CHAPTER 23 Drugs for Treating Orofacial Pain Syndromes
The management of chronic orofacial pain, as compared with acute pain, requires an in-depth knowledge of pharmacology and pharmacotherapy because chronic pain disorders are a heterogeneous group of conditions with various pathologic mechanisms and characteristics requiring diverse families of medications for treatment. Dentists do not generally use these medications because dentistry has traditionally focused on acute pain problems. The pharmacologic characteristics of opioids are discussed in Chapter 20, and the pharmacologic characteristics of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are discussed in Chapter 21. Treatment of acute pain in dentistry is addressed in Chapter 47.
With more recent advances in understanding chronic pain disorders and recognition that these disorders affect the orofacial region, dentists are now being educated to manage chronic pain and use medications traditionally used only in a medical setting. This chapter reviews the medications used for chronic orofacial pain disorders and relates them to known or putative disorders and pain mechanisms.
When a patient is evaluated for chronic orofacial pain, the clinician must determine which of various potential conditions may be the source of the pain. In general, after eliminating intracranial and extracranial sources, the clinician has narrowed the differential diagnosis to musculoskeletal, neurovascular, and peripheral or central neuropathic pain, or combinations of these. These categories of pain have different pathophysiologic mechanisms and require different treatment modalities or strategies. Intertwined with the pain issues are psychological issues that have developed in conjunction with chronic pain. These issues must be dealt with to optimize treatment of pain and obtain a beneficial outcome.
Often medications used to treat one condition may be useful for another. Tricyclic antidepressants (TCAs), used to treat depression, are useful in prophylaxis of migraine and may be the most effective drugs for treating certain neuropathic or musculoskeletal pain disorders. In addition, medications may be used differently in each of the pain categories. To understand chronic orofacial pain, the clinician needs to understand the mechanisms behind the various conditions because this knowledge may be helpful in choosing the medications that would be most beneficial for the patient. This chapter reviews the medications used to treat these categories of chronic pain and elaborates on the general and specific mechanisms of action, if known, for each of the medications listed. This chapter does not discuss the use of opioids for chronic pain other than to indicate that in cases of intractable pain resulting from cancer or other conditions such as chronic neuropathy resulting from failed temporomandibular joint (TMJ) surgery, long-term use of opioids may be the only option for helping the patient, although this is rare because opioids are generally less effective in treating neuropathic pain than several other drugs.
To understand chronic pain and its pharmacologic management, it is necessary to understand the 5-hydroxytryptamine (5-HT) system and its impact on pain modulation. Besides chronic pain, alteration in 5-HT function has been implicated in numerous other clinical conditions, including affective disorders, obsessive-compulsive disorders, schizophrenia, anxiety states, phobic disorders, eating disorders, migraine, and sleep disorders. Serotonin receptors are found on presynaptic and postsynaptic neurons. The two key presynaptic neurons are 5-HT1A and 5-HT1D. The postsynaptic 5-HT receptors include 5-HT1A, 5-HT1D, 5-HT2A, 5-HT2C, 5-HT3, and 5-HT4. Presynaptic receptors function as autoreceptors, controlling the release of serotonin and serotonergic action potentials. The 5-HT1A receptor is a somatodendritic autoreceptor that slows action potentials. The presynaptic 5-HT1D autoreceptor detects 5-HT being released into the synaptic cleft and inhibits further release; the 5-HT1D receptor is also called a terminal autoreceptor.
A wide range of drugs affects 5-HT neurotransmission, including antidepressants (TCAs, selective serotonin reuptake inhibitors [SSRIs], and heterocyclic antidepressants), hallucinogens, anxiolytics, antiemetics, antimigraine agents, atypical antipsychotics, and appetite suppressants. Many other drugs not generally considered to affect the 5-HT system nevertheless have an assumed effect on 5-HT receptors because of the influence they have on conditions that are linked to 5-HT dysregulation, such as migraine.
Since 1868, serum (sero-) from blood clots was known to possess a substance that caused blood vessels to constrict, increasing their smooth muscle tone (-tonin). Subsequent physiologic studies of this vasoconstrictive activity vacillated between some unknown substance and epinephrine as the cause. Eventually, the issue was clarified when it was observed that the serum constricted frog vascular and rabbit intestinal preparations, whereas epinephrine caused only relaxation of the gut. Because no evidence of epinephrine was found in the blood plasma, it was assumed that vasoconstriction was caused by a substance in the coagulated blood, and by the early 1900s the source of that substance was identified with platelets.
Janeway and associates20 did a thorough investigation of the vasoconstrictive substance and noted that it was not present in uncoagulated or citrated blood, that it was definitely associated with platelets, that it was soluble in water more than ether or chloroform, and that the factor did not depend on the clot formation but on the disintegration of the platelets in the clot. The substance itself was eventually isolated and named serotonin by Rapport and colleagues in 1948.36 Shortly after this, Rapport and colleagues identified the agent as 5-HT, and Hamlin and Fischer18 reported synthesizing it in 1951.
