refer to these compounds. Opiates are defined as compounds isolated from the opium poppy (morphine and codeine) that act at opioid receptors, whereas opioids are compounds of any structural type that interact with the opioid receptors and include peptides as well as fully synthetic small organic molecules; however, these terms are often used interchangeably. Opioid analgesics include morphine and its synthetic analogs, partial agonists, mixed-acting agonist-antagonists, pure antagonists, and peptides found in brain and other tissues. Although the mixed-acting agonist-antagonists and many of the endogenous peptides do not always resemble morphine in their actions, the term opioid is used to refer to the entire group of drugs.

The non-opioid analgesics include the nonsteroidal antiinflammatory drugs (NSAIDs), typified by aspirin and ibuprofen. These compounds relieve mild to moderate pain and have antipyretic and antiinflammatory properties. Acetaminophen is similar to the NSAIDs in relieving mild to moderate pain and has antipyretic activity; however, acetaminophen is devoid of antiinflammatory activity. All of the non-opioid analgesics are used to treat pain arising from integument structures such as headache and myalgia, dysmenorrhea, and some types of postoperative pain, as well as fever. The NSAIDs are effective for inflammatory disorders, such as osteoarthritis and rheumatoid arthritis, which are characterized by inflammation, pain, and subsequent tissue damage. Although NSAIDs do not affect the causative factors or prevent the progression of arthritic disorders, they can provide welcome relief from the associated pain and inflammation and improve the mobility of bone joints, thereby improving quality of life.

It is now apparent that aspirin and other NSAIDs have therapeutic value for indications other than pain, fever, and inflammation. A low dose of aspirin inhibits platelet aggregation and, when taken prophylactically, lowers the incidence of myocardial infarction and stroke in patients at high risk for ischemic cardiovascular events. More recent findings indicate that chronic treatment with aspirin or other NSAIDs reduces the incidence of colorectal and certain other cancers.

The third group of analgesics includes compounds that do not relieve pain from tissue damage (i.e., nociceptive pain) but can provide relief in specific pain syndromes such as neuropathic pain, gout, migraine headache, and fibromyalgia. Neuropathic pain results from changes in sensory neurons that render them hyperactive, even in the absence of nociceptive stimuli. It is often a chronic condition that is impervious to standard analgesic drugs. However, neuropathic pain is ameliorated by tricyclic antidepressants and compounds used to treat seizure disorders, drugs that are not thought of as primary analgesic agents.

Gout, or gouty arthritis, is the most common cause of inflammatory joint disease in men over age 40. Caused by deposition of urate crystals in bone joints accompanied by increased blood uric acid concentrations, it is treated symptomatically with NSAIDs, corticosteroids, or colchicine to decrease inflammation and with specific drugs to correct the underlying hyperuricemia.

Migraine, one of three primary types of headache, afflicts as many as 10% of the population. In addition to causing pain and suffering, it has a large economic impact from direct healthcare costs and lost productivity. Migraine is treated with the NSAIDS, ergot derivatives, and the serotonin (5-HT) receptor agonists (“triptans”), the latter often the most effective for aborting a migraine headache.

Fibromyalgia is a chronic disorder characterized by pain in muscle, ligaments, and tendons, fatigue, and sleep problems. It is more common in women than men, and symptoms vary widely. Fibromyalgia is treated with NSAIDs, acetaminophen, and pregabalin, an anticonvulsant that is also used to alleviate neuropathic pain associated with post-herpetic neuralgia and diabetic peripheral neuropathy.

The principal uses of the opioids, NSAIDs, and acetaminophen are listed in the Therapeutic Overview Box.

Therapeutic Overview
Opioids
Relief of most types of moderate to severe visceral or somatic pain
Symptomatic treatment of acute diarrhea
Cough suppression
Treatment of opiate addiction and alcoholism
Anesthetic adjunct
Overdose can be reversed by opioid receptor antagonists
NSAIDs and Acetaminophen
Relief of mild to moderate somatic pain including headache, toothache, myalgia, and arthralgia
Reduce fever
Prophylaxis of myocardial infarction and stroke
NSAIDs only
Relief in inflammatory disorders including rheumatoid arthritis, osteoarthritis, gout, and ankylosing spondylitis

Mechanisms of Action

Neurophysiology of Pain

Sensations of pain are modulated by both ascending and descending pathways in the central nervous system (CNS). Noxious or nociceptive stimuli activate highly developed endings on primary afferent neurons, termed nociceptors (pain receptors). These stimuli give rise to action potentials that are transmitted along afferent neurons into the dorsal horn of the spinal cord. A-delta (Aδ) fibers are small, myelinated, rapidly conducting afferent neurons that terminate in lamina I of the spinal cord. They have a relatively high threshold for activation by mechanical and thermal stimuli and mediate sharp and localized pain, often termed somatic pain. C-fibers are even smaller unmyelinated afferent neurons and hence are slower conducting. They are polymodal and are activated by mechanical, thermal, or chemical stimuli. They terminate in lamina II of the spinal cord (substantia gelatinosa) and mediate dull, diffuse, aching, or burning pain sometimes called visceral pain (see Chapter 13, Fig. 13-5). Aδ and C-fibers release excitatory amino acids in the dorsal horn; C-fibers, which are stimulated by bradykinin and prostaglandins (PGs) released from local damaged cells, release substance P and other neuropeptides. These neurotransmitters activate secondary neurons that form the ascending spinothalamic pathway, which projects to supraspinal nuclei in the thalamus and then to the limbic system and cerebral cortex (Fig. 36-1, A).

FIGURE 36–1 A, Ascending spinothalamic tract pain-transmitting pathway and descending pain-inhibitory pathway originating in the midbrain. B, Possible synaptic connections in the dorsal horn and mediators that may influence the transmission of pain stimuli.

Descending pain-inhibitory systems originate in the periaqueductal gray region of the midbrain and from several nuclei of the rostroventral medulla oblongata and project downward to the dorsal horn. These descending systems release norepinephrine (NE), 5-HT, and other neurotransmitters and thereby inhibit the activity of the ascending pain pathways, either through direct synaptic contacts or indirectly by activating inhibitory interneurons. These pathways are illustrated in Figure 36-1, B.

Opioids

Three major families of opioid peptides have been identified: the enkephalins, endorphins, and dynorphins. They are derived from precursor molecules encoded by separate genes—proenkephalin, proopiomelanocortin, and prodynorphin, respectively. Although found primarily in the CNS, some opioid peptides, notably the enkephalins, also exist in peripheral tissues such as nerve plexuses of the gastrointestinal (GI) tract and the adrenal medulla (Table 36-1).

TABLE 36–1 Principal Endogenous Opioid Peptides

Opioid Family	Precursor	Distribution
Enkephalins	Proenkephalin	Widely throughout the CNS, especially in interneurons, including those associated with pain pathways and emotional behavior; also found in some peripheral tissues
Endorphins	Proopiomelanocortin	β-Endorphin in hypothalamus, nucleus tractus solitarius, and anterior lobe of the pituitary where it is co-released with adrenocorticotrophin in response to stress
Dynorphins	Prodynorphin	Dynorphin A (1-17) in the magnocellular cells of the hypothalamus and posterior lobe of the pituitary gland where it co-localizes with vasopressin; shorter-chain dynorphins distributed widely in the CNS, some associated with pain pathways, especially in the spinal cord

Enkephalinergic interneurons in the dorsal horn produce presynaptic inhibition of primary afferent neurons and postsynaptic inhibition of secondary neurons in ascending pathways. Shorter-chain products of prodynorphin, notably dynorphin A (1-8), like the enkephalins, occur in interneurons distributed widely throughout the CNS and are prevalent in laminae I and II of the spinal cord.

