Preventive headache treatments

Preventive medications for headaches

The so-called antiserotonin drugs were the first drugs used to prevent migraine attacks. They continue to be used to this day. Methysergide is an ergot derivative that has a complex effect on the serotonergic and other neurotransmitter systems. Other antiserotonin drugs, such as cyproheptadine, pizotifen, and lisuride, are also capable of preventing migraine attacks. The tricyclic antidepressant amitriptyline is also an effective preventive agent for migraine. Moreover, this effect of the drug does not depend on its antidepressant action. A common feature of all these drugs is the ability to block 5-HT _2A receptors.

It is well known that methysergide is able to block contraction of vascular and nonvascular smooth muscle by acting on 5-HT receptors. However, it is unlikely that blockade of these receptors explains the therapeutic effect of antiserotonin agents, since other 5-HT receptor antagonists, such as mianserin, ketanserin, and ICI 169,369, do not have a prophylactic effect on migraine. It is assumed that the vasoconstrictor action of methysergide and its active metabolite methylergometrine explains its therapeutic activity. Inhibition of neurogenic inflammation with long-term administration of methysergide may also explain its ability to prevent migraine attacks.

Fozard and Kalkman (1994) suggested that activation of 5-HT _2B and possibly 5-HT _2C receptors may play a decisive role in the initiation of a migraine attack. This hypothesis was based on the ability of metachlorophenylpiperazine, an agonist of these receptors, to provoke migraine attacks in controls and migraine patients, and on the fact that the doses of a number of prophylactic antimigraine agents correlated with their ability to block 5-HT _2B receptors. This correlation was found for such classical 5-HT _2B receptor antagonists as methysergide, pizotifen, Org GC 94, cyproheptadine, mianserin, as well as agents that do not usually belong to this group, such as amitriptyline, chlorpromazine, propranolol. An additional argument was that ketanserin and pindolol, which have no antimigraine activity, are weak antagonists of 5-HT _2B receptors. Moreover, 5-HT _2B receptor mRNA was detected in all blood vessels examined, and activation of these receptors caused endothelium-dependent vasodilation, mainly due to the release of nitric oxide. This, in turn, may activate and sensitize trigeminovascular neurons and initiate the process of neurogenic inflammation associated with migraine.

GABAergic agents

Valproic acid has a variety of effects on neurotransmitter-mediated and non-neurotonic cellular processes, and may therefore have therapeutic effects in a variety of clinical situations. Enhancement of GABAergic transmission is probably its best-known action. Valproic acid increases brain GABA levels by stimulating the GABA-synthesizing enzyme glutamate decarboxylase and inhibiting the activity of enzymes that metabolize GABA. In addition, valproic acid modulates several other neurotransmitter systems, including those that use excitatory and inhibitory amino acids, serotonin, dopamine, and enkephalins as mediators, although it remains unknown whether these effects are due to the direct action of valproic acid or are mediated by enhanced GABAergic transmission. At therapeutic concentrations, valproic acid inhibits prolonged repetitive discharges induced by depolarization of cortical and spinal neurons in mice (McLean, Macdonald, 1986). This effect is apparently due to a slowdown in the recovery of voltage-dependent sodium channels after their inactivation.

The efficacy of valproic acid as an antimigraine agent may be explained by its action at different levels of the migraine cascade. For example, valproic acid-induced enhancement of GABAergic transmission may suppress pathological processes in the cortex that presumably underlie migraine aura. Valproic acid has also been shown to reduce plasma protein extravasation in a rodent model of neurogenic inflammation of the meninges. This effect is blocked by the GABA _A receptor antagonist bicuculline, but is mimicked by drugs acting on the GABA _A receptor complex, including muscimol, benzodiazepines, zolpidem, and the neurosteroid allopregnanolone. At the level of the caudal trigeminal nucleus, where meningeal afferent fibers predominantly terminate, valproic acid has been shown to reduce the activation of layer I and II neurons after intracisternal administration of capsaicin. This effect appears to be mediated by GABA receptors, since it is mimicked by butalbital and allopregnanolone and blocked by the GABA _A receptor antagonist bicuculline.

Structurally, gabapentin is GABA covalently linked to a lipophilic cyclohexane ring. Unlike GABA, gabapentin readily crosses the blood-brain barrier. Although gabapentin was developed as a centrally acting GABA receptor agonist, it does not bind to GABA receptors or mimic the actions of GABA when delivered iontophoretically to neurons in primary culture. Gabapentin appears to act by enhancing GABA release through unknown mechanisms. Its molecular targets may be close to or identical to a site resembling the L-amino acid transport protein. Gabapentin has no persistent effect on prolonged repetitive firing of neurons and has no significant effect on calcium channel function. The drug does not act on neurotransmitter receptors or ion channel binding sites. Because gabapentin appears to increase synaptic GABA levels, its effect is likely mediated by GABA receptors and may therefore resemble the effects of valproic acid on headache.

The use of carbamazepine and phenytoin for migraine prophylaxis is based on the unproven hypothesis that migraine is related to epilepsy. Carbamazepine is an iminostilbene with a structure reminiscent of tricyclic antidepressants and phenytoin. Its mechanism of action is not fully understood. Carbamazepine has been shown to be effective in several different experimental models of epilepsy. Phenytoin inhibits the propagation of epileptic activity induced by electroshock by reducing membrane excitability. Its ability to reduce poettetanic potentiation in the stellate ganglion and spinal cord of rats may indicate possible additional mechanisms in the treatment of neuralgias.

Nonsteroidal anti-inflammatory drugs

NSAIDs, which have anti-inflammatory, analgesic and antipyretic effects, are widely used both to relieve headaches and to prevent them. These drugs block cyclooxygenase, which converts arachidonic acid into prostaglandins and thromboxane, but have minimal effect on lipoxygenase, which ensures the production of leukotrienes. Most modern NSAIDs inhibit cyclooxygenase types 1 and 2. It is believed that inhibition of cyclooxygenase type 2 mediates, at least in part, the antipyretic, analgesic and anti-inflammatory effects of NSAIDs, while inhibition of cyclooxygenase type 1 causes undesirable side effects (primarily gastric ulcer), which are associated with a decrease in the production of prostaglandins and thromboxane. While aspirin, indomethacin, and ibuprofen have a higher affinity for cyclooxygenase type 1 than for cyclooxygenase type 2, diclofenac and naproxen inhibit both isoforms of the enzyme with equal intensity. Drugs that preferentially block cyclooxygenase type 2 are not currently used to treat headache. Meloxicam and other drugs that have been shown in vitro to have some selectivity for COX-2 are used to treat osteoarthritis.

NSAIDs include the salicylic acids, including aspirin, which irreversibly acetylates COX, and several other classes of organic acids, including propionic acid derivatives (eg, ibuprofen, naproxen, ketoprofen, flurbiprofen), acetic acid derivatives (eg, indomethacin and diclofenac), and enolinic acids (eg, piroxicam), all of which compete with arachidonic acid for the active sites on COX. Although acetaminophen has little anti-inflammatory effect and is more effective as an antipyretic and analgesic, it does not share some of the side effects of NSAIDs, such as gastrointestinal injury or blockade of platelet aggregation.

NSAIDs are usually classified as mild analgesics, but the type and intensity of pain are important factors when assessing analgesic activity. For example, NSAIDs are superior to opioids in some forms of postoperative pain. They are also particularly effective when inflammation sensitizes pain receptors to mechanical and chemical stimuli that are normally painless. This sensitization is likely due to a decrease in the excitation threshold of the polymodal nociceptor located on C fibers. Increased excitability of central neurons in the spinal cord may also play a role. Although the exact mechanism of action of NSAIDs on central structures is unknown, these drugs can inhibit prostaglandin synthesis in neurons of the brain, slowing the circulation of norepinephrine and serotonin, and blocking the release of serotonin in response to painful stimuli. Aspirin and ketorolac have also been shown to inhibit the caudal nucleus of the trigeminal nerve in cats.