Meanwhile, in Italy, in a separate series of studies, Erspamer and Asero8 isolated a substance from the mucosa of rabbit stomach and found that it was abundant in the enterochromaffin cells of the gut, could be extracted with alcohol and acetone, was an amine that affected smooth muscle, and was deactivated by deamination. Erspamer and Asero named it enteramine. By 1952, serotonin and enteramine had been chemically identified as 5-HT, eventually leading to international wrangling over the naming of 5-HT. It was argued that “enteramine” was inaccurate because the substance was found in places other than the gut, and “serotonin” was equally inadequate from the points of origin and pharmacologic action. In 1986, when the International Serotonin Club was organized, American researchers prevailed over the European contingent in naming the substance serotonin by arguing that serotonin was the most widely accepted name, 5-hydroxytryptamine was too long, and 5-HT was only an abbreviation (but one used here).
Stimulation of the periaqueductal gray (PAG) was shown to modulate nociception on a spinal level.28 This effect is known as stimulation-produced analgesia (SPA). Although a number of areas have been studied in animals, human studies of necessity have been limited. In humans, stimulation of the midbrain region of the PAG and areas slightly more rostral in the periventricular gray matter of the hypothalamus are known to produce SPA. Neurosurgeons were able to show SPA in humans by stimulating the equivalent human midbrain sites. Researchers had determined that electrical stimulation of brainstem PAG produced analgesia in animals. Although the exact boundaries of the responsive area were not clearly defined, the sites most responsive to SPA were: ventral to the midbrain cerebral aqueduct; in the PAG; sites lateral to this structure; the rostroventral medulla (RVM), including the midline nucleus raphe magnus (NRM) and reticular formations; the hypothalamus; the frontal lobe; and the spinal cord. Areas outside of the midbrain have not been systematically studied.
Most of the projections from the RVM/PAG are tryptaminergic. Injection of morphine in the PAG also has a similar antinociceptive effect and is thought to be mediated by activation of a raphe-spinal pathway. Other studies have implicated descending 5-HT fibers and other non–5-HT–containing fibers in this process. Increased production of 5-HT in the bulbospinal 5-HT neurons supports the role of 5-HT in modulation of pain in these pathways. Studies of the raphe pathways have confirmed that with such stimulation there is a concomitant increase in 5-hydroxyindoleacetic acid (5-HIAA), a major metabolite of 5-HT, in the dorsal horn, implicating activation and degradation of 5-HT in the process.
5-HT is a biogenic monoamine and is widely distributed throughout the plant and animal kingdom. In mammals, the highest concentrations are found in the enterochromaffin cells of the gastrointestinal mucosa, central nervous system (CNS), and blood platelets. The structure of 5-HT is shown in Figure 23-1. Its most notable features are the hydroxyl group on position 5 of the indole nucleus and the primary amine nitrogen that can accept a proton, making the compound hydrophilic and unable to pass the blood-brain barrier easily. Rapport and colleagues36 found the substance in the brain, indicating that it must be synthesized and perform some unidentified function there. It was subsequently assumed that 5-HT was associated with psychiatric disorders such as depression and schizophrenia when it was shown that the psychedelic drug lysergic acid diethylamide (LSD) antagonized 5-HT function. 5-HT is now known to be involved in many behavioral and psychiatric disorders, such as schizophrenia, obsessive-compulsive disorder, depression, and anxiety, and drugs that have an effect on the 5-HT system have been beneficial in treating these disorders (see Chapter 12).
Despite earlier suggestions that 5-HT was a neurotransmitter synthesized in the brain, the actual localization of 5-HT neurons was not determined for at least 10 more years. By using lesioning and fractionation techniques, 5-HT was grossly associated with specific neuronal elements, but it was impossible to observe the relationship directly until fluorescence histochemical techniques were developed. This process had inherent problems, however, that made identification a significant challenge. Dahlström and Fuxe,7 using immunocytochemical techniques, localized 5-HT–associated neurons in nine discrete clusters of cells along the midline of the upper brainstem and pons. These 5-HT–containing cell bodies, designated B1 to B9, corresponded for the most part to the dorsal raphe nuclei. Only approximately 40% to 50% of the dorsal raphe nuclei are serotonergic neurons, and some serotonergic nuclei are found outside the midline raphe nuclei area, although the major brain concentration is in the dorsal raphe nuclei.
