Preventive treatment of headache

Prophylactic drugs against headache

The so-called antiserotonin drugs are the first drugs that have been used to prevent migraine attacks. They continue to be used until now. Metisergide is an ergot derivative, which has a complex effect on serotonergic and other neurotransmitter systems. Other antiserotonin drugs, such as cyproheptadine, pisothiphene and lisuride, are also capable of preventing migraine attacks. An effective preventive tool for migraine is the tricyclic antidepressant amitriptyline. And this effect of the drug does not depend on its antidepressant effect. A common feature of all these drugs is the ability to block 5-HT _2A receptors.

It is well known that metisergide is able to block the reduction of vascular and non-vascular smooth muscles by acting on 5-HT receptors. However, it is unlikely that the blockade of these receptors explains the therapeutic effect of antiserotonin agents, since other 5-HT receptor antagonists, for example, mianserin, ketanserin and ICI 169,369, do not have a prophylactic effect on migraine. It is suggested that the vasoconstrictive effect of metisergide and its active metabolite, methylergometrine, explains its therapeutic activity. The inhibition of neurogenic inflammation with long-term intake of metisergide can also explain its ability to prevent migraine attacks.

Fozard and Kalkman (1994) suggested that the activation of 5-HT _2B - and possibly 5-HT _2C receptors can play a decisive role in initiating a migraine attack. This hypothesis was based on data on the ability of metachlorophenylpiperazine, an agonist of these receptors, to provoke migraine attacks in control subjects and migraine patients, and that the doses of a number of prophylactic antimigraine drugs correlated with their ability to block 5-HT _2B receptors. This correlation was found for such classical antagonists of 5-HT _2B receptors as metisergide, pizotifen, Org GC 94, cyproheptadine, mianserin, as well as agents that usually do not belong to this group, for example, amitriptyline, chlorpromazine, propranolol. An additional argument was that ketanserin and pindolol, which do not have antimigraine activity, are weak antagonists of 5-HT _2B receptors. Furthermore, mRNA 5-HT _2C receptor is found in all examined blood vessels, and activation of these receptors induced endothelium-dependent vasodilation, mainly due vysvobozheniya nitrogen oxide. This, in turn, can activate and sensitize trigeminovascular neurons and initiate the process of neurogenic inflammation associated with migraine.

GABA-ergic means

Valproic acid has multiple effects on neurotransmitter mediated and non-mediated cellular processes, so it can have therapeutic effects in various clinical situations. The amplification of GABAergic transmission is probably the most well-known of its action. Valproic acid increases the content in the brain GABA, stimulating the synthesizing GABA enzyme - glutamate decarboxylase and inhibiting the activity of enzymes that metabolize GABA. In addition, valproic acid modulates several other neurotransmitter systems, including excitatory and inhibitory amino acids, serotonin, dopamine, enkephalins as a mediator, although it remains unknown whether these effects are a direct effect of valproic acid or mediated by GABAergic transmission gain. In therapeutic concentrations, valproic acid inhibits prolonged repeated discharges caused by depolarization of cortical and spinal neurons in mice (McLean, Macdonald, 1986). This effect, apparently, is due to a delay in the recovery of potential-dependent sodium channels after their inactivation.

The effectiveness of valproic acid as antimigraine can be explained by its effect on different levels of the migraine cascade. For example, the increase in GABAergic transmission caused by valproic acid can suppress the pathological processes in the cortex, which presumably underlie the migraine aura. It is also shown that valproic acid weakens the extravasation of plasma proteins in the model of neurogenic inflammation of the meninges in rodents. This effect is blocked by the GABA _A receptor antagonist by bicuculline, but is simulated by drugs acting on the GABA _A receptor complex, including muscimol, benzodiazepines, zolpidem, and neurosteroids by allopregnanolone. At the level of the caudal trigeminal nucleus, where meningeal afferent fibers predominate, it has been shown that valproic acid reduces the activation of the I and II layers neurons after intracisternal administration of capsaicin. This effect appears to be mediated by GABA receptors, since it is mimed by butalbital and allopregnanolone and is blocked by the GABA _A receptor antagonist by bicuculline.