β-Endorphin and longer-chain dynorphins, such as dynorphin A (1-17), have a more limited distribution in the CNS and may not influence pain processing directly. Rather, they may have hormonal roles in responses to stress and fluid homeostasis, respectively. The structures of the three classical families of opioid peptides are shown in Figure 36-2.

FIGURE 36–2 The major families of opioid peptides—endorphins, enkephalins, dynorphins—are derived from distinct precursor molecules—proopiomelanocortin, proenkephalin A, prodynorphin—and are encoded by three distinct genes.

Three major opioid receptors have been identified by pharmacological means and molecular cloning and are designated μ, κ, and δ (Table 36-2). They are also referred to by either their International Union of Pharmacology nomenclature (OP₃, OP₂, and OP₁, respectively) or their molecular biological nomenclature (MOP, KOP, and DOP, respectively). All three receptors belong to the superfamily of G-protein-coupled receptors with the characteristic seven transmembrane-spanning regions (see Chapter 1). Activation of these receptors decreases synthesis of cyclic adenosine monophosphate, increases K⁺ conductance, and decreases Ca⁺⁺ conductance, effects illustrated in Figure 36-3. Because changes in K⁺ and Ca⁺⁺ conductances inhibit neuronal activity, activation of any of the three opioid receptors usually results in decreased neuronal transmission.

TABLE 36–2 Opioid Receptors and their Ligands

Receptor	Endogenous Ligand	Drug Ligands
μ Receptor (OP₃/MOP)	Enkephalins	Morphine
	β-Endorphin	Buprenorphine
	Endomorphins (?)	Methadone
		Meperidine
		Fentanyl
κ Receptor (OP₂/KOP)	Dynorphins	Butorphanol
κ Receptor (OP₂/KOP)		Pentazocine
δ Receptor (OP₁/DOP)	Enkephalins	None to date
δ Receptor (OP₁/DOP)	β-Endorphin

FIGURE 36–3 Mechanism of action of opioids on neurons. Opioid receptors μ, δ, and κ are coupled negatively to adenylyl cyclase (AC) by G-proteins (G_i). Activation of an opioid receptor by an agonist decreases activity of adenylyl cyclase, resulting in a decrease in the production of cyclic adenosine monophosphate (cAMP). This leads to an increase in the efflux of K⁺ and cellular hyperpolarization and a decrease in the influx of Ca⁺⁺ and lower intracellular concentrations of free Ca⁺⁺. The overall consequence is a decrease in the neuronal release of neurotransmitters. Opioid receptors also may be coupled by G-proteins to intracellular second messengers other than cAMP.

The selectivity of opioid receptors for endogenous and drug ligands is shown in Table 36-2. The anatomical distribution of opioid receptors is consistent with the actions of the opioids—that is, they are found prominently among structures of the ascending and descending pain-modulatory pathways. All clinically important effects of morphine and morphine-like drugs are mediated by μ receptors. Some of the effects of mixed-action opioids, including analgesia at the level of the spinal cord, sedation, and the dysphoria that occurs at high doses, are mediated by κ receptors. With the exception of the opioid antagonists, there are currently no therapeutic agents that interact with μ receptors in a clinically meaningful way. In cases in which opioids can be resolved into optical isomers, the levorotatory isomer usually has a considerably higher affinity for opioid receptors than does its dextrorotatory counterpart. The structures of morphine and representative agonist/antagonist compounds are shown in Figure 36-4.

FIGURE 36–4 Structures of morphine and representative partial-agonist, agonist-antagonist, and antagonist opioid drugs.

NSAIDs and Acetaminophen

The mechanism of action, all of the therapeutic effects, and many of the side effects of the NSAIDs are due to inhibition of cyclooxygenase (COX), an enzyme involved in the metabolism of the eicosanoids. The eicosanoids are derivatives of arachidonic acid and include the leukotrienes synthesized by the action of 5-lipoxygenases, and the PGs and thromboxanes (TXs) synthesized by the action of the COXs (see Chapter 15, Fig. 15-1). Two distinct COX enzymes have been identified. COX-1 is constitutively expressed and is involved in “housekeeping tasks” in cells. COX-2 occurs constitutively in some tissues but is largely inducible, and induction results in a marked increase in the rate of synthesis and release of COX products, particularly the PGs. Aspirin acetylates both COX enzymes, inhibiting their activity irreversibly, whereas other nonselective NSAIDs inhibit the COX enzymes reversibly. The COX-2 inhibitors are 8- to 35-fold more selective for COX-2 relative to COX-1 and inhibit COX-2 irreversibly in a time-dependent manner. The functional consequences of inhibition of COX-2 relative to COX-1 are depicted in Figure 36-5. Structures of aspirin, acetaminophen, and the COX-2 inhibitor celecoxib are shown in Figure 36-6.

FIGURE 36–5 NSAIDs produce their therapeutic effects and many side effects by inhibiting the cyclooxygenase (COX) enzymes. Drugs that inhibit COX-2 selectively may produce fewer adverse side effects than do those that inhibit both isoforms of the enzyme.

FIGURE 36–6 Structures of aspirin, acetaminophen, and celecoxib.

At the site of injury, PGs sensitize nociceptors to many chemical mediators of pain, including bradykinin, cytokines, and certain amino acids and neuropeptides, and to mechanical and thermal stimuli. In addition, PGs and prostacyclin (PGI₂) promote blood flow to injured tissues, resulting in leukocyte infiltration. These effects, together with leukotriene-induced increases in vascular permeability and attraction of polymorphonuclear leukocytes, lead to edema and inflammation. Peripheral inflammation also is associated with an increased expression of COX-2 in the dorsal horn of the spinal cord. Viruses and bacterial endotoxins, through a chain of events, induce COX-2 in the preoptic nuclei of the hypothalamus, the thermoregulatory center of the body. Prostaglandin E₂, in particular, is a potent pyrogen that raises the set-point of the thermoregulatory center, resulting in elevated body temperature. Thus inhibition of COX-2 can be an effective treatment for certain types of pain, inflammation, and fever.

Drugs for Specific Pain Syndromes

Neuropathic Pain

Neuropathic pain is the result of injury to peripheral sensory nerves and is different from the nociceptive pain caused by tissue damage, in which sensory nerves are activated by chemical mediators of pain. There are many causes of nerve injury, including physical trauma, metabolic and autoimmune disorders, viral infection, chemotoxicity, and chronic inflammation. Nearly half of all diabetic patients experience peripheral neuropathies eventually. Neuropathic pain states often are associated with hyperalgesia (increased sensitivity to normally painful stimuli) and allodynia (pain caused by stimuli that are not normally painful; e.g., touch).