Bradykinin released from plasma kininogen and cytokines such as tumor necrosis factor, interleukin-1, interleukin-8 are particularly important in the development of pain associated with inflammation. These substances promote the release of prostaglandins and, possibly, other substances causing hyperalgesia. Neuropeptides, such as substance P and CGRP, may also participate in the pathogenesis of the pain syndrome. Indomethacin and acetylsalicylic acid have been shown to block meningeal neurogenic inflammation after stimulation of the trigeminal ganglion or administration of substance P. This inhibitory effect is observed within 5 min after stimulation of the trigeminal ganglion, which excludes a significant role for inducible COX-2 in the mechanism of NSAID action in this model.

Opioids

Opioids reduce the response to pain stimuli by acting on various areas of the CNS, including the periaqueductal gray matter, the rostral-ventral medulla oblongata, the substantia nigra, and the posterior horn of the spinal cord. Several subclasses of the major opioid receptor categories mediate the effects of endogenous ligands. Three distinct families of endogenous peptides have been identified: enkephalins, endorphins, and idynorphins. Each of these peptides is derived from a distinct precursor and has a different distribution in the brain.

Although morphine is relatively selective for mu receptors, it can interact with other receptor types, especially at high doses. Most opioids used clinically, including meperidine, are relatively selective for mu receptors, reflecting their proximity to morphine. Codeine has very low affinity for opioid receptors, and its analgesic effects are due to its conversion to morphine. Propoxyphene also binds preferentially to mu receptors, although less selectively than morphine, producing analgesic effects and other central effects similar to morphine-like opioids. Although highly selective mu receptor agonists have been developed, antagonists are more useful in identifying these receptors. Using antagonists, researchers have determined that morphine produces analgesia at either the spinal (mu2) or supraspinal (mu2) level. When administered systemically, morphine acts primarily on supraspinal mu2 receptors. At the same time, respiratory depression and constipation associated with weakened gastrointestinal motility are explained primarily by its action on mu2 receptors.

In the spinal cord and probably in the trigeminal nucleus, the effects of opioids are mediated by activation of inhibitory receptors located presynaptically on primary afferent fibers and by postsynaptic hyperpolarization of projection neurons. Morphine blocks the effect of exogenously administered substance P by an inhibitory postsynaptic action on interneurons and projection neurons of the spinothalamic tract that send noniceptive information to higher centers of the brain. In addition, peripheral receptors modulate the excitability of small afferent endings that innervate inflamed tissues and reduce hyperalgesia.

In the periaqueductal gray matter, opioid agonists indirectly activate bulbospinal tracts and rostral projections to the forebrain and modulate afferent flow to brainstem structures.

Tricyclic antidepressants

Antidepressants have been used for many years in the treatment of pain on the grounds that they reduce associated depression. However, the fact that amitriptyline is the only antidepressant proven to prevent migraine attacks suggests that the antimigraine effect is not due to the antidepressant effect. Tricyclic antidepressants were originally thought to exert their therapeutic effect by increasing the concentration of norepinephrine and serotonin in the synaptic cleft, causing adaptive changes in postsynaptic receptors, including beta-adrenergic receptors and 5-HT ₂ receptors. Imipramine and the selective serotonin reuptake inhibitor fluoxetine act similarly to amitriptyline but have only minimal prophylactic effects on migraine.

It was suggested that the effect of amitriptyline could be explained by the blockade of 5-HT _2A receptors, however, as studies have shown, the action of antiserotonin drugs is not associated with the blockade of this type of receptors. Blockade of vascular 5-HT _2B receptors was also considered as a possible mechanism of action. Of interest is the data that amitriptyline weakens inflammatory hyperalgesia in rats due to a mechanism not associated with the inhibition of monoamine reuptake, possibly due to the blockade of NMDA receptors. The significance of this mechanism of action is confirmed by the data that other tricyclic antidepressants, such as desipramine, as well as cyproheptadine and carbamazepine, in a certain concentration reduce the increase in intracellular Ca ²⁺ in neuronal cultures mediated by the activation of NMDA receptors.