Structurally, gabapentin is a GABA covalently linked to a lipophilic cyclohexane ring. Unlike GABA, gabapentin easily penetrates the blood-brain barrier. Although gabapentin has been developed as a centrally acting GABA-receptor agonist, it does not bind to GABA receptors and does not mimic the effect of GABA when it is iontophoretically applied to neurons in the primary culture. Apparently, gabapentin acts by enhancing the release of GABA at the expense of unknown mechanisms. Its molecular targets may be close or identical to a region resembling the L-amino acid transporter protein. Gabapentin does not have a permanent effect on prolonged repeated discharges of neurons and does not have a significant effect on the functioning of calcium channels. The drug does not affect the receptors of neurotransmitters or the binding sites of ion channels. Since gabapentin appears to increase the synaptic level of GABA, its effect is probably mediated by GABA receptors and, therefore, may resemble the action of valproic acid on the headache.

The use of carbamazepine and phenytoin for the prevention of migraine is based not on the unproven assumption of the connection between migraine and epilepsy. Carbamazepine is iminostilbene with a structure resembling tricyclic antidepressants and phenytoin. The mechanism of its action is not fully understood. Carbamazepine has been shown to be effective in several different experimental models of epilepsy. Phenytoin inhibits the spread of epileptic activity induced by electric shock, reducing the excitability of membranes. Its ability to reduce the potentiation potential in the stellate node and spinal cord of rats may indicate possible additional mechanisms in the treatment of neuralgia.

Non-steroidal anti-inflammatory drugs

NSAIDs that have anti-inflammatory, analgesic and antipyretic effects are widely used both for relief of headache, and for its prevention. These drugs block cyclooxygenase, which turns arachidonic acid into prostaglandins and thromboxane, but have minimal effect on lipoxygenase, which is provided by leukotrient products. Most modern NSAIDs inhibit cyclooxygenase 1 and 2 types. It is believed that inhibition of type 2 cyclooxygenase mediates, at least in part, the antipyretic, analgesic and anti-inflammatory effects of NSAIDs, whereas the inhibition of type 1 cyclooxygenase causes unwanted side effects (primarily gastric ulcer) that are associated with a decrease in the production of prostaglandins and thromboxane. While aspirin, indomethacin and ibuprofen have a higher affinity for type-1 cyclooxygenase than for type-2 cyclooxygenase, diclofenac and naproxen both inhibit both isoforms of the enzyme with equal intensity. Preparations, mainly blocking cyclooxygenase type 2, are not currently used to treat headaches. Meloksikam and other drugs possessing, as shown in vitro, a certain selectivity for COX-2, are used to treat osteoarthritis.

NSAIDs include salicylic acids, including aspirin, which irreversibly acetylates COX and several other classes of organic acids, including propionic acid derivatives (for example, ibuprofen, naproxen, ketoprofen, flurbiprofen), acetic acid derivatives (eg, indomethacin and diclofenac) and enolin acids (for example, piroxicam), they all compete with arachidonic acid for the active sites of COX. Although acetaminophen has a weak anti-inflammatory effect and is more effective as an antipyretic and analgesic. It is not characterized by some side effects of NSAIDs, for example, damage to the gastrointestinal tract or blockade of platelet aggregation.