Additional studies have shown that the lateral and dorsolateral pontine tegmentum, which contain many noradrenergic neurons, are also involved in nociceptive modulation when stimulated, and these sites send projections to the PAG, the RVM, and the spinal cord. The projections from the lateral and dorsolateral pons are noradrenergic and possess important α2-adrenergic receptors. In animal studies, norepinephrine (NE) applied directly to the spinal cord blocks response to nociception through selective inhibition of the nociceptive dorsal horn neurons (see Chapter 20). Lesioning the white matter of the dorsolateral funiculus of the spinal cord blocks the inhibitory effect of SPA and confirms the existence of a descending modulatory pathway that travels through the dorsolateral funiculus. Further studies of the dorsolateral funiculus projections to the spinal cord have found that most of the brainstem projections arise in the RVM and dorsolateral pons, with few projections from the PAG. This finding implies that the PAG projections must be relayed through the RVM. This has been confirmed by studies showing that the major neuronal input to the RVM is from the PAG and adjacent structures, and lesioning or blocking RVM cells eliminates the analgesic effect obtained from PAG stimulation.
Anti–5-HT antibody labeling has identified 5-HT in all dorsal horn laminae, but the highest densities are found in laminae I, II, IV, V, and X. The RVM projections terminate mainly in laminae I, II, and V. These areas are important for pain because this is where the central terminals of afferent nociceptors and cell bodies of second-order neurons are found. This dorsal horn area is the major “switchboard” for pain, and stimulation of the PAG and RVM modulates nociceptive activity here (see Chapter 20).
Immunocytochemical studies have also found 5-HT reactive cells in the area postrema, the caudal locus coeruleus, and around the interpeduncular nucleus. Through lesioning studies, it has been observed that the caudal clusters project mainly to the medulla and spinal cord, the rostral clusters project to the telencephalon and diencephalon, and the more centrally located clusters project rostrally and inferiorly. In general, 5-HT cells send axons through virtually every part of the CNS, however, and more recent findings indicate a lack of pattern to this innervation.
Transmission of sensory and particularly nociceptive messages by afferent fibers entering the dorsal horn of the spinal cord is under control of pathways originating in the ventromedial medulla. It had been observed that neurons from the medullary raphe nuclei and particularly the NRM project predominantly to the dorsal horn, including the superficial laminae and the area around the central canal, and are involved in a descending inhibitory pathway for modulation of nociceptive input. Because the area was found to have an abundance of 5-HT–containing neurons, researchers postulated that 5-HT was a descending pain modulatory system neurotransmitter. 5-HT–containing neurons are located in the rostroventromedial medulla and caudal pons, and particularly in the NRM, the nucleus paragigantocellularis, and the ventral portion of the nucleus gigantocellularis. More recent studies have described other descending projections from the bulbomesencephalon to the spinal cord that do not contain 5-HT and are more numerous within the medulla and caudal pons, indicating that descending modulation is not limited to 5-HT fibers.24
Immunocytochemical studies of antibodies directed against 5-HT have shown that two distinct types of 5-HT neurons innervate the cerebral cortex of many mammals. The studies have found fine axons with small varicosities originating from the dorsal raphe nuclei and beaded axons with large spherical varicosities originating from the median raphe nuclei. Apparently the two types of axons have different regional and laminar distributions and exhibit different sensitivities to neurotoxic drugs such as 3,4-methylenedioxymethamphetamine, commonly referred to as “ecstasy.” The fine axons seem to be more sensitive to the neurotoxic effects, with loss of functions that may be long-term or permanent. Cooper and associates6 suggested that laboratory animal findings may relate to humans’ use of the drug because the doses commonly used by recreational drug users are similar to what are used in animal studies. Ecstasy users have shown a 26% decrease in 5-HIAA, the 5-HT metabolite. The decrease in metabolite may indicate a decrease of 5-HT function in the brain related to loss of some 5-HT neurons. The functional distinction between these two types of neurons generally remains unclear, however.
5-HT is synthesized from the amino acid l-tryptophan (see Figure 23-1). Although platelets contain large amounts of 5-HT, it only accumulates rather than being synthesized there. Synthesis in the CNS involves active transport of tryptophan through the blood-brain barrier. Tryptophan is derived primarily from the diet, and its elimination from the diet can profoundly decrease brain 5-HT. In addition, the active transport of tryptophan is affected by its concentration in the blood and the relative concentration of other amino acids that are transported by the same active transport mechanism. l-Tryptophan is converted in serotonergic neurons containing the enzyme tryptophan hydroxylase (l-tryptophan-5-monooxygenase).
The initial synthesis step is hydroxylation of tryptophan at the 5 position to form 5-hydroxytryptophan (see Figure 23-1). Tryptophan hydroxylase, the enzyme responsible for this reaction, occurs in low concentrations in most tissues, including the brain, and has proved to be difficult to isolate.