In neuropathic pain, primary afferent neurons are hyperactive, discharging spontaneously (in the absence of an identifiable noxious stimulus), and there is a cascade of changes to neurons in dorsal root ganglia and in the dorsal horn of the spinal cord. These changes present multiple targets for pharmacological intervention, among which are increases in the expression and activity of Na⁺ channels. Several drugs introduced to treat seizure disorders have been shown to be effective in the treatment of neuropathic pain. These agents include carbamazepine and lamotrigine, which inhibit voltage-dependent Na⁺ channels, and pregabalin, which binds to an auxiliary subunit of voltage-gated Ca⁺⁺ channels to decrease the release of several neurotransmitters (see Chapter 34). The tricyclic antidepressants (see Chapter 30) have also been shown to be effective for this condition.

Fibromyalgia

Fibromyalgia is believed currently to result from an increased sensitivity of the brain to pain signals as a consequence of a decreased pain threshold. This process, referred to as central sensitization, may result from alterations in both neurotransmitters and an increased sensitivity of pain receptors triggered by repeated nerve stimulation.

The anticonvulsant pregabalin was the first drug approved by the U.S. Food and Drug Administration in 2007 specifically for the management of fibromyalgia. As mentioned, pregabalin decreases the activity of voltage-gated Ca⁺⁺ channels and is thought to dampen Ca⁺⁺-mediated neurotransmitter release. Other drugs for fibromyalgia include the antidepressants such as amitriptyline and muscle relaxants such as cyclobenzaprine.

Gout

As mentioned, gout is an inflammatory disease caused by increased uric acid in the blood and the deposition of uric acid crystals in bone joints. Uric acid is a waste product formed from the catabolism of purines and normally dissolves in blood and is excreted by the kidneys. However, if too much uric acid is formed or too little is excreted, urate crystals precipitate. Crystals in the joints and surrounding tissue attract leukocytes, which attempt to phagocytose them, releasing inflammatory mediators in the process. In classical acute gout, the big toe is the body part most often the site of the inflammatory response and associated pain. Gout occurs in approximately 0.6% of men and 0.1% of women, primarily after menopause.

Drugs from several pharmacological classes are used to treat or prevent gout. The NSAIDs and the corticosteroids (see Chapter 39) attenuate inflammatory responses to urate crystals and the associated pain. Colchicine also reduces the inflammatory response, but through a different mechanism. Colchicine binds to tubulin in leukocytes, causing microtubules to disaggregate. This affects the structure of the cells, inhibiting their migration into the inflamed area and reducing phagocytic activity.

Specific drugs are used to correct the underlying hyperuricemia in gout. Allopurinol, a structural analog of the purine hypoxanthine, inhibits the enzyme xanthine oxidase (Fig. 36-7), blocking the metabolism of hypoxanthine and xanthine to uric acid and lowering blood urate concentrations. Normally, approximately 90% of filtered urate is resorbed and only 10% is excreted. The uricosuric agents probenecid and sulfinpyrazone increase urate excretion by competing with uric acid for the renal tubular acid transporter so less urate is resorbed.

FIGURE 36–7 Blockade of uric acid synthesis by allopurinol and its oxidated metabolite, oxypurinol.

Migraine

Migraine is a neurovascular syndrome characterized by throbbing unilateral headache and often a premonitory prodrome or aura, nausea, vomiting, photophobia, blurry vision, and GI and other unpleasant symptoms. Almost three times more women than men suffer from migraine. Although many triggers of migraine episodes have been identified, the pathophysiology of the disorder is not clear. Migraine may involve release of monoamines and vasoactive peptides from trigeminal neurons and structures in the brainstem, which first cause cerebral vasoconstriction and then vasodilation, the latter associated with neurogenically induced inflammation and increased expression of COX-2 in some brain areas. 5-HT appears to be involved in migraine episodes, possibly by facilitating neuronal release of vasoactive substances, directly affecting the tone of cerebral vessels, or by activating cranial nociceptors.

Migraine episodes can be aborted or lessened in intensity in most patients by drugs that activate 5-HT₁ receptors. The triptans such as sumatriptan are relatively selective agonists at 5-HT_1B/D receptors, whereas ergot derivatives such as ergotamine are partial agonists at presynaptic 5-HT₁ and other 5-HT receptors and at some catecholamine receptors. The mechanism of action of these drugs is uncertain but may involve direct constriction of intracranial arterioles, reversing the abnormal cerebral vasodilation that occurs in migraine. It has also been suggested that activation of presynaptic 5-HT₁ autoreceptors reduces neuronal release of vasoactive substances into the perivascular space.

The NSAIDs also bring relief from migraine episodes in many patients. They are presumed to attenuate the neurogenically induced inflammatory response through inhibition of COX-2. Other drugs are also used as preventive therapy, including tricyclic antidepressants, especially amitriptyline (see Chapter 30), and the β adrenergic receptor blockers propranolol and timolol (see Chapter 11).

Pharmacokinetics

Opioids

Many opioids are administered parenterally, even though they are well absorbed from the GI tract. However, some opioids, such as morphine and the antagonist naloxone, undergo extensive first-pass metabolism in the liver, greatly reducing their bioavailability and therapeutic efficacy after oral administration. Although morphine often is administered orally for management of chronic pain, oral administration is much less potent compared with parenteral administration. Drugs with greater lipophilicity, including fentanyl and buprenorphine, are well absorbed through the nasal and buccal mucosa. The most lipophilic of opioids, including fentanyl, are absorbed transdermally as well. Serum protein binding ranges from approximately 30% for morphine to 80% to 90% for fentanyl and its derivatives. The pharmacokinetic profile of an opioid is a major determinant of its therapeutic use.

Because of their physicochemical properties, the speed of onset and duration of action of opioids do not always correlate with their plasma concentrations or elimination half-lives. For example, the rise in plasma concentrations of morphine long precedes the onset of analgesia because this hydrophilic drug penetrates the blood-brain barrier very slowly. In contrast, plasma concentrations of fentanyl closely parallel its therapeutic effect. Because of the rapid redistribution of lipophilic fentanyl from brain to lean body mass, its short duration of action is not predictable from its elimination half-life, which exceeds that of the longer-acting morphine. Opioids with relatively long elimination half-lives can accumulate in the body upon repeated dosing, thereby prolonging their duration of action. Remifentanil, a fentanyl analog ester, is so rapidly metabolized by plasma esterases that its plasma half-life is only 10 to 20 minutes. It does not accumulate upon repeated or slow continuous administration.

Opioids are metabolized mainly in the liver, usually to more polar and less active or inactive compounds. The mechanisms involved include N-dealkylation, conjugation of hydroxyl groups, and hydrolysis. However, metabolites account for most of the opioid activity of codeine (3-methoxymorphine) and its analogs, heroin (diacetylmorphine) and tramadol, which have weak affinity for the μ opioid receptor and have little activity themselves. The two hydroxyl groups of morphine are conjugated with glucuronic acid to produce two metabolites. Morphine-3-glucuronide is inactive, but morphine-6-glucuronide has a higher affinity for the μ opioid receptor and is a more potent analgesic than morphine. Morphine-6-glucuronide accumulates during long-term morphine treatment, and measurable amounts are found in cerebrospinal fluid. However, morphine-6-glucuronide is relatively polar and penetrates the blood-brain barrier poorly. Thus the extent to which it contributes to the analgesic effect of morphine administered acutely is unknown.