NSAIDs are usually classified as mild analgesics, but when evaluating analgesic activity it is important to consider the type and intensity of pain. For example, in some forms of postoperative pain, NSAIDs have an advantage over opioids. In addition, they are particularly effective in situations where inflammation causes sensitization of pain receptors that begin to respond to painless in normal conditions mechanical and chemical stimuli. This sensitization, apparently, is explained by a decrease in the excitation threshold of a polymodal nociceptor located on C-fibers. In addition, a certain value may have an increase in the excitability of central neurons in the spinal cord. Although the exact mechanism of action of NSAIDs on central structures is unknown, these drugs can inhibit the synthesis of prostaglandins in neurons of the brain, slowing down the circulation of noradrenaline and serotonin, and also blocking the release of serotonin in response to pain stimuli. It is also shown that acetylsalicylic acid iketorolac inhibits 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 contribute to the release of prostaglandins and, possibly, other substances that cause hyperalgesia. Neuropeptides, for example, substance P and CGRP can also participate in the pathogenesis of the pain syndrome. It has been shown that indomethacin and acetylsalicylic acid block meningeal neurogenic inflammation after stimulation of the trigeminal ganglion or the introduction of P. This inhibitory effect is observed within 5 min after stimulation of the trigeminal ganglion, which excludes the significant role of the induced COX-2 in the mechanism of action of NSAIDs on this model.

Opioids

Opioids reduce the response to pain stimuli, acting on various zones of the central nervous system, including the near-conductor gray matter, the rostral-ventral section of the medulla oblongata, the black substance, and the horn of the spinal cord. A number of subclasses of major categories of opioid receptors mediate the effects of endogenous ligands. Three different families of endogenous peptides have been identified: enkephalins, endorphins, idinorphins. Each of these peptides is a derivative of a separate precursor and has a different distribution in the brain.

Although morphine has a relatively selective effect on mu receptors, it is able to interact with other types of receptors, especially in high doses. Most opioids used in clinical practice, including meperidine, relatively selectively act on mu receptors, reflecting their proximity to morphine. Codeine has a very low affinity for opioid receptors, and its analgesic effect is associated with its transformation into morphine. Propoxyphene also predominantly binds to mu receptors, although less selectively than morphine, causing an analgesic effect and other central effects similar to morphine-like opioids. Although highly selective agonists of mu receptors have been developed, antagonists are more useful in identifying these receptors. Using antagonists, researchers found that morphine causes analgesia either at the spinal level (mu2) or at the supraspinal level (mu2). With systemic administration, morphine acts mainly on supraspinal mu2 receptors. At the same time, respiratory depression, constipation associated with weakening motility of the gastrointestinal tract, are explained, mainly by its action on mu2 receptors.

In the spinal cord and, probably, in the nucleus of the trigeminal nerve, the effects of opioids are mediated by activation of inhibitory receptors localized presynaptic on primary afferent fibers, as well as post-synaptic hyperpolarization of projection neurons. Morphine blocks the effect of exogenously introduced substance P due to inhibitory postsynaptic action on intercalary neurons and projection neurons of the spinotalamic tract, sending non -ceptive information to the overlying centers of the brain. In addition, peripheral receptors modulate the state of excitability of small afferent endings innervating inflamed tissues and reducing hyperalgesia.

In the near-conductor gray matter, opioid agonists indirectly activate the bulbospinal pathways and rostral projections to the anterior parts of the brain, and also modulate the afferentation flow to the stem structures.

Tricyclic antidepressants

For years, antidepressants have been used in the treatment of pain on the grounds that they are able to reduce concomitant depression. However, the fact that amitriptyline is the only antidepressant whose ability to prevent migraine attacks has been demonstrated proves that the antimigraine effect is not associated with an antidepressant effect. Initially, it was believed that tricyclic antidepressants exert a therapeutic effect by increasing the concentration of noradrenaline and serotonin in the synaptic cleft, causing adaptive changes in postsynaptic receptors, including beta-adrenoreceptors and 5-HT ₂ receptors. Imipramine and selective serotonin reuptake inhibitor fluoxetine act in the same way as amitriptyline, but they give only minimal preventive effect with migraine.