Tryptophan hydroxylase has a rate-limiting requirement for oxygen. In addition, mounting evidence suggests that the system adjusts to the amount of tryptophan available. It has been shown that drug treatments affecting the 5-HT system are soon counteracted by a built-in feedback mechanism involving regulation of the synthesis of 5-HT. Short-term treatment with lithium salts initially increases tryptophan uptake, resulting in increased amounts of tryptophan being converted to 5-HT; however, with long-term treatment, increased uptake is still measured, but the synthesis of 5-HT from the increased tryptophan returns to pretreatment levels.
5-Hydroxytryptophan is rapidly decarboxylated to form 5-HT by the aromatic enzyme l-amino acid decarboxylase, which is the same enzyme that catalyzes the decarboxylation of l-dopamine in catecholamine neurons (see Figure 23-1). Because the rate of the reaction is so rapid and requires less substrate than the initial reaction, the action of tryptophan hydroxylase in the first step is regarded as the rate-limiting step in the synthesis of 5-HT, and drugs targeting the action of the decarboxylase have not been shown to be effective.
The synthesis of 5-HT is markedly increased with the electrical stimulation of serotonergic soma. This is the result of enhanced conversion of tryptophan to 5-HT and depends on extracellular Ca++. Because, as discussed previously, the rate-limiting step is the action of tryptophan hydroxylase on tryptophan, it is likely that Ca++ affects the Ca++-dependent phosphorylation of the enzyme, increasing its availability.
Similar to other monoamines, 5-HT is stored in vesicles within the cell. Drugs such as reserpine and tetrabenazine that inhibit the activity of the transporter mechanism within the vesicular membrane deplete the brain content of 5-HT. The storage of 5-HT in vesicles requires an active transport mechanism to transfer the molecule from the cytosol to the storage vesicle.
5-HT is also metabolized in the liver by the enzyme monoamine oxidase (MAO) (see Figure 23-1). The product of this reaction is 5-hydroxyindoleacetaldehyde, which is oxidized further by aldehyde dehydrogenase to form the final acid metabolite, 5-HIAA, which is excreted (see Figure 23-1). It had been suggested that increased levels of either of the metabolites of 5-HT or the concentration of 5-HT itself would affect its metabolism, but it has been noted that using MAO inhibitors to block metabolism does not affect the synthesis of 5-HT, and concentrations increase to three times greater than controls. If the elimination of 5-HIAA is blocked by the drug probenecid, the 5-HIAA levels continue to increase without apparent feedback inhibition. The implication of these findings is that the synthesis of 5-HT is not affected by changes in concentrations of its metabolites.
Presynaptic reuptake of 5-HT from the synaptic cleft is a major mechanism for controlling the synaptic concentration and action of 5-HT. The presynaptic terminals of serotonergic neurons contain high-affinity uptake sites that are involved in this process by using a plasma membrane transporter protein that can transport 5-HT in either direction depending on the concentration gradient. The transporter proteins involved in this process are composed of 12 membrane-spanning proteins that are Cl− and Na+ dependent. Although older TCAs inhibit the reuptake of 5-HT, they also have a variable capacity to inhibit NE reuptake and affect other systems and receptors (see Chapter 12). SSRIs that have shown great utility in moderating depression, anxiety, and obsessive-compulsive disorders also inhibit the 5-HT transporter proteins. These medications are more 5-HT selective with more limited effects on the NE transporter.
In 1957, Gaddum and Picarelli11 reported two separate 5-HT receptors in peripheral smooth muscle preparations studied in vitro. Since then, there has been an exponential development of information relating to 5-HT receptor types and functions, and numerous receptor subtypes have been identified and cloned more recently. Nevertheless, the complete picture of how 5-HT and its receptors modulate pain remains obscure. There are now seven main family groups of receptors, but current understanding attributes most of the 5-HT actions relative to pain to the families designated 5-HT1, 5-HT2, 5-HT3, 5-HT4, and 5-HT7. Each receptor family is operationally and structurally distinct, each having its own separate transducing system.
Although other more recently identified 5-HT receptors also show characteristics indicative of separate classes or families of 5-HT receptors, not all receptors for 5-HT are fully included in the classification system at this time because of a lack of needed characterization through cDNA cloning and amino acid sequencing of their proteins or data concerning their operational and transductional characteristics. This situation applies to the 5-HT1E, 5-HT1F, 5-HT5, and 5-HT6 receptors, which have been cloned and their amino acid sequence defined, although their operational and transductional characteristics are unclear, and the final nomenclature is unsettled. Fourteen different 5-HT receptor subtypes have been identified.
As mentioned, seven classes or families of 5-HT receptors have been identified and designated 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. Each class has subtypes (with the exception of 5-HT3), and all have been identified in the brain. Localization of the receptors in the CNS and spinal cord is variable, and not all 5-HT receptors are found in all locations. Within the spinal cord itself there is variability in the location of different receptors. Because 5-HT1, 5-HT2, and 5-HT3 receptors have the highest distribution in the dorsal horn, it is assumed that they are involved in sensory processing. In general, the 5-HT1 family is assumed to be inhibitory, and the other classes are thought to be excitatory; however, 5-HT2 and 5-HT3 receptors have been linked to an antinociceptive response as measured by some animal models. Much work is still to be done before the 5-HT–modulating system is fully understood.
