Drugs to Control Pain

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Chapter 36 Drugs to Control Pain

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
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).

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.


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.

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
κ Receptor (OP2/KOP) Dynorphins Butorphanol
δ Receptor (OP1/DOP) Enkephalins None to date

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.

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.

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.


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.


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-HT1B/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).



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