It was suggested that the effect of amitriptyline could explain the blockade of 5-HT _2A receptors, however, studies have shown that the effect of antiserotonin drugs is not associated with blockade of this type of receptors. The blockade of vascular 5-HT _2B receptors was also considered as a possible mechanism of action. It is interesting to note that amitriptyline weakens inflammatory hyperalgesia in rats due to a mechanism not associated with inhibition of monoamine reuptake, possibly due to 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, at a certain concentration reduce the activation of the intracellular level of Ca ²⁺ mediated by activation of NMDA receptors in cultures of neurons.

Antagonists of calcium channels

Calcium channel antagonists (calcium antagonists), also known as slow channel inhibitors or Ca ²⁺ entry blockers , are a heterogeneous group of drugs, including several classes of drugs that block various types of Ca ²⁺ channels. The basis for the use of calcium channel antagonists as a means of preventing migraine attacks was their ability to prevent cerebral vasospasm and protect the nerve cells from hypoxia, which was believed to occur during migraine attacks. Nevertheless, it is now believed that these phenomena do not play a significant role in migraine. Nimodipine is more effective than flunarizine, it prevents the calcium-induced spasm of the cerebral and temporal arteries in humans. However, this contrasts with the data that flunarizine is the most effective among calcium channel antagonists for the prevention of migraine attacks, whereas the effectiveness of nimodipine is at best minimal. This suggests that the effect of flunarisin is related to its direct effect on the central nervous system.

Blockade of calcium channels is not the only mechanism of action of flunarizine, which also interacts with central histaminergic, dopaminergic and serotonergic receptors. It is suggested that calcium channel antagonists prevent migraine attacks by inhibiting cortical spreading depression (CRD), a possible cause of migraine attack. However, only high doses of flunarizine were able to increase the CRP threshold, and in other studies these data could not be reproduced. Intraventricular administration of calcium channel antagonists to mice caused analgesia, but the efficacy of nimodipine in this model was higher than that of uflunarizine.

[1], [2], [3], [4], [5], [6], [7]

Beta-blockers

The ability of beta-adrenoblockers to prevent migraine attacks was accidentally discovered by scientists who reported a reduction 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, timolol. In contrast, a number of other drugs, including acetabutolol, oxprenolol, alprenolol, and pindolol have proven ineffective in migraine headaches. In this regard, it is suggested that only drugs that are devoid of intrinsic sympathomimetic activity possess anti-migraine action.

Some beta-blockers interact with 5-HT _1A receptors in the brain in both animals and humans. Stimulation of these receptors on the serotonergic neurons of the seam nuclei inhibits their discharge. The inhibitory effect of 5-HT1 _{| A} receptor agonists can be blocked by propranolol. Nevertheless, beta-blockers strongly differ in the degree of affinity for 5-HT _1A receptors. For example, pindolol - a drug in which this property is particularly pronounced, does not have antimigraine activity. In contrast, a number of beta-adrenoblockers with antimigrenous 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 at all with all 5-HT receptor subtypes, but, as two independent clinical trials have shown, it is an effective antimigraine. Thus, the antimigrenous effect of some beta-adrenoblockers can not be explained only by their ability to block 5-HT receptors.

According to some sources, the antimigrenous effect of beta-blockers can be explained by their effect on central catecholaminergic systems. In the study of contingent negative deviation (CCV) -related to the events of a slow negative cerebral potential recorded with the help of surface electrodes when performing the task for a simple psychomotor reaction with a warning stimulus-it was shown that the patients with migraine in comparison with healthy ones and those suffering from a tension headache , this potential is substantially increased, and its extinction is weakened. But against the background of treatment with beta-blockers there is a normalization of CCW. This indicates that the ability of these drugs to prevent migraine attacks can explain the effect on the central nervous system. It should, however, be noted that although atenolol does not penetrate the blood-brain barrier badly, it is quite effective antimigraine. Thus, the mechanism of action of beta-adrenoblockers in migraine remains unclear.