The 5-HT1D receptor, also called the terminal autoreceptor, is found on the presynaptic button. It turns off the release of serotonin in response to the presence of serotonin in the synaptic cleft. The receptor is also found on postsynaptic neurons and has been implicated in migraine pathophysiology. The 5-HT1A receptor, also known as a somatodendritic autoreceptor, is found primarily on the dendrites and cell bodies of the serotonin neurons but performs a similar function in regulating the release of serotonin. When these receptors are activated or stimulated by serotonin or drugs that mimic serotonin action, the receptor causes a blockade of serotonin release. When the receptors are blocked by receptor blocking medications, the receptor is no longer able to inhibit serotonin release. Serotonin release is also modulated by an α2-adrenergic heteroreceptor on the terminus of the serotonin neurons. This receptor is activated by NE resulting in the inhibition of serotonin release.
The 5-HT1 family of receptors (Table 23-1) produces its cellular action by inhibiting adenylyl cyclase and opening K+ channels. Binding studies with autoradiographic ligands have shown binding sites throughout the spinal cord gray matter, raphe nuclei, and substantia gelatinosa, with the higher concentrations in laminae I and II of the dorsal horn and lower in lamina VII in the ventral horn. The hippocampus, the substantia nigra, and dorsal raphe contain the highest concentrations.
Taiwo and Levine42 showed that 5-HT1A receptors are implicated in peripheral mechanical hyperalgesia. They reported that the hyperalgesia could be blocked by selective 5-HT1A antagonists injected locally. It was also shown in various pain models that the 5-HT1-3 receptors all mediated pain. Powell and Dykstra35 suggested that 5-HT1A receptor agonists may reduce the effects of morphine in an electrical shock model for pain. This same effect was not seen with agonists at 5-HT2, 5-HT3, or α2-adrenergic receptors.
Autoradiographic studies have shown that half of the spinal cord binding sites involve the 5-HT1A receptor, with the greatest concentration in the superficial layers of the dorsal horn in the lumbar cord, rather than in the cervicothoracic segments. The 5-HT1A receptor has been implicated in anxiety, but may also be involved in migraine. Antianxiety drugs such as buspirone act as agonists on this receptor.
5-HT1B is a postsynaptic vascular receptor found primarily on cerebral blood vessels and to a smaller extent on coronary arteries and trigeminal ganglia neurons. Stimulation of the 5-HT1B receptor results in numerous smooth muscle contraction actions such as vasoconstriction, closing of atrioventricular shunts, and bronchoconstriction, and platelet aggregation. Although there are a few receptors on coronary arteries, 5-HT1B agonists cause some degree of coronary artery constriction.
As indicated previously, the 5-HT1D receptor functions as a presynaptic autoreceptor on trigeminovascular sensory afferent fibers, modulating neurotransmitter release such as 5-HT, substance P (SP), acetylcholine, NE, and calcitonin gene–related peptide (CGRP). 5-HT1D is the most widespread 5-HT receptor in the brain and is thought to be the main 5-HT receptor involved in migraine. As discussed previously, the 5-HT1 family of receptors is inhibitory through action of the Gi protein. Activation of the 5-HT1D receptors on subdural blood vessels involved in migraine pathophysiology decreases or stops action potential formation, resulting in the aborting of migraine.
5-HT2A receptors are found in layers three and five of the cerebral cortex, the subcortical gray matter, the brainstem, and the spinal cord. These receptors, similar to the other non–5-HT1 family of receptors, are excitatory. Activation of 5-HT2 receptors results in closure of K+ channels and activation of phospholipase C. The 5-HT2B receptor has been associated with cerebrovascular endothelium, and it has been suggested that migraine is caused by sensitization of these receptors. 5-HT bioavailability increases during development of the migraine attack and is attended by production and release of nitric oxide (NO). Nitroglycerin, a donor of NO, is known to cause headache when used to control angina, and this effect is blocked by indomethacin, which antagonizes the effect of NO. Patients who have analgesic rebound headache have a greater density of postsynaptic 5-HT2 receptors on platelet membranes than migraine patients who do not have analgesic rebound headache. The implication is that chronic ingestion of analgesics may cause a depletion of 5-HT and concomitant upregulation of 5-HT2 receptors, leading to more headache.