The accumulation of normeperidine, the N-demethylated product of meperidine, can result in convulsions. Significant amounts accumulate in patients receiving multiple large doses of meperidine over a relatively short time, in patients with renal insufficiency, and in people taking drugs that interfere with its metabolism, including monoamine oxidase (MAO) inhibitors.

The pharmacokinetic parameters of opioid drugs are summarized in Table 36-3.

TABLE 36–3 Pharmacokinetic Parameters of Opioids

NSAIDs and Acetaminophen

All of the antipyretic analgesics have good oral bioavailability, ranging from 80% to 100%, and are distributed throughout the body. Some are also formulated as rectal suppositories and have good bioavailability by that route as well, and some are applied topically. Ketorolac often is administered parenterally; bioavailability is essentially 100%.

Aspirin (acetylsalicylic acid) has a low pK_a and is well absorbed from the acidic environment of the stomach and duodenum, the part of the GI tract that accounts for much of the absorption of the NSAIDs. Aspirin has a plasma half-life of only 15 minutes because it undergoes rapid hydrolysis to salicylic acid, which has therapeutic effects similar to those of the parent drug. The half-life of salicylic acid ranges from 2 to 3 hours at doses used to treat pain and fever to as high as 12 hours at doses sometimes used to treat inflammatory disorders. Approximately 75% is conjugated with glycine in the liver to form the inactive salicyluric acid, which is excreted by the kidneys, along with glucuronide conjugates and 10% free salicylic acid. At alkaline pH, up to 30% of a dose may be excreted as free salicylic acid, which is why sodium bicarbonate is administered to alkalinize the urine in treating toxic concentrations. The limited hepatic pool of glycine and glucuronide available for conjugation results in elimination of salicylate by first-order kinetics at low doses and by zero-order kinetics at higher doses. This accounts for the increasing half-life with increasing dose.

Other NSAIDs are metabolized by cytochrome P450 enzymes and by other pathways in the liver, usually to inactive compounds. Some drugs, such as naproxen and indomethacin, are demethylated before being conjugated and excreted. Piroxicam and fenoprofen are hydroxylated, whereas ibuprofen and meclofenamate are hydroxylated and carboxylated before they are conjugated with glucuronic acid and excreted. Sulindac is somewhat unique in that it is metabolized to an active sulfide and undergoes extensive enterohepatic cycling, accounting for its relatively long elimination half-life. Nabumetone, like sulindac, is a prodrug; approximately 35% undergoes rapid hepatic metabolism to the active compound 6-methoxy-2-naphthylacetic acid.

Approximately half of the NSAIDs now in clinical use are cleared from the body rapidly and have an elimination half-life <6 hours, whereas others have a longer duration of action, with half-lives in excess of 8 hours. Because of the key roles of the liver and kidneys in inactivating (or activating) and excreting NSAIDs, drug doses should be adjusted and some drugs avoided entirely in patients with impaired hepatic function or renal failure. Most NSAIDs are highly bound to plasma proteins, especially albumin. This creates the potential for interactions with other drugs that also bind extensively to plasma proteins. The binding of some NSAIDs is saturable, and free drug concentration rises at higher doses.

Acetaminophen (paracetamol in many countries), like the NSAIDs, is a weak acid that is almost completely absorbed from the GI tract and the rectum. Peak plasma concentration is achieved within 1 hour, and distribution is relatively uniform throughout the body. Acetaminophen is converted almost completely to inactive metabolites in the liver. A small proportion is oxidatively metabolized via cytochrome P450 enzymes to N-acetyl-p-benzoquinoneimine (NAPQI), which is conjugated with glutathione and excreted. NAPQI is highly reactive with and binds covalently to sulfhydryl groups. If the glutathione content of the liver is depressed by disease or fasting, or is depleted by high concentrations of the intermediate metabolite, NAPQI interacts with sulfhydryl-containing hepatocellular proteins, which can lead to hepatic necrosis. Glutathione-depleting concentrations of NAPQI occur after acute overdose with acetaminophen and can also occur after high doses (>4gm/day) in patients taking drugs that induce cytochrome P450s.

The pharmacokinetic parameters for the NSAIDs and acetaminophen are shown in Table 36-4.

TABLE 36–4 Pharmacokinetic Parameters of NSAIDs and Acetaminophen

Drugs for Specific Pain Syndromes

Neuropathic Pain and Fibromyalgia

The pharmacokinetics of the anticonvulsants and antidepressants used for neuropathic pain and fibromyalgia are presented in Chapter 34 and Chapter 30, respectively.

Gout

All drugs used primarily for the treatment of gout have good oral bioavailability. Colchicine and allopurinol also come in injectable forms; however, it is best not to inject colchicine because of its toxicity. After metabolism in the liver, colchicine undergoes biliary excretion.

Allopurinol is oxidized to oxypurinol (alloxanthine), which, like the parent compound, is an inhibitor of xanthine oxidase (see Fig. 36-7) and is largely excreted by the kidneys. Inhibition of xanthine oxidase by oxypurinol is irreversible and accounts for most of the therapeutic effects of allopurinol.

Probenecid inhibits the renal tubular secretion of weak acids and can elevate plasma concentrations of weakly acidic drugs taken concomitantly—for example, many NSAIDs. This is used to advantage in situations in which it is necessary to maintain high plasma levels of cephalosporins, penicillin, and other β-lactam antibiotics (see Chapter 46).

Migraine

Sumatriptan is administered orally, subcutaneously, or intranasally. Oral bioavailability is 15%, and peak plasma concentrations are reached in 1.5 to 2 hours. In contrast, subcutaneous administration results in 97% bioavailability and peak plasma concentrations in 10 to 20 minutes. Protein binding is low, and the elimination half-life is 2 to 2.5 hours. Sumatriptan is metabolized in the liver by MAO-A. After subcutaneous administration, approximately 60% of a dose is excreted renally (20% unchanged) and the rest by the biliary-fecal route. Relief from pain of severe migraine begins within 10 minutes of injection, and half of patients experience relief within 30 minutes. The onset of action is slower when given orally, with peak relief in more than half of patients occurring within 2 hours (Fig. 36-8).

FIGURE 36–8 Time course of headache relief during a migraine attack after administration of a placebo or sumatriptan by either the oral (PO, 100 mg) or subcutaneous (SC, 6 mg) route. The ordinate indicates the percentage of patients who reported no headache or only mild headache at the corresponding time point. The graph is based upon data obtained from the U.S. Food and Drug Administration and from GlaxoSmithKline.

The newer triptans have better oral bioavailability, ranging from 40% (zolmitriptan) to 60% to 75% (almotriptan, naratriptan) and are taken only by this route. They are metabolized 25% to 50% in the liver by MAO-A (except naratriptan, which is metabolized by microsomal enzymes), and metabolites and unchanged drug are excreted in urine and bile. Among the available drugs, only zolmitriptan has an important active metabolite; it is more potent than the parent compound and probably contributes to the therapeutic effect. Elimination half-lives range from 2 to 6 hours.