Calcium channel antagonists

Calcium channel antagonists (calcium antagonists), also known as slow channel inhibitors or Ca ²⁺ entry blockers, are a heterogeneous group of drugs that include several classes of drugs that block different types of Ca ²⁺ channels. The rationale for the use of calcium channel antagonists as prophylactic agents for migraine attacks was their ability to prevent cerebral vasospasm and protect nerve cells from hypoxia, which was thought to occur during migraine attacks. However, these phenomena are now considered to be of minor importance in migraine. Nimodipine is more effective than flunarizine in preventing calcium-induced cerebral and temporal artery spasm in humans. However, this contrasts with data showing that flunarizine is the most effective calcium channel antagonist in preventing migraine attacks, while the efficacy of nimodipine is minimal at best. This gives reason to assume that the effect of flunarizine is associated with its direct action on the central nervous system.

Calcium channel blockade is not the only mechanism of action of flunarizine, which also interacts with central histaminergic, dopaminergic, and serotonergic receptors. It is assumed that calcium channel antagonists prevent migraine attacks by inhibiting cortical spreading depression (CSD), a possible cause of migraine attacks. However, only high doses of flunarizine were able to increase the CSD threshold, and other studies failed to reproduce these data. Intraventricular administration of calcium channel antagonists to mice caused analgesia, but nimodipine was more effective than flunarizine in this model.

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Beta-blockers

The ability of beta-blockers to prevent migraine attacks was accidentally discovered by scientists who reported a decrease in the severity of migraine in a patient with angina who took propranolol. Numerous clinical trials have confirmed the effectiveness of propranolol and other beta-blockers, including nadolol, metoprolol, and timolol. In contrast, a number of other drugs, including acetabutolol, oxprenolol, alprenolol, and pindolol, have proven ineffective in migraine. In this regard, it is assumed that only those drugs that lack intrinsic sympathomimetic activity have an antimigraine effect.

Some beta-blockers interact with 5-HT _1A receptors in the brain of both animals and humans. Stimulation of these receptors on serotonergic neurons of the raphe nuclei inhibits their discharge. The inhibitory effect of 5-HT _1A receptor agonists can be blocked by propranolol. However, beta-blockers vary greatly in their affinity for 5-HT _1A receptors. For example, pindolol, a drug that has a particularly pronounced property in this area, has no antimigraine activity. In contrast, a number of beta-blockers that have antimigraine activity, including propranolol and timolol, have only moderate affinity for 5-HT _1A receptors. Consequently, there is no correlation between affinity for this type of receptor and antimigraine activity. In addition, atenolol does not interact with all 5-HT receptor subtypes at all, but, as shown by two independent clinical trials, is an effective antimigraine agent. Thus, the antimigraine effect of some beta-blockers cannot be explained only by their ability to block 5-HT receptors.

According to some data, the anti-migraine effect of beta-blockers can be explained by their effect on the central catecholaminergic systems. In the study of the contingent negative deviation (CND) - the slow negative cerebral potential associated with events, recorded using surface electrodes during the performance of a task on a simple psychomotor reaction with a warning stimulus - it was shown that in untreated migraine patients, compared with healthy individuals and individuals suffering from tension headache, this potential is significantly increased, and its extinction is weakened. However, against the background of treatment with beta-blockers, the CND is normalized. This indicates that the ability of these drugs to prevent migraine attacks can be explained by their effect on the central nervous system. It should be noted, however, that although atenolol poorly penetrates the blood-brain barrier, it is a fairly effective anti-migraine agent. Thus, the mechanism of action of beta-blockers in migraine remains unclear.

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Dopamine receptor antagonists

Phenothiazines, such as chlorpromazine or prochlorperazine, have a three-ring structure in which two benzene rings are linked by sulfur and nitrogen atoms, and a carbon side chain extends from the nitrogen atom. The constantly expanding group of heterocyclic neuroleptics also includes entatiomeric substituted benzamides, which include metoclopramide, widely used in gastrointestinal diseases. Phenothiazines and benzamides are dopamine receptor antagonists with a wide spectrum of pharmacological activity. They also have a blocking effect of varying intensity on serotonin and histamine receptors, adrenergic and cholinergic receptors.