Although the exact role of 5-HT neuronal modulation is still unclear in migraine, the medications that seem to give the most benefit have definite 5-HT activity. The role of 5-HT in platelets during the ictal phase of migraine is apparently important but remains to be defined. All aspects of the 5-HT system seem to come into play during a migraine attack and not only the 5-HT1 receptors, but also 5-HT2 receptors. It has been observed that some of the most commonly used compounds in migraine prophylaxis—propranolol, pizotifen, methysergide, cyproheptadine, amitriptyline, and chlorpromazine—have an antagonistic effect on specific subtypes of the 5-HT2 receptor family, now known as the 5-HT2B/5-HT2C (formerly 5-HT1C) receptors. This hypothesis is supported by previous observations that the 5-HT2 receptor agonist m-chlorophenylpiperazine (m-CPP) triggers migraine in susceptible individuals when it is administered at doses high enough to activate 5-HT2B/2C receptors.21
The 5-HT3 receptor is found mainly in the lower brainstem and on the presynaptic terminals of small-diameter unmyelinated nociceptive afferents in substantia gelatinosa where they may be involved in pain processing. The 5-HT3 receptor is the only ion-gated cation channel receptor in the 5-HT receptor family. It causes increased conductance for Na+, K+, and Ca++ and depolarization of the involved cell membrane. It has been shown that 5-HT3 receptors participate in the nociceptive activity in the dorsal horn and are probably involved in the antinociceptive effect when 5-HT is administered intrathecally. This receptor has also been implicated in emesis associated with migraine. The “triptans,” which have been developed for symptomatic treatment of migraine through their agonist action on the 5-HT1D/1B receptors, also are antagonists of the 5-HT3 receptor, relieving nausea.
In contrast to the inhibitory effects of the 5-HT1 receptors, the 5-HT4 family of receptors is positively coupled to adenylyl cyclase, provoking second messenger activation of cyclic adenosine 3′,5′-monophosphate (cAMP). This receptor has high concentration in the gut, and antagonists of the receptor prevent development of increased bowel activity that would be stimulated by 5-HT or 5-hydroxy-l-tryptophan sensitization. Ghelardini and colleagues13 reported that 5-HT4 agonists had an antinociceptive effect, raising pain thresholds in mice and rats.
The 5-HT7 receptor subtype activates adenylyl cyclase with consequent closure of K+ channels. The 5-HT7 receptor was shown more recently to mediate cerebrovascular smooth muscle relaxation, independent of any mechanism in the endothelium. Because of its action on the regulation of vascular tone, it has been proposed to have a role in migraine. This role has been supported by observations that 5-HT7 receptor–linked relaxation has been observed in dog basilar and middle cerebral arteries, together with other circumstantial evidence such as the high affinity of antimigraine drugs for the 5-HT7 receptor and the high expression of 5-HT7 transcripts in animal and human brain vessels. 5-HT7 receptor mRNA and second messenger cAMP levels were elevated in cultured smooth muscle cells from human brain vessels, possibly indicating that this same mechanism is operating in the human brain. This mechanism would allow for 5-HT7 receptor action affecting dilation of meningeal blood vessels without direct interaction with dural blood vessel endothelium and may indicate a role for 5-HT7 receptors in human brain blood vessels during the migraine attack.
Researchers have identified two major 5-HT receptor–linked signal transduction pathways. One pathway regulates ion channels, and the other is a multistep enzyme-mediated pathway. The second pathway requires a G protein to link the receptor to the internal effector molecule. In the case of the 5-HT1 family of receptors, the link is Gi protein because the response is inhibition of adenylyl cyclase.
As noted previously, the 5-HT2 G protein–linked family of receptors is coupled to phospholipase C, leading to a variety of intracellular actions. The G protein–type linkage of the 5-HT2 receptor to its second messenger system is Gq. Activation of adenylyl cyclase was the first signal transduction pathway to be linked to metabotropic 5-HT receptor activity, but the specific receptor linkages to 5-HT4, 5-HT6, and 5-HT7 were not identified until more recently. The 5-HT4 receptor has been found in the human atrium and guinea pig ileum; 5-HT6 found in the cortex has been shown to have a high affinity for TCA drugs, and 5-HT7 is found in the brain and heart.
As noted earlier, the 5-HT3 receptor differs from the other 5-HT receptors because it does not have G protein linkage but is associated directly with a ligand-gated ion channel. The receptor has been found on peripheral sensory, autonomic, and enteric neurons and in the cortex, hippocampus, and area postrema, mediating excitation by inducing neurotransmitter release.
The 5-HT system modulates activity in diverse regions of the brain and spinal cord. It is suggested that the system coordinates various sensory and motor patterns associated with behavioral states. 5-HT activity is highest during waking and lowest during sleep. Descending neurons are involved in pain modulation in the dorsal horn and motor activity in the ventral horn. 5-HT activity is absent during rapid eye movement sleep when physical movement is limited, although the animal is in a state of heightened internal arousal. The increased 5-HT activity during waking periods aids in enhancing motor neuron excitability.