Ergotamine and dihydroergotamine are absorbed erratically and undergo significant first-pass metabolism. Ergotamine is available as a sublingual tablet and dihydroergotamine as a nasal spray and a solution for intramuscular or IV injection. Both are metabolized in the liver and excreted in the bile. The onset of relief ranges from 5 minutes after IV dihydroergotamine to 0.5 to 2 hours after sublingual ergotamine.

Relationship of Mechanisms of Action to Clinical Response

Opioids

The experience of pain involves transduction, transmission, and perception of nociceptive stimuli, as well as the subsequent emotional reaction. Opioid analgesics affect both transmission of nociceptive information and its perception and also modify the reactive component of the experience. Transmission of nociceptive stimuli along ascending spinothalamic pathways is reduced when μ and κ opioid receptors on presynaptic and postsynaptic neurons in the spinal cord and brain are activated. Opioids also inhibit ascending pathways indirectly by activating descending pain-inhibitory pathways. The overall effect is an elevation of the pain threshold, which is the minimum intensity at which a stimulus is perceived as painful.

Pathological pain elicits emotional responses that include anxiety, fear, and a general state of suffering, which are accompanied by changes in autonomic and endocrine functions. Opioid analgesics blunt these emotional effects, probably by actions on receptors in the limbic system. The ability to tolerate pain increases as emotional effects are blunted, even in the absence of large changes in pain threshold. Thus the emotional reaction to pain may be reduced even when pain perception remains unaltered. Opioids are unique among analgesics in this regard.

Analgesia

In general, all morphine-like drugs are equally effective in alleviating pain except for codeine, propoxyphene, and tramadol, which are less effective. A particular drug is often chosen based on its speed of onset, duration of action, and oral bioavailability. Fentanyl and its derivatives, with rapid onsets and short durations of action, are used almost exclusively IV in anesthesiology to manage pain during and immediately after surgery (see Chapter 35). Virtually all opioids exert their analgesic effects through μ opioid receptors in brain and spinal cord. Tramadol is an exception, being a racemic mixture with the ‘d or +’ isomer binding to μ opioid receptors and inhibiting neuronal 5-HT reuptake, and the ‘l or -’ isomer inhibiting NE reuptake and stimulating α₂ adrenergic receptors.

Opioid analgesics are most effective in the management of dull, diffuse, continuous pain, with adequate doses relieving even sharp, localized, intermittent pain. A standard dose produces satisfactory relief in approximately 90% of patients with mild to moderate postoperative pain and in 65% to 70% of patients with moderate to severe postoperative pain. The degree of relief may decline after several days or more of frequent administration, as tolerance develops. Within limits, tolerance is overcome by increasing the dose and restoring the analgesic response. The pain relief conferred by opioids is often accompanied by drowsiness, mental clouding, and an elevated mood (i.e., euphoria). Although the euphoria is associated with a potential for abuse, in patients with pain it is more likely to be a secondary consequence of pain relief.

Codeine and propoxyphene by themselves are not suitable for treating severe pain. To increase their effectiveness, they (and other opioids) are sometimes administered in combination with a non-opioid antipyretic analgesic, especially aspirin or acetaminophen. Because the sites and mechanisms of action of opioid and antipyretic analgesics differ, the combination usually results in a greater analgesic effect than that achieved with maximally effective doses of either drug alone.

Several newer delivery systems for opioids are now available. A fentanyl transdermal patch is used to treat patients with chronic pain, and fentanyl administered intranasally is used to relieve acute pain. Some morphine-like opioids, especially morphine and fentanyl, are administered intrathecally and epidurally to control pain during and after surgery and to treat otherwise intractable pain. Patient-controlled analgesia allows patients to deliver opioids on demand within preset limits by activating a microprocessor-controlled pump that delivers a bolus dose through an IV or epidural catheter. Because patients can self-medicate whenever the need arises, the quality of pain control is usually better than that provided by doses administered at predetermined intervals. When high drug concentrations need to be maintained over long periods, as in certain chronic pain syndromes and in pain associated with cancer and other terminal illnesses, there are sustained-release oral formulations of morphine and oxycodone.

Cough Suppression

The sites of cough-suppressant (antitussive) action are areas in the brainstem that mediate the cough reflex. Codeine and hydrocodone are opioids commonly used for cough suppression. Dextromethorphan is a widely used antitussive found in many over-the-counter medications; it is the d-isomer of the opioid agonist levomethorphan. Dextromethorphan has negligible affinity for opioid receptors and does not produce analgesia. Its antitussive effect appears to be mediated by other mechanisms in the brainstem.

Antidiarrheal Effect

Morphine-like drugs also are used for symptomatic treatment of diarrhea because they have prominent effects on GI motility. Morphine delays gastric emptying and causes spasmodic increases in intestinal smooth muscle tone, decreasing propulsive movements and allowing more time for water resorption. Morphine also reduces intestinal secretions, drying and solidifying the stool, and increases anal sphincter tone. These effects are mediated largely by μ opioid receptors located on nerve plexuses in GI smooth muscle. Because they produce their constipating and antidiarrheal effects locally, loperamide and diphenoxylate are used exclusively to treat diarrhea. These drugs produce few side effects and have little potential for abuse, because they do not enter the CNS readily.

Partial-agonist opioids are characterized by intermediate to high affinity for μ opioid receptors but lower efficacy for μ receptor activation as compared with morphine. Therefore, under appropriate conditions, they can antagonize the effects of higher efficacy μ opioid receptor agonists. Mixed-action opioids also bind to κ receptors, which mediate at least some of their effects. Both groups of drugs are usually as efficacious as morphine in relieving pain of moderate intensity but may be less effective when pain is severe.

The pure opioid antagonists bind with high affinity and selectivity to opioid receptors but lack intrinsic activity and do not activate the receptors. The prototype naloxone (see Fig. 36-4) is used clinically, chiefly to reverse the respiratory depressant effect of opioid agonists. Administered IV, naloxone rapidly restores normal respiration and reverses virtually all effects of the agonist. If naloxone is administered before or along with an agonist, the effects of the agonist are blocked. Naloxone must be readministered periodically because of its short half-life. Its affinity for μ receptors is significantly greater than its affinity for κ or δ receptors. Therefore higher doses are required to reverse the effects of mixed-action opioids (mediated at κ receptors).

Naloxone and other antagonists can precipitate a full-blown withdrawal syndrome in people who are physically dependent on an opioid (see Chapter 37). If there is a possibility of physical dependence in an overdosed patient, it is recommended that he or she be started on a low dose of naloxone. The dose can be increased gradually to reverse respiratory depression and restore consciousness while minimizing withdrawal intensity.

Naloxone is a specific opioid antagonist and is of little value in treating overdoses of drugs that do not act at opioid receptors. In addition, it will not exacerbate effects of non-opioids, and its pharmacological specificity can be useful in differential diagnosis of comatose patients.

Naltrexone has the same pharmacological characteristics as naloxone but has a longer duration of action and superior oral bioavailability. High doses taken orally produce prolonged blockade of opioid receptors, an effect used to advantage in therapy of some abusers. Naltrexone is also approved for the treatment of alcoholism by blocking the role of endogenous opioids in alcohol craving (see Chapter 32).

NSAIDs and Acetaminophen

Although selecting a drug to relieve pain or fever is relatively simple, choosing a drug to treat one of the several arthritic disorders is more complex. Selection is based on the patient’s response over time and considerations such as duration of action and cost. Adequate symptom relief must be balanced with untoward side effects, both of which are variable, even with the same drug. Combinations of two or more NSAIDs, or of NSAIDs and acetaminophen, are available for treating pain, but their use is rarely justified. Because antipyretic analgesics have similar mechanisms of action, the maximum effect of a drug combination is unlikely to be greater than the effect of an optimal dose of a single drug.

Analgesia

Aspirin, the prototype NSAID, remains one of the most commonly used and effective agents for treating headache and mild to moderate pain arising from muscles, tendons, joints, and soma. A dose of 650 to 1000 mg produces acceptable relief in 60% to 80% of patients. Aspirin is far less effective in providing relief of severe pain and pain from visceral organs, which usually require an opioid. However, unlike the opioids, aspirin and other NSAIDs do not cause analgesic tolerance or physical dependence and are not abused. Some of the major differences between aspirin and morphine, the prototype opioid analgesic, are listed in Table 36-5.

TABLE 36–5 Comparison of Analgesic Effects of Morphine and Aspirin

Parameter	Morphine	Aspirin
Type of pain relieved	Visceral, somatic	Somatic
Intensity of pain relieved	Moderate to severe	Mild to moderate
Site of action	CNS	Local
Tolerance development	Yes	No
Physical dependence development	Yes	No
Abuse potential	High	None

Other NSAIDs have analgesic effects similar to those of aspirin. Ibuprofen and naproxen, which are available over the counter, have become popular alternatives and might be slightly more effective in treating dysmenorrhea. Ketorolac most often is used to treat postoperative pain, because it can be administered parenterally. It was originally thought to be as effective as morphine in relieving severe postoperative pain, but subsequent experience has shown that its analgesic efficacy is comparable with other NSAIDs. Selective COX-2 inhibitors are approved for the treatment of acute pain in adults and primary dysmenorrhea. Their greatest value appears to be in relieving pain caused by chronic inflammatory conditions such as osteoarthritis and rheumatoid arthritis.

Acetaminophen is also a popular alternative to aspirin for treating pain, especially by patients who are discomforted by aspirin’s side effects. It has analgesic potency and efficacy similar to aspirin. However, because it is devoid of antiinflammatory activity, it may be less effective in treating pain caused by inflammation. The mechanism of the analgesic effect of acetaminophen has been something of a mystery. It shares analgesic and antipyretic activity with the NSAIDs but lacks other actions associated with inhibition of COX. It is possible that its analgesic effect, like its antipyretic effect, is mediated via an action on the CNS. Interestingly, COX-3, a splice variant of COX-1 in brain and spinal cord, is weakly inhibited by acetaminophen. This finding raises the possibility that acetaminophen acts through another, as-yet-unknown variant or isoform of COX.

Antipyresis

The current approach to fever is to treat it only if it is debilitating and if lowering the elevated temperature will make the patient feel better. The NSAIDs and acetaminophen are antipyretic at the same doses that produce analgesia. By lowering the hypothalamic thermoregulatory set-point, they promote autonomic reflexes that cause loss of body heat, notably peripheral vasodilation and sweating. However, they are effective only in instances where elevated body temperature is caused by the increased synthesis of PGs such as in infectious disease and autoimmune disorders.

Although a causal relationship has yet to be established, there is a significant epidemiological relationship between the use of aspirin in children with certain viral infections (e.g., influenza, chickenpox) and the occurrence of Reye’s syndrome. It is not known if similar relationships exist for other NSAIDs. Because of these uncertainties, acetaminophen has become the drug of choice for treating fever in children.

Antiinflammation

The term arthritis encompasses dozens of conditions affecting body joints and connective tissue that afflict 10% to 15% of the population. Osteoarthritis, the most common arthritic disorder, affects at least 20 million Americans, and rheumatoid arthritis, an autoimmune disorder, 2 million more. The doses of NSAIDs needed to treat these and other inflammatory disorders often are higher than analgesic doses. Because many inflammatory disorders are chronic, drug selection is influenced by side effects and cost. For example, aspirin has a long and successful history of treating rheumatoid arthritis. However, many patients cannot tolerate the GI or other side effects of daily doses as high as 4 to 6 g. The range and incidence of side effects with high daily doses of other NSAIDs that inhibit both COX-1 and COX-2 are more or less similar to those of aspirin. Nevertheless, the severity of side effects and the adequacy of the therapeutic effect varies, and one NSAID may be preferred over another. Selective COX-2 inhibitors are as effective as the older NSAIDs in treating inflammatory disorders but have a lower incidence of GI side effects associated with chronic administration.

Other Indications

Low doses of aspirin are used prophylactically to inhibit platelet aggregation by patients at high risk for serious vascular events such as myocardial infarction or stroke (see Chapter 26).

NSAIDs including aspirin, celecoxib, and sulindac have been found to lower the risk for or the extent of colorectal cancer in patients who have a familial history of adenomatous polyps or who have been previously treated for colorectal cancer.

Drugs for Specific Pain Syndromes

Neuropathic Pain

Neuropathic pain syndromes are caused by many factors, some yet to be identified, and are difficult to manage. They are largely unresponsive to NSAIDs and only occasionally respond to opioid analgesics. Opioids can be used in responsive patients, although the side effects associated with chronic administration, including tolerance, must be addressed. However, neuropathic pain often can be alleviated by drugs ineffective in treating acute nociceptive pain. Notable among these are anticonvulsant drugs and tricyclic antidepressants.

Carbamazepine, lamotrigine, gabapentin, and pregabalin are currently the anticonvulsant drugs used most often to treat neuropathic pain (see Chapter 34). Carbamazepine has well-documented efficacy in the treatment of trigeminal neuralgia and may be beneficial in several other neuropathic pain syndromes including diabetic neuropathy. Lamotrigine is also of benefit in trigeminal neuralgia, while gabapentin is indicated for post-herpetic neuropathy and appears to reduce pain associated with a variety of syndromes, including phantom-limb pain, Guillain-Barré syndrome, and diabetic neuropathy. Pregabalin appears to have a profile similar to gabapentin and has also been found to be of benefit for the pain associated with sciatica. Because gabapentin seems to improve measures of mood and quality of life and has a relatively favorable profile of side effects, it is becoming the antiepileptic drug of choice for treating a range of neuropathies.

Clinical studies have demonstrated the efficacy of tricyclic antidepressants for pain relief in diabetic and post-herpetic neuropathies and in several other syndromes. Presumably, the drugs act via descending pain-inhibitory pathways, which contain noradrenergic and serotonergic neurons (see Fig. 36-1). Indeed, tricyclic antidepressants that inhibit reuptake of both NE and 5-HT such as amitriptyline, and perhaps the newer combination agents (see Chapter 30), may be more effective than drugs that selectively block reuptake of only one neurotransmitter. The analgesic effect of these agents is likely independent of their antidepressant effect, because onset of pain relief occurs more rapidly and at lower doses.

Fibromyalgia

The pain and stiffness of fibromyalgia may be improved by acetaminophen, but effectiveness varies. The NSAIDs, including aspirin, ibuprofen, and naproxen, may be of use in conjunction with acetaminophen but are not effective for pain relief by themselves. Pregabalin has been shown to decrease pain and improve function in individuals with this disorder.

Gout

Colchicine, the oldest gout-specific drug, reduces the inflammation and pain from acute gouty arthritis within 12 hours. It is used in lower doses, sometimes combined with probenecid, to treat chronic gout that is complicated by recurrence of acute attacks.

NSAIDs also provide symptomatic relief from the inflammation and pain of acute gout. Indomethacin is used most often, although ibuprofen, naproxen, sulindac, and piroxicam are also effective. Corticosteroids are efficacious antiinflammatory agents (see Chapter 39), and when used appropriately for short-term treatment of acute gout, are a safe alternative.

Allopurinol, which inhibits production of uric acid, is used in therapy of chronic gout and in hyperuricemias that develop as a result of other treatments, such as chemotherapy or radiation therapy. Uricosuric agents can also provide effective therapy of chronic gout in patients with normal renal function. However, they can exacerbate acute gouty arthritis and should not be administered until the acute attack has abated.

Migraine

The frequency of migraine episodes may range from one to two per year to more than one per week and the severity from mild to intense. A migraine usually lasts for several hours but can extend into days. Treatment of acute migraine depends on the characteristics of the headache and the concurrent existence of other medical conditions such as cardiovascular disease and pregnancy.

NSAIDs and acetaminophen are first-line drugs for treating mild to moderate migraine if not accompanied by nausea and vomiting and severe migraine in patients whose headaches have responded well to NSAIDs in the past. There is considerable evidence supporting the effectiveness of aspirin, ibuprofen, and naproxen, especially when taken at the first indication of a migraine episode. Ketorolac is sometimes administered parenterally to abort moderate to severe episodes. Several combination preparations are available that contain acetaminophen, aspirin, and caffeine; aspirin, caffeine, and the barbiturate butalbital; or acetaminophen, caffeine, and butalbital. With the exception of intranasal butorphanol, opioids are not recommended for treating migraine, because therapeutic efficacy has not been documented.

The triptans are the drugs of choice for aborting severe migraine or mild to moderate migraine that is unresponsive to NSAIDs. All clinically available triptans are, for the most part, equally effective; 60% to 80% of patients experiencing migraine report no headache or only mild headache 2 to 4 hours after taking a maximum dose. However, a patient may respond better to one drug than to another. Because sumatriptan is formulated for intranasal and subcutaneous administration, it is often preferred when nausea and vomiting are prominent components of the migraine episode. The awkwardness of giving oneself a subcutaneous injection, as opposed to swallowing a tablet, is offset by its more rapid onset of action. Advent of the triptans has led to a decline in the use of ergots, which are generally less effective than triptans and take longer to bring relief, especially if they are not taken at the start of a migraine episode.

Ergotamine has been used for many years for the treatment of moderate to severe migraine. However, it is less effective than the triptans. Dihydroergotamine is the most widely used ergot and can be injected or used intranasally. It is especially useful for individuals who do not respond to triptans.

Individuals exhibiting frequent episodes or those who cannot take vasoconstrictors or are refractory to acute treatment should receive prophylactic treatment to prevent headaches. For predictable and limited attacks of migraine, such as those that may occur during menstruation, a brief course of NSAIDs, an ergot alkaloid, or a triptan is recommended beginning several days before the anticipated onset. For continuous prophylaxis, several groups of agents are effective including the β adrenergic receptor antagonists propranolol and timolol, the anticonvulsants valproic acid and topiramate, the tricyclic antidepressants including amitriptyline and nortriptyline, and the Ca⁺⁺-channel blocker verapamil. Drugs used to abort migraine are not typically used prophylactically, owing largely to unacceptable side effects with prolonged administration.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

The major clinical problems associated with the use of drugs used for pain and inflammation are listed in the Clinical Problems Box.

Opioids

Respiratory Depression

Depression of respiration is the most serious side effect of opioid analgesics and is the principal cause of death from overdose. Opioids decrease the sensitivity of chemoreceptors in the brainstem to carbon dioxide, a normal stimulus of ventilatory reflexes. The result is a blunting of the ventilatory response to increases in the PCO₂ in blood and cerebrospinal fluid (see Fig. 35-9). At equally effective analgesic doses, most opioids, including partial agonists and mixed-acting drugs, produce a similar degree of respiratory depression, as indexed by elevation of blood PCO₂. Depression of respiration increases with increasing dose, but partial agonists and mixed-action opioids produce proportionately smaller changes in respiration than do morphine-like drugs. The respiratory depressant effect of opioids is at least additive, if not super-additive, with that produced by other CNS depressants such as general anesthetics, sedative-hypnotics, and alcohol. Tolerance tends to parallel analgesic tolerance but does not protect against the respiratory depressant effect of non-opioid drugs.

The mild respiratory depression produced by therapeutic doses of opioids is normally of little clinical consequence. However, opioid analgesics must be used cautiously in patients with traumatic head injuries, because increased PCO₂ causes cerebral vasodilation, which increases intracranial pressure. Caution must also be exercised when treating patients with a lowered respiratory reserve, such as patients with emphysema or those who are morbidly obese.

Constipation

Constipation is a troublesome side effect when opioids are used to treat pain and is made worse by the fact that little or no tolerance develops. Patients treated over the long term with opioid analgesics often require laxatives. Mixed-action opioids produce less constipation than morphine-like opioids. By constricting the sphincter of Oddi, opioids may exacerbate the pain of biliary colic and are contraindicated in patients with suspected gallbladder disease.

Nausea

Opioid analgesics stimulate the chemoreceptor trigger zone in the area postrema. Nausea, sometimes with vomiting, is a common side effect, particularly of agents administered parenterally. The incidence of vomiting is highest in ambulatory patients, indicating a vestibular component. Tolerance to the emetic effect develops rapidly in many patients.

Endocrine Effects

Opioids have few significant endocrine effects. Activation of μ opioid receptors in the hypothalamus inhibits the release of gonadotropin-releasing hormone. This lowers the plasma concentration of luteinizing hormone and testosterone, which can cause menstrual cycle irregularities and male sexual impotence. Activation of μ receptors inhibits diuresis, whereas activation of κ receptors increases diuresis by inhibiting the release of antidiuretic hormone.

Miosis

Most opioids cause pupillary constriction by stimulating the Edinger-Westphal nucleus of the oculomotor nerve. Constriction of the pupil is used clinically to gauge the adequacy of pain relief. Because miosis is apparent even in a person tolerant to most other drug effects, it is an aid in the diagnosis of overdose. Hypoxia can, however, mask the miotic effect.

Cardiovascular Effects

The cardiovascular system is relatively unaffected by opioid analgesics. High IV doses of morphine and some related drugs cause a decrease in peripheral resistance and a decline in blood pressure. These effects are rarely clinically significant in supine patients. Some opioids cause a vagally mediated reflex bradycardia, which can be blocked with atropine. Morphine, meperidine, and several other opioids can release histamine from mast cells in peripheral tissues upon IV administration, resulting in transient vasodilation, hypotension, and itching (see Chapter 14). Histamine release is one of the few effects of opioid drugs not mediated by opioid receptors and prevented by naloxone. Pentazocine and butorphanol have mild sympathomimetic effects, causing minor increases in heart rate and blood pressure.

Immunosuppression

Animal studies have shown that opioid analgesics suppress the immune system, including natural killer cell activity. Some immunosuppressive effects occur at the level of cells of the immune system, whereas others are mediated centrally and are blocked by opioid antagonists. The mechanisms and clinical significance of immunosuppression remain unclear.

Tolerance

Tolerance develops to most effects of the opioids. With repeated drug administration, larger doses are necessary to produce the original response. Tolerance develops rapidly to emetic effects; more gradually to analgesic, endocrine, and respiratory depressant effects; and virtually not at all to constipating and miotic effects. A point may be reached in highly tolerant patients where further dose increases no longer achieve pain relief. Tolerance also develops to the effects of mixed-action opioids, but at a slower rate.

Pharmacologically specific cross-tolerance is observed with the opioids—that is, a person tolerant to the analgesic and respiratory depressant effects of morphine will also be tolerant to those effects of other morphine-like drugs. The extent of cross-tolerance is a function of efficacy. Thus an opioid with higher efficacy than morphine, such as methadone or fentanyl, may relieve pain that is no longer controlled by morphine or other lower-efficacy drugs. There is no cross-tolerance between opioid and non-opioid drugs.

Physical Dependence and Abuse

Continuous exposure to an opioid analgesic results in development of physical dependence, a state in which the body has adapted to the presence of the drug and requires it for normal function. When administration is terminated or an antagonist is administered, withdrawal symptoms occur as discussed in Chapter 37.

NSAIDs and Acetaminophen

GI Effects

Epigastric distress is the most common side effect produced by the NSAIDs and the one most likely to cause a patient to stop taking a drug. Symptoms include nausea, dyspepsia, heartburn, and abdominal discomfort. A single analgesic dose of aspirin can cause occult bleeding, and four doses taken over 24 hours can cause minute lesions of the gastric mucosa. These effects are not clinically significant. However, antiinflammatory doses taken chronically result in peptic ulcers in 15% to 25% of patients and in major upper GI events such as ulceration, bleeding, and perforation in 2% to 5% of patients.

The adverse GI side effects are due to two distinct actions. The first, a physical interaction between the drug and the gastric mucosa, can be reduced by taking the medication with meals and with adequate amounts of fluids to facilitate complete dissolution of tablets. The second is due to COX-1 inhibition and the resulting loss of cytoprotective eicosanoids (see Chapter 15). Because they largely spare COX-1, selective COX-2 inhibitors produce a lower incidence of significant upper GI complications than do nonselective NSAIDs.

Acetaminophen produces minimal GI side effects, even with prolonged administration, and is a good alternative for patients who require an analgesic but cannot tolerate the GI effects of NSAIDs. Indeed, acetaminophen produces none of the side effects associated with the NSAIDs. Its primary clinical problem is hepatic dysfunction.

Renal Effects

Eicosanoids have only a modest role in renal homeostasis under normal physiological conditions—that is, PGE₂ inhibits Na⁺ and K⁺ resorption, and NSAIDs have little effect on renal function in healthy individuals; transient fluid retention and edema are the most common side effects. However, in patients who have either actual or effective circulatory volume depletion (e.g., congestive heart failure, renal insufficiency), renal perfusion is maintained largely by PGI₂. These patients are at greater risk to develop edema and other NSAID-induced renal side effects such as hyperkalemia, hypertension, interstitial nephritis, and rarely, renal failure. Side effects are for the most part dose-dependent and reversible. The kidney is one of several tissues where COX-2 is expressed constitutively; thus renal side effects also occur with COX-2-selective NSAIDs.

Cardiovascular Effects

Aspirin and other nonselective NSAIDs prolong bleeding time by inhibiting COX-1 in platelets, preventing synthesis of TXA₂. Clinical manifestations of this effect are usually negligible, because TXA₂ is only one of several mediators of platelet aggregation. Upper GI bleeding is the most common spontaneous bleeding event associated with the use of nonselective NSAIDs. However, NSAIDs pose a more serious risk in patients with impaired hemostasis and in those taking other drugs that inhibit clotting. Because nonselective NSAIDs increase the risk of postoperative bleeding and of postparturition hemorrhage, their use should be avoided before surgical procedures and during the peripartum period. Selective COX-2 inhibitors do not inhibit platelet aggregation or prolong bleeding time, because COX-2 does not occur in platelets. On the other hand, selective COX-2 inhibitors can increase the incidence of major cardiovascular events (e.g., myocardial infarction) in high-risk patients because they prevent the production of PGI₂, which inhibits platelet aggregation, in vascular epithelial cells without the benefit of blocking TXA₂ production in platelets.

CNS Effects

Aspirin can cause salicylism, a syndrome characterized by tinnitus, hearing loss, dizziness, confusion, and even headache. Salicylism is dose-dependent and reversible. It is usually associated with high doses, but sensitive individuals may experience it after a single analgesic dose.

Hypersensitivity

Hypersensitivity to aspirin occurs in a small percentage of the population and is manifest by an anaphylactoid reaction that can include rhinitis, urticaria, flushing, hypotension, and bronchial asthma. Middle-aged patients with asthma, nasal polyps, or urticaria are at a higher risk for aspirin hypersensitivity than is the general population. The mechanisms are unknown but may be due to increased levels of lipoxygenase products formed by diversion of arachidonic acid metabolism. Patients with aspirin hypersensitivity also are hypersensitive to other nonselective NSAIDs. Although there is no evidence for hypersensitivity to selective COX-2 inhibitors yet, these drugs are not recommended for use in patients with known NSAID hypersensitivity.

Acute Overdose

Acute overdose with aspirin or acetaminophen results in effects not seen at therapeutic doses. The syndrome produced by each drug is unique. Among the events in acute aspirin intoxication are ventilatory changes, metabolic acidosis, nausea, vomiting, hyperthermia, and stupor (Table 36-6). Treatment depends upon the severity of intoxication, which can be determined by measuring plasma salicylate levels, and is largely supportive: gastric lavage, alkalinizing the urine, cooling the body, and IV fluids containing HCO₃⁻ and glucose. Acute aspirin overdose is a leading cause of accidental poisoning in children.

TABLE 36–6 Relationship Between Blood Salicylate Level and Therapeutic and Toxic Effects

Blood Salicylate Level (μg/mL)	Effect	Consequence
50-100	Analgesia, antipyresis
150-300	Antiinflammatory
200-350	Salicylism	Tinnitus, dizziness, nausea
≤350	Hyperventilation	Respiratory alkalosis
450-800	Disrupted carbohydrate metabolism, sweating, vomiting, uncoupled oxidative phosphorylation, depressed respiration, increasing acidosis and body temperature	Metabolic acidosis, dehydration, hyperthermia, respiratory acidosis, delirium, convulsions, coma