Phenothiazines and benzamides block nausea and vomiting induced by apomorphine and some ergot alkaloids, which interact with central dopamine receptors in the chemoreceptor trigger zone of the medulla oblongata. The antiemetic effect of most neuroleptics occurs at low doses. The effect of drugs or other factors causing vomiting due to their action on the nodose ganglion or locally on the gastrointestinal tract is not blocked by neuroleptics, although highly active piperazines and butyrophenones sometimes relieve nausea caused by vestibular stimulation.

Although the mechanism of action of phenothiazines in migraine is unknown, it is suggested that chlorpromazine may affect serotonergic transmission. Another possible explanation is that the antipsychotic effect causes indifference to pain, which leads to its weakening.

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Other substances

Lithium. The lightest of the alkali metals, it shares properties with sodium and potassium ions. Although trace amounts of lithium are found in animal tissues, its physiological role remains unknown. Two lithium salts, lithium carbonate and lithium citrate, are currently used as therapeutic agents. At therapeutic concentrations, lithium ions (Li ⁺ ) do not have a significant psychotropic effect on healthy individuals, which distinguishes them from other psychotropic agents. Lithium salts were introduced into psychiatry in 1949 for the treatment of mania. Although their exact mechanism of action is unknown, many aspects of their cellular action have been investigated. An important feature of Li ⁺, which distinguishes it from sodium and potassium ions, is the small gradient in distribution across biological membranes. Although lithium can replace sodium in the generation of the action potential in a nerve cell, it cannot be considered an adequate substrate for the Na ⁺ pump and, therefore, cannot maintain the membrane potential. It remains unclear whether there is an interaction between Li ⁺ and the transport of other monovalent or divalent cations in nerve cells.

Lithium can disrupt neural transmission by affecting neurotransmitters, receptors, and the second messenger system. For example, it is believed that the antidepressant, antimanic, and prophylactic antimigraine effects of lithium are associated with its effect on serotonergic transmission. It has also been shown that lithium can affect the concentration of peptides in various areas of the rat brain. Thus, long-term lithium administration increases substance P-like immunoreactivity in the striatum, nucleus accumbens, and frontal cortex, but not in the hypothalamus, hippocampus, or brainstem. It has also been found that lithium blocks the dilation of the isolated ophthalmic artery of a pig caused by substance P and vasoactive intensinal peptide, but not CGRP.

Phenelzine. The first monoamine oxidase (MAO) inhibitors used in the treatment of depression were derivatives of hydrazine, a substance with pronounced hepatotoxicity. Phenelzine is a hydrazine analogue of phenethylamine, a substrate of MAO. Hydrazine compounds are irreversible MAO inhibitors that act at a specific site on the molecule: they attack and inactivate the flavin prosthetic group after oxidation of the MAO drug to form active intermediates. MAO inhibitors have been used for migraine prophylaxis based on the assumption that they can increase endogenous serotonin levels. However, an open trial of phenelzine found no correlation between its prophylactic effect in migraine and an increase in platelet 5-HT levels. Modulation of monoaminergic transmission in the central nervous system probably better explains the therapeutic effect of phenelzine in migraine. Like other antidepressants, MAO inhibitors cause a gradual decrease in the sensitivity of 5-HT ₂ receptors and beta-adrenergic receptors in the brain.

Glucocorticoids

They are able to prevent or suppress inflammation in response to various factors, including radiation, mechanical, chemical, infectious and immunological. Suppression of inflammation is, at least in part, associated with inhibition of phospholipase A2 activity, which leads to a decrease in the synthesis of prostaglandins and leukotrienes and may explain the antimigraine effect of these drugs. Various mechanisms are involved in the suppression of inflammation by glucocorticoids. It is currently known that glucocorticoids inhibit the production of factors that are crucial in the generation of an inflammatory response. As a result, the release of vasoactive and chemotoxic factors decreases, the secretion of lipolytic and proteolytic enzymes decreases, and leukocyte extravasation is weakened. Glucocorticoids also inhibit the production of interleukins (IL-1, IL-2, IL-3, IL-6) and tumor necrosis factor alpha (TNFa).

Dexamethasone has been shown to selectively inhibit cyclooxygenase-2 expression. Thus, this enzyme may be an additional target for glucocorticoids. Moreover, dexamethasone and other glucocorticoids have antiemetic effects, although the mechanism of this effect is unknown.