The raphe nuclei 5-HT neurons display spontaneous discharge activity of one to five spikes per second, releasing 5-HT into the presynaptic cleft. The neurons possess negative feedback autoreceptors that limit the amount of discharge and release of 5-HT. The autoreceptors seem to function only when the discharge and release of 5-HT reaches levels greater than the normal background activity inherent in the neurons. Dysfunction of the autoreceptor regulation has been associated with some forms of neuropathy, and the autoreceptor may provide a therapeutic target for medications. Although in some areas microelectrophoretically administered 5-HT can have an excitatory effect on the discharge rate, the most common response in 5-HT–containing neuron tracts is inhibition of the discharge rate.
5-HT released from neurons has presynaptic and postsynaptic receptor effects. There are many options for affecting the availability of 5-HT directly, either by inhibiting the processes that decrease its availability or by enhancing the processes that make it available (Figure 23-2). Figure 23-2 shows sites of interaction with known drugs that influence the 5-HT system. Of all the options, reuptake blockade of 5-HT by TCAs is the most common mechanism of 5-HT active medications prescribed for the treatment of depression and chronic pain; however, the issue of availability of 5-HT to help modulate pain has yet to be settled.
FIGURE 23-2 Possible drug sites for influencing 5-HT neurotransmission. The sites of potential drug action on the 5-hydroxytryptamine (5-HT) neuron are enumerated from 1 to 6. Site 1 represents the modulation of enzymatic action forming the 5-HT precursor and ultimately 5-HT from tryptophan. Site 2 is a potential target for drugs that affect the storage vesicles of 5-HT. Reserpine and tetrabenazine are known to interrupt the storage and cause release of 5-HT. Site 3 targets the release mechanism itself; however, there are currently no known agents that act to interrupt or increase the action of the transporter proteins that carry the 5-HT molecule across the membrane. Site 4 involves the reuptake mechanism that brings 5-HT back into the intracellular environment to be repackaged in the vesicles. Numerous drugs inhibit the reuptake of 5-HT (see Chapter 12). Site 5 refers to the 5-HT autoreceptor. Blockade of this receptor site allows more presynaptic release of 5-HT. Site 6 focuses on the action of monoamine oxidase that converts the free 5-HT to the metabolic product 5-HIAA. Monoamine oxidase (MAO) inhibitors such as phenelzine block this action. SSRIs, Selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.
Sicuteri and associates40 were the first to note a relationship between 5-HT and migraine in their report on the significant increase in 5-HIAA in the urine of migraine subjects during attacks. Subsequent data did not show a consistent increase in 5-HIAA in all patients with migraine. Nevertheless, the relationship between migraine and 5-HT became solidified at that time and has been elucidated further to the present. Further studies have noted increases in plasma 5-HT, decreases in 5-HT platelet content, and increases in 5-HIAA content in cerebrospinal fluid in migraine patients. These observations support the theory that migraine is caused by chronic 5-HT dysregulation. Further support for the role of 5-HT in migraine has come from clinical positron emission tomography scan studies in patients during migraine attacks showing increased blood flow in the highly serotonergic dorsal raphe nucleus area.
In the Middle Ages, epidemics of a gangrenous disorder known as “holy fire” or “St. Anthony’s fire” were afflicting communities in Europe. The condition was so named because of the attendant burning experienced by the sufferer. The disorder soon became associated with the grain of rye that had been contaminated with the ergot fungus Claviceps purpurea. In 1918, the ergot alkaloid ergotamine was isolated from the fungus and was found to have sympatholytic activity (see Chapter 7). Shortly thereafter, it was proposed for use as a therapeutic agent for migraine.
Ergotamine has a complex mode of action involving a variety of receptor activities, not only with 5-HT receptors, but also with dopamine and NE receptors. The vasoconstrictive effect, the most notable characteristic of this medication, can become problematic with overuse, leading to claudication of extremities. The major vasoconstrictive activity is noted in the carotid circulation; the cephalic arteriovenous anastomoses; the pulmonary, cerebral, temporal, and coronary arteries; and the blood pressure. These effects are short-lived, although constriction of leg arteries can last 8 hours. Chronic overuse becomes a problem, and clinicians need to monitor users carefully.
Ergot derivatives are nonselective partial agonists and antagonists at 5-HT receptors, having high affinity for the 5-HT1B, 5-HT1D, 5-HT1F, and 5-HT2 receptors and low to moderate affinity for the 5-HT1C and 5-HT3 receptors. It is currently believed that their primary mode of action in alleviating migraine attacks is through their action on the 5-HT1B/1D receptors, inhibiting neurogenic inflammation and nociceptor activity. Table 23-1 lists some 5-HT receptors and related medications and some indications for the drugs.
Ergotamine is a nonselective 5-HT partial agonist/antagonist and acts at multiple receptors accounting for therapeutic and adverse effects. For migraine, ergotamine acts primarily as a 5-HT1D receptor agonist, inhibiting depolarization of the dural blood vessel–associated nociceptors. The beneficial effect of ergotamine in treating migraine likely occurs by blocking neurogenic inflammation possibly through prejunctional inhibition of neuropeptide release. Ergotamine is commonly available as Cafergot, a tablet or suppository that is a combination of ergotamine and caffeine. Patients should be instructed regarding the possibility of developing rebound headache if using ergotamine more than two times per week.
Ergotamine is used as an abortive drug at the onset of the migraine attack. Typically, abortive medications have to be taken early in the onset of the migraine because absorption and distribution are impaired as the gastric symptoms of migraine increase. The combination of caffeine with ergotamine speeds gastric absorption, getting the medication into the system more rapidly. In addition to the adverse effects listed in Box 23-1, ergotamine can cause gangrene and damage to blood vessels. The drug is given for short periods at carefully controlled doses.
Dihydroergotamine was introduced in 1945, approximately 10 years after ergotamine. Past and more recent studies have determined that the venoconstrictive effect is significantly greater than the arterial effect. It is a nonselective 5-HT receptor partial agonist/antagonist. In addition, it is a nonselective antagonist at dopaminergic receptors with partial agonist/antagonist activity at α adrenoceptors. The half-life of dihydroergotamine is approximately 10 hours, which is longer than ergotamine and all but one of the triptans. This longer half-life may explain the lower likelihood for rebound adverse effects in headache compared with ergotamine and the shorter acting triptans (see later). This longer half-life makes dihydroergotamine a useful medication for chronic migraine, which tends to return within hours of treatment with either ergotamine or the triptans with shorter half-life.
Dihydroergotamine comes in a parenteral form and as a nasal spray. The parenteral form can be used intravenously, intramuscularly, or subcutaneously. The nasal form has a bioavailability of less than 65%, which may significantly limit its ability to abort a headache in many patients. This medication has definite advantages over the triptans with short half-life and is associated with lower vasoconstrictive potential. Dihydroergotamine is useful in the hospital to treat protracted unresponsive migraine. Side effects and contraindications for dihydroergotamine, ergotamine, and the other ergot alkaloids are listed in Box 23-1. Methylergonovine and methysergide, semisynthetic ergot alkaloids, are discussed subsequently.
The new family of triptan antimigraine drugs represents the most dramatic advance in the understanding and treatment of migraine. They are classified as 5-HT1B/1D receptor agonists. Discovery of the first of these drugs, sumatriptan, came after the 5-HT1B/1D receptor was linked with migraine. When it became apparent that the receptor had an inhibitory G protein–linked action on the host vascular and nociceptor neurons, agonist agents were sought that could act with the receptor to stop the attack. Sumatriptan was originally thought to act primarily on nociceptor 5-HT1D receptors, but action was also noted on dilated dural blood vessels. Sumatriptan-sensitive sites of action in the pain transmission pathway have been identified centrally and suggested as additional putative antimigraine targets for brain-penetrant triptan derivatives. Sumatriptan has selective affinity for 5-HT receptor subtypes, 5-HT1B and 5-HT1D. More recent development of 5-HT receptor subtype–specific compounds and antibodies has allowed a more precise identification of the vascular and neuronal sites of action, providing a basis for a more targeted therapeutic approach.
Moskowitz29,30 developed the concept of neurovascular inflammation in the trigeminovascular system as a migraine mechanism. He observed that sumatriptan’s action on peripheral neuronal 5-HT1D receptors blocked subsequent release of neuropeptides such as SP and CGRP that were responsible for the development of neurovascular inflammation with concomitant swelling of the dural blood vessels. Moskowitz then proposed that the blood vessel dilation and plasma extravasation noted during the migraine attack was an epiphenomenon of the migraine and not the cause of the migraine, as had been proposed by Graham and Wolff.17
The 5-HTlB receptor was discovered in humans after the discovery of the 5-HT1D receptor. It is expressed on human brain blood vessels where it induces contraction of dural blood vessels. An untoward observation of the effect of sumatriptan is the induced contraction of human coronary arteries, which also is most likely mediated by the 5-HT1B receptors. Although the cardiac effect is not severe, it is a concern and has led to some more recent efforts to find a compound that would not have an agonistic effect on the coronary 5-HT1B contractile receptors.
Centrally located 5-HT receptor targets in the trigeminal nucleus caudalis have also become the focus of research as potential targets for intervention in acute treatment of migraine. 5-HT1B and 5-HT1D receptors have been identified in the nucleus caudalis. On the basis of protein and mRNA localization studies, presynaptic 5-HT1B/1D and postsynaptic 5-HT1F receptors have been identified. These central 5-HT receptors may be potential sites of action for the new generation of brain-penetrant tripta/>