[8], [9], [10], [11], [12], [13], [14], [15]

Dopamine receptor antagonists

Phenothiazines, for example, chlorpromazine or prochlorperazine, have a three-ring structure in which two benzene rings are connected by sulfur and nitrogen atoms, and the side carbon chain leaves the nitrogen atom. To the constantly expanding group of heterocyclic antipsychotics are entantiomeric substituted benzamides, including metoclopramide, which is widely used in gastrointestinal diseases. Phenothiazines and benzamides are antagonists of dopamine receptors with a wide spectrum of pharmacological activity. They also have a blocking effect of varying severity on serotonin and histamine receptors, adreno- and cholinergic receptors.

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

Although the mechanism of action of phenothiazines in migraine is not known, it is suggested that chlorpromazine is able to influence serotonergic transmission. Another possible explanation is that due to the antipsychotic effect, there is indifference to pain, which leads to its weakening.

[16], [17], [18], [19], [20], [21], [22]

Other substances

Lithium. The lightest of alkali metals has common properties with sodium and potassium ions. Although trace amounts of lithium are found in the tissues of animals, its physiological role remains unknown. Currently, two lithium salts, lithium carbonate and lithium citrate, are used as a therapeutic agent. In the therapeutic concentration, 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 the precise mechanism of their action is unknown, many aspects of cellular action have been studied. An important feature of Li ⁺, which distinguishes it from sodium and potassium ions, is a small gradient in the distribution relative to biological membranes. Although lithium can replace sodium in the process of generating an action potential in a nerve cell, it can not be considered an adequate substrate for the Na ⁺ pump and therefore can not support the membrane potential. It remains unclear whether there is interaction between Li ⁺ and the transport of other monovalent or divalent cations by nerve cells.

Lithium can disrupt the neural transmission, affecting the neurotransmitters, receptors, the second mediator system. So, for example, it is believed that antidepressant, antimanic and prophylactic anti-migraine actions of lithium are associated with its effect on serotonergic transmission. It is also shown that lithium is able to influence the concentration of peptides in different regions of the rat brain. Thus, with prolonged use of lithium, the substance of P-like immunoreactivity in the striatum, the contiguous nucleus and the frontal cortex, but not in the hypothalamus, hippocampus or trunk, increases. It was also found that lithium blocks the expansion of the isolated porcine eye artery caused by substance P and the vasoactive intrastinal peptide, but not CGRP.

Fenelzin. The first monoamine oxidase inhibitors (MAO) used to induce depression were derivatives of hydrazine, a substance with pronounced hepatotoxicity. Fenelzin is a hydrazine analogue of phenethylamine, a substrate of MAO. Hydrazine compounds are irreversible MAO inhibitors that act on a specific region of the molecule: they attack and inactivate the flavin prosthetic group after oxidizing the MAO preparation to form active intermediates. MAO inhibitors have been used to prevent migraine, based on the assumption that they are able to increase the level of endogenous serotonin. However, an open study of phenelzine did not reveal a correlation between its prophylactic effect on migraine and an increase in the level of 5-HT in platelets. Modulation of monoaminergic transfer to the central nervous system seems to explain better 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-adrenoreceptors 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, at least in part, is associated with inhibition of the activity of phospholipase A2, which leads to a decrease in the synthesis of prostaglandins and leukotrienes and can explain the antimigraine effect of these drugs. Various mechanisms are involved in the suppression of inflammation by glucocorticoids. It is now known that glucocorticoids inhibit the production of factors that are crucial in generating 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, in addition, inhibit the production of interleukins (IL-1, IL-2, IL-3, IL-6) and tumor necrosis factor alpha (TNFa).

It was shown that dexamethasone selectively inhibits the expression of cyclooxygenase-2. Thus, this enzyme can be an additional target for glucocorticoids. Moreover, dexamethasone and other glucocorticoids have an antiemetic effect, although the mechanism of this effect is unknown.