Medications to treat headaches

Medicines used for headaches

Ergot alkaloids

Ergot alkaloids have been widely used for over half a century both to relieve and prevent migraine and cluster headache attacks. The use of these drugs is based mainly on long-term clinical experience rather than on the results of controlled studies. Side effects of all ergot alkaloids are similar, but with dihydroergotamine they are less frequent and less severe than with ergotamine. The list of side effects includes nausea, vomiting, painful muscle spasms, weakness, acrocyanosis, chest pain. Contraindications: pregnancy, coronary heart disease and other cardiovascular diseases, peripheral vascular disease, history of thrombophlebitis, Raynaud's phenomenon, uncontrolled arterial hypertension, severe liver and kidney dysfunction.

Ergotamine tartrate is a classic remedy for relieving migraine and cluster headache attacks. Ergotamine is often produced in combination with other agents - caffeine, phenobarbital or belladonna alkaloids in forms for oral administration, sublingual or as suppositories. In the treatment of migraine, the effective dose is from 0.25 to 2 mg, depending on the route of administration. The effectiveness of ergotamine is significantly higher when taken at the onset of a migraine attack. When using ergotamine, there is a risk of abuse, which can contribute to the transformation of episodic migraine attacks into chronic daily headaches. Very rarely, abuse of ergotamine leads to the development of ergotism, the dose of the drug usually exceeds 10 mg per week. Ergotism is characterized by peripheral cyanosis, intermittent claudication, finger necrosis, and infarctions of various organs.

When stopping an attack of cluster headache, taking the drug sublingually (1-2 mg) is preferable to taking it orally because of its faster onset of action. For many years, ergotamine was the only preventive drug for cluster headaches and was used in a dose of 2-4 mg (orally or in suppositories). As a rule, patients with cluster headaches tolerate ergotamine well. However, like any vasoconstrictor, ergotamine should be prescribed with caution to men over 40 years of age.

Dihydroergotamine (DHE) is a reduced form of the ergot alkaloid available as an injectable that has a weaker vasoconstrictor effect on peripheral arteries than ergotamine. Until recently, DHE was the mainstay of non-opioid treatment for severe migraine attacks. Unlike ergotamine, DHE can be effective even when given during an advanced migraine attack. When given intravenously, DHE causes less nausea than ergotamine; however, it is recommended that an antiemetic be administered before DHE injection.

To relieve a migraine attack (non-migraine status), DHE is prescribed as follows:

1. at the beginning of an attack - 1-2 mg of DHE intramuscularly or subcutaneously, no more than 3 mg can be administered again within 24 hours;
2. against the background of a severe attack - 5 mg of prochlorperazine or 10 mg of metoclopramide intravenously, after 10-15 minutes, administer DHE intravenously at a dose of 0.75-1 mg over 2-3 minutes;
3. If the attack is not relieved within 30 minutes, 0.5 mg of DHE can be administered intravenously again.

The most common side effect of DHE is diarrhea, which can be treated with oral diphenoxylate. Contraindications to intravenous DHE include: variant angina, pregnancy, ischemic heart disease, uncontrolled hypertension, peripheral vascular disease, severe liver and kidney disease.

DHE is also used to relieve cluster headache attacks (at a dose of 0.5-1.0 mg). According to a double-blind crossover study, intranasal administration of DHE reduced the severity of the attack, but not its duration.

Methysergide was introduced into clinical practice in the 1960s. It was one of the first drugs to prevent migraine and cluster headache attacks. The ability of methysergide to reduce the frequency, severity, and duration of migraine attacks has been proven in double-blind controlled trials. The recommended dose is 2 to 8 mg/day. Unfortunately, methysergide can cause serious complications in the form of retroperitoneal, pericardial, or pleural fibrosis. Since these complications can be fatal, methysergide is usually used in the most severe cases of migraine when other preventive measures are ineffective. Fibrotic complications are reversible at an early stage, so after every 6 months of treatment with methysergide, it is recommended to take a break for 6-8 weeks. Early symptoms of retroperitoneal fibrosis include decreased urine output and pain in the back or lower extremities.

Methysergide is effective in approximately 70% of patients with episodic cluster headache. Fibrotic complications are less likely in patients with cluster headache than in patients with migraine, since the duration of drug administration usually does not exceed 3 months.

In addition to fibrosis and side effects typical of ergotamines, methysergide can cause depression, drowsiness, dizziness, and peripheral edema.

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Calcium channel antagonists (calcium antagonists)

Calcium channel antagonists (calcium antagonists) are used primarily to treat hypertension and vasospasm. They were initially proposed for the treatment of migraine attacks as a means of inhibiting the development of the vasospastic phase. Of the calcium antagonists, flunarizine is the most effective in migraine, but it is not approved for use in the United States. Several clinical trials of nimodipine in migraine have yielded mixed results. Of the other calcium antagonists, only verapamil has proven effective enough in double-blind clinical trials and can be used to prevent headache attacks.

Verapamil is used in the prophylactic treatment of migraine and cluster headache at a dose of 160-480 mg/day. In two small controlled double-blind trials, it was more effective in preventing migraine attacks than placebo. An open study showed that verapamil reduced the likelihood of cluster headache attacks in 69% of cases. In another double-blind study, verapamil was as effective as lithium in treating cluster headache. Side effects: arterial hypotension, edema, fatigue, nausea, constipation, and occasionally headache. The drug is contraindicated in bradycardia, cardiac conduction disorders, sick sinus syndrome, and when beta-blockers are needed.

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Antidepressants

Antidepressants of various pharmacological classes are widely used in the prophylactic treatment of migraine, chronic tension headache, post-traumatic and chronic daily headache. Heterocyclic drugs such as amitriptyline, imipramine, nortriptyline, clomipramine, doxepin and trazodone are used for migraine prophylaxis. The evidence for the effectiveness of amitriptyline is most compelling. Although there are many advocates for the use of selective serotonin reuptake inhibitors such as fluoxetine, sertraline and paroxetine, there is no convincing evidence to support their effectiveness.

Amitriptyline is a tertiary amine whose efficacy in headaches has been proven in double-blind, placebo-controlled studies. In addition, amitriptyline is one of the most effective treatments for post-traumatic headache and the drug of choice for chronic tension headache and mixed headache with features of migraine and tension headache. For migraine, amitriptyline is used in a dose of 10 to 150 mg/day and higher (subject to good tolerability). For chronic tension headache and post-traumatic headache, higher doses may be required - up to 250 mg/day. The therapeutic effect may appear 4-6 weeks after the start of treatment. In some cases, the use of amitriptyline is limited by its anticholinergic side effects - dry mouth, tachycardia, constipation and urinary retention. Other possible side effects include a decrease in the threshold of epileptic activity, increased appetite, increased photosensitivity of the skin, and a sedative effect, which is particularly common. To reduce the sedative effect, amitriptyline is prescribed once, 1-2 hours before bedtime, and treatment is started with a low dose (e.g., 10 mg/day), and then the dose is slowly increased over several weeks (e.g., by 10 mg every 1-2 weeks). Contraindications include recent myocardial infarction, concomitant use of other tricyclic antidepressants or MAO inhibitors, closed-angle glaucoma, urinary retention, pregnancy, cardiovascular disease, kidney disease, or liver disease.

Doxepin is another tricyclic antidepressant that can reduce the severity of tension headaches. Doxepin is prescribed in a dose of 10 to 150 mg / day. Side effects and contraindications are the same as those of amitriptyline.

Maprotiline is a tetracyclic antidepressant that may be useful in chronic tension-type headache. In a small, double-blind, placebo-controlled study, maprotiline 75 mg/day reduced headache severity by 25% and increased the number of headache-free days by 40%. At a dose of 25-150 mg/day, the drug is used to treat depression. In patients with headache, maprotiline should be tried at a low dose. Side effects include drowsiness, tachycardia, and a decrease in the threshold for epileptic activity. Contraindications include recent myocardial infarction, the need for concomitant use of MAO inhibitors, and epilepsy.

Fluoxetine is a selective serotonin reuptake inhibitor that has been reported to reduce migraine severity at 20–40 mg/day. However, in a large placebo-controlled study, 20 mg/day had no effect on migraine but did provide significant improvement in patients with chronic daily headache. Fluoxetine is sometimes used empirically for chronic tension headache. Side effects include insomnia, abdominal pain, and tremor. Contraindications include hypersensitivity to the drug, the need for MAO inhibitors, and liver disease.

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Anticonvulsants

Anticonvulsants such as phenytoin and carbamazepine have been used empirically for migraine and facial pain for many years. Compelling evidence of efficacy exists for only one anticonvulsant, valproic acid. Preliminary data suggest that gabapentin and topiramate may be effective for migraine.

Valproic acid is a drug that has relatively recently come into use for migraine prophylaxis. The ability of valproic acid or divalproex sodium to reduce the frequency of migraine attacks has been proven in several double-blind controlled clinical trials. Small open trials have shown the effectiveness of these drugs in cluster headache and chronic daily headache. Treatment with divalproex sodium begins with a dose of 125-250 mg/day, then the dose is increased by 125 mg every 1-2 weeks until a significant decrease in headache frequency is achieved. The effective dose ranges from 750 to 2000 mg/day in 3 doses. The goal is to achieve maximum therapeutic effect with minimal tolerable side effects. Side effects of valproic acid include nausea, drowsiness, tremor, transient hair loss, weight gain, inhibition of platelet aggregation, and minimal changes in liver function tests. In children, valproic acid may cause symptoms resembling Reye's syndrome. Like other anticonvulsants, valproic acid has a teratogenic effect. When taking the drug in the first trimester of pregnancy, 1-2% of children are born with neural tube defects. Contraindications to prescribing valproic acid: liver disease, proposed surgery, pregnancy, blood clotting disorders.

Gabapentin is an anticonvulsant that may prevent migraine attacks in a small, double-blind, open-label study. Side effects include only transient drowsiness and mild dizziness. Gabapentin's relatively benign side effects make it a promising drug, but its antimigraine effect needs to be studied more thoroughly.

Acetazolamide is a carbonic anhydrase inhibitor prescribed at a dose of 500-1000 mg twice daily for the treatment of benign intracranial hypertension. The drug acts by inhibiting the production of cerebrospinal fluid. Acetazolamide is also sometimes used at a dose of 250 mg twice daily to prevent acute mountain sickness, one of the main manifestations of which is headache. Side effects include paresthesia, nephrolithiasis, anorexia, gastrointestinal disturbances, transient myopia, drowsiness, and fatigue. There are isolated reports of renal dysfunction resembling sulfanilamide nephropathy. The drug is contraindicated in patients with nephrolithiasis, liver failure, or kidney failure.

Acetaminophen is an analgesic and antipyretic drug that, at a dose of 650-1000 mg, is often very effective in treating mild migraines and tension headaches. In severe headaches, acetaminophen is often ineffective, but its effectiveness can be significantly increased when combined with barbiturates, caffeine, or opioids. Mild to moderate headaches during pregnancy should be treated with acetaminophen. Gastric side effects with acetaminophen are much less pronounced than with NSAIDs. In general, side effects are rare when taking the drug in therapeutic doses. Toxic doses of the drug can cause liver necrosis.

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Beta-blockers

Beta-blockers are widely used as antihypertensive agents. In clinical trials, antimigraine effect was revealed in five drugs, including non-selective beta-blockers propranolol at a dose of 40-200 mg/day, nadolol at a dose of 20-80 mg/day, timolol at a dose of 20-60 mg/day, as well as beta-adrenergic receptor blockers atenolol - 25-150 mg/day and metoprolol - 50-250 mg/day. Side effects of these drugs include decreased ability of the bronchi to expand, arterial hypotension, bradycardia, fatigue, dizziness, gastrointestinal disorders (nausea, diarrhea, constipation), depression, sleep disorders, memory loss. Contraindications: bronchial asthma, chronic obstructive pulmonary diseases, heart failure, cardiac conduction disorders, peripheral vascular disease, diabetes mellitus with unstable blood sugar levels.

Busperone is an azapiron anxiolytic, a partial agonist of 5-HT _1A receptors. It was reported that at a dose of 30 mg/day it is as effective in the prophylactic treatment of chronic tension headache as amitriptyline at a dose of 50 mg/day. Side effects: dizziness, nausea, headache, irritability, agitation. Contraindications: hypersensitivity to the drug, taking MAO inhibitors.

Butalbital is a barbiturate that (in an amount of 50 mg), along with caffeine (50 mg), aspirin (325 mg), or acetaminophen (325-500 mg), is part of several combination analgesic drugs widely used to treat migraines and tension headaches. Some drugs also contain codeine. The recommended dose is 2 tablets every 4 hours, but not more than 6 tablets per day. These combinations are appropriate for rare episodes of moderate to severe headaches. However, if these drugs are used more often than once a week, there is a risk of abuse and rebound headaches. When using butalbital, both doctors and patients should be aware of the risk of abuse. Side effects: drowsiness, dizziness, shortness of breath, gastrointestinal disorders. Combined analgesics are contraindicated in case of hypersensitivity to any of their components, history of drug dependence, as well as kidney and liver pathology.

Isometeptene mucate is a mild vasoconstrictor (65 mg per capsule) used in combination with acetaminophen (325 mg) and the mild sedative dichloralphenazone (100 mg). It is used to relieve moderate tension headaches and migraine pain. When a headache occurs, take 2 capsules, then repeat the dose by 1 capsule every hour, but no more than 5 capsules in 12 hours. Side effects: dizziness, tachycardia, occasionally - skin rashes. Experience shows that this drug is less likely to cause rebound headaches than other combination analgesics, but like any other analgesic, it is not recommended to use it daily. Contraindications: glaucoma, severe liver, kidney or heart disease, arterial hypertension, the need to take MAO inhibitors.

Corticosteroids are often administered intravenously in the treatment of status migrainosus and treatment-resistant cluster headache. In these situations, dexamethasone is most often used, administered at 12-20 mg intravenously. In chronic and episodic forms of cluster headache, as well as in status migrainosus, prednisolone is also prescribed orally in a gradually decreasing dose after intravenous dexamethasone or from the very beginning of treatment. However, the effectiveness of corticosteroids in cluster headache has not been proven in controlled clinical trials. Prednisolone is usually prescribed at a dose of 60-80 mg per day for a week, and then the drug is gradually discontinued over 2-4 weeks. Doses should be selected individually. Side effects: hypernatremia, hypokalemia, osteoporosis, aseptic necrosis of the hip, gastric ulcer, gastrointestinal bleeding, hyperglycemia, hypertension, mental disorders, weight gain. Corticosteroids are contraindicated in mycobacterial or systemic fungal infections, ocular herpes, and if there is a history of hypersensitivity to these drugs.

Lithium carbonate is used for the prophylactic treatment of episodic and chronic cluster headache. Its efficacy has been demonstrated in more than 20 open clinical trials. Since the drug has a narrow therapeutic window, it is recommended to test the serum lithium content 12 hours after administration during treatment. The therapeutic concentration in the blood is from 0.3 to 0.8 mmol / l. In cluster headache, lithium has a therapeutic effect at a low concentration in the blood. With the simultaneous use of NSAIDs and thiazide diuretics, the concentration of lithium in the serum may increase. On average, the daily dose of lithium varies from 600 to 900 mg, but it should be adjusted taking into account the concentration of the drug in the serum. Side effects: hand tremor, polyuria, thirst, nausea, diarrhea, muscle weakness, ataxia, accommodation disorder, dizziness. Contraindications: severe exhaustion, kidney and heart disease, dehydration, ginatremia, need to take diuretics or angiotensin-converting enzyme inhibitors.

Metoclopramide is a benzamide derivative often combined with NSAIDs or DHE for the relief of severe migraine attacks. In a double-blind study, metoclopramide (10 mg intravenously) was shown to be superior to placebo in the relief of severe migraine attacks in the emergency department when used alone. This is somewhat surprising since other studies have failed to demonstrate additional relief of nausea or enhancement of analgesic effect when metoclopramide was added to ergotamine. Suggested dose: 5-10 mg intravenously. Side effects: akathisia, drowsiness, dystonic reaction. Contraindications: need for neuroleptics, pregnancy, breastfeeding, pheochromocytoma.

Neuroleptics are used as an alternative to opioid analgesics or vasoconstrictors in the emergency department to relieve severe migraine attacks. The beneficial effects of the drugs are associated with antiemetic, prokinetic, and sedative effects.

Chlorpromazine is a phenothiazine-derived neuroleptic sometimes used for severe migraine attacks when vasoactive drugs or opioids are contraindicated or ineffective. In a small, double-blind, parallel study, pain relief with chlorpromazine was not statistically significant. In a larger, blinded, comparative study, chlorpromazine was significantly more effective than intravenous meperidine or dihydroergotamine. The need for intravenous administration, the possibility of developing arterial hypotension, drowsiness, and akathisia limit the use of chlorpromazine. Before administering chlorpromazine, it is necessary to establish an intravenous infusion system and administer 500 ml of isotonic sodium chloride solution. Only after this, 10 mg of chlorpromazine is administered, then the same dose can be repeated after 1 hour. After the administration of the drug, it is necessary to measure blood pressure regularly, and the patient should remain in bed for an hour. Instead of chlorpromazine, prochlorperazine can be administered, 10 mg intravenously, while there is no need for preliminary infusion of isotonic solution. If necessary, the drug is administered again after 30 minutes. Side effects: orthostatic hypotension, drowsiness, dry mouth, dystonic reaction, malignant neuroleptic syndrome. Neuroleptics are contraindicated in case of hypersensitivity to them, as well as if it is necessary to take other drugs that depress the central nervous system.

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Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) have analgesic, anti-inflammatory, and antipyretic effects by inhibiting cyclooxygenase activity. Inhibition of cyclooxygenase blocks the formation of proinflammatory prostaglandins and platelet aggregation. These drugs can be used both to relieve migraine and tension headache attacks and for short-term preventive therapy for migraine and some other types of headache. In this regard, it is difficult to correlate the prophylactic efficacy of drugs with their ability to inhibit platelet function. There are no data on the comparative efficacy of various NSAIDs that would be obtained in adequate clinical trials.

NSAIDs are most commonly used to treat primary headaches such as migraine or tension headaches.

Preparations	Initial dose (mg)	Repeat dose (mg)
Aspirin	900-1000	975
Ibuprofen	600-800	600
Ketoprofen	50-75	50
Naprosin	500-825	500
Naproxen	550	275
Ketorolac (orally)	20	10
Indomethacin (suppositories)	50	-

In addition, some NSAIDs are effective in preventing migraines. These include aspirin 675 mg twice daily, naprosyn 250 mg twice daily, naproxen 550 mg twice daily, ketoprofen 50 mg three times daily, and mefenamic acid 500 mg three times daily. Naproxen has been shown to be effective in treating menstrual migraine, which is particularly difficult to treat, in controlled trials.

Side effects of NSAIDs are mainly associated with a negative effect on the gastrointestinal tract. These include dyspepsia, diarrhea, gastritis, and increased bleeding. With prolonged use of high doses, kidney dysfunction is possible. With toxic levels of drugs in the blood, tinnitus may occur. Contraindications: peptic ulcer, hypersensitivity to other NSAIDs, chronic anticoagulant therapy, liver or kidney disease, age under 12 years.

Indomethacin is a methylated indole derivative. The drug is uniquely effective in several relatively rare forms of headache, including chronic paroxysmal hemicrania, benign cough headache, headache induced by physical effort and sexual activity, and idiopathic piercing headache.

Treatment of these forms of headache begins with a dose of 25 mg twice daily, then increases every few days until attacks cease. This sometimes requires increasing the dose to 150 mg/day. Once the condition has stabilized, the dose is gradually reduced to the minimum effective value (usually from 25 to 100 mg/day). There are significant individual differences in the effective dose. Although headaches often return after the maintenance dose is discontinued, long-term remissions are possible.

Indomethacin can cause serious gastrointestinal complications with prolonged use, including dyspepsia, gastric ulcer, gastrointestinal bleeding. Other side effects are also possible - dizziness, nausea, hemorrhagic rash. It is important to find the minimum effective dose, which reduces the likelihood of these side effects. In the form of an elixir or suppositories, indomethacin is better tolerated than in tablet form. Contraindications: hypersensitivity to the drug, bronchial asthma, urticaria and rhinitis when using NSAIDs, peptic ulcer.

Ketorolac tremethamine is a potent nonsteroidal anti-inflammatory drug that is available in tablet form and as an injection solution. The drug can be administered intramuscularly (60-90 mg) to treat severe migraine attacks as an alternative to narcotic analgesics, especially in the presence of nausea and vomiting. However, in one study, this expensive treatment method was less effective than a combination of DHE and metoclopramide. However, in some patients, ketorolac has a good effect and can be especially useful in situations where intravenous administration is difficult or if vasoactive agents such as DHE or sumatriptan are contraindicated. Side effects: gastrointestinal disorders, arterial hypotension, skin rashes, bronchospasm, increased bleeding - are possible even with short-term use. Like other NSAIDs, ketorolac can cause nephropathy with long-term use. Contraindications are the same as for other NSAIDs.

Opioid (narcotic) analgesics

Opioid (narcotic) analgesics are widely used in combination preparations for oral administration for moderate to severe attacks of migraine, tension-type headache, and cluster headache. In addition, intramuscular or intravenous opioids (eg, meperidine) are often used to relieve severe migraine attacks in the emergency department. Adverse reactions include drowsiness, dizziness, nausea, vomiting, constipation, ataxia, and dependence. Contraindications to the use of narcotic analgesics include hypersensitivity, drug dependence, or the need for MAO inhibitors. Oral or intranasal opioids should be avoided in the treatment of chronic tension-type headache until all other alternatives have been exhausted. However, in certain situations, such as pregnancy or severe vascular disease, opioid analgesics may be the only available treatment. The group of opioid analgesics includes codeine (15-60 mg), hydrocodone (2.5-10 mg), oxycodone (5-10 mg), propoxyphene (65-200 mg), meperidine (50-100 mg). Despite the previously expressed opinion about the low risk of abuse with intranasal use of butorphanol, patients with migraine very often have a tendency to independently increase the dose of the drug.

Before prescribing opioids for chronic headache, the purpose, dosage, and duration of treatment should be clearly defined. The possibility of rebound headache and dependence should be discussed with the patient in detail.

Meperidine in combination with an antiemetic is widely used in the emergency department for the treatment of severe migraine attacks, despite the lack of double-blind, placebo-controlled clinical trials to support its efficacy. One comparative study found it to be less effective than DHE. Meperidine should be used primarily in patients with infrequent severe attacks and in patients with contraindications to other agents (e.g., patients with severe peripheral, cerebral, or coronary artery disease, or pregnancy).

Sumatriptan is a serotonin receptor agonist that causes vasoconstriction of meningeal vessels and suppresses neurogenic inflammation in them. In large-scale double-blind clinical trials, subcutaneous administration of 6 mg sumatriptan significantly reduced headache within 1 hour in 80% of patients, while placebo relieved headache in only 22% of cases (Moskowitz, Cutrer, 1993). After administration of sumatriptan, a decrease in nausea, vomiting, photophobia and phonophobia was also noted. The drug was equally effective if administered within 4 hours of the onset of an attack. When taken in tablet form (25 and 50 mg), the drug acted much more slowly. Currently, a form for intranasal administration of sumatriptan is also produced. The drug is administered intranasally at a dose of 20 mg, the effect in this case appears within 15-20 minutes.

Subcutaneous administration of sumatriptan allows rapid relief of cluster headache attacks. In a double-blind, placebo-controlled study, sumatriptan reduced pain and scleral injection in three-quarters of patients within 15 minutes. Since a significant proportion of patients with cluster headache are middle-aged men, who are at high risk of coronary heart disease, sumatriptan and other vasoconstrictors should be used with caution in this category of patients.

Side effects of sumatriptan are usually transient and include a feeling of pressure in the head, neck and chest, a tingling sensation in the neck and scalp, and sometimes dizziness. Contraindications: diagnosed or suspected ischemic heart disease, pregnancy, vasospastic angina, uncontrolled hypertension.

Phenelzine is a MAO inhibitor sometimes used at doses of 15 to 60 mg/day to prevent migraine attacks in patients resistant to other treatments. The only evidence of its effectiveness came from an open study of 25 patients with severe migraine unresponsive to other treatments. These patients were given phenelzine at a dose of 45 mg/day for up to 2 years. Twenty of them had a greater than 50% reduction in headache frequency. The combination of phenelzine with sumatriptan appears to be safe (Diamond, 1995). The possibility of hypertensive crises after ingestion of tyramine-containing products or administration of sympathomimetic agents limits the use of phenelzine; it is indicated mainly for severe migraine resistant to other treatments. Other possible side effects include: orthostatic hypotension, urinary retention, gastrointestinal disorders, hepatotoxicity, and ejaculation disorders. Phenelzine should not be combined with sympathomimetics, including anti-nasal drugs, anti-asthmatic agents, anorexigens, other MAO inhibitors, and dibenzapine-derivative antidepressants. Patients taking phenelzine should limit their intake of tyramine-containing foods, including fermented cheeses, alcoholic beverages, sauerkraut, sausages, liver, beans, etc. Contraindications to the use of the drug include pheochromocytoma, heart failure, and liver dysfunction.

Furosemide is a loop diuretic sometimes used at a dose of 40-160 mg/day to treat benign intracranial hypertension as a means of suppressing cerebrospinal fluid production. Patients taking furosemide should increase their potassium intake. Side effects: nausea, vomiting, anorexia, jaundice, vasculitis, tinnitus, dizziness, accommodation disorder, anemia, thrombocytopenia, dermatitis, orthostatic hypotension, hypokalemia. Contraindications: hypersensitivity and pregnancy.

Cyproheptadine is especially widely used as an antihistamine. In addition, in doses of 4 to 24 mg / day, it is used to prevent migraine attacks in children and adults, sometimes with cluster headache. In an open study, cyproheptadine in a dose of 12-24 mg / day completely eliminated headache attacks in 15 patients out of 100, and caused significant improvement in another 31% of patients. In another open study, it was effective in 65% of cases. Side effects: drowsiness, dry mouth, urinary retention, weight gain. Contraindications: glaucoma, hypersensitivity to the drug, the need for MAO inhibitors, peptic ulcer, prostatic hyperplasia, pyloroduodenal obstruction.

Serotonergic agents

Serotonin (5-HT) is the neurotransmitter most often mentioned when discussing the pathogenesis of migraine. However, most evidence for its involvement in the development of migraine is indirect. For example, during an attack, the concentration of 5-HT in platelets is reduced by 30%, and in plasma - by 60%. Reserpine, which depletes reserves of biogenic amines, causes atypical headache in migraine patients, probably by increasing the release of 5-HT from intracellular depots. Similarly, chlorophenylpiperazine (CPP), the main metabolite of the antidepressant trazodone, can cause migraine-like pain in humans by activating 5-HT _2B and 5-HT _2C receptors. Perhaps the most convincing evidence of the involvement of 5-HT in the pathogenesis of migraine is the ability of drugs that interact with 5-HT receptors to relieve migraine attacks (ergot alkaloids and sumatriptan) or prevent them (methysergide, pizotifen, cyproheptadine).

Currently, 15 different types of 5-HT receptors have been identified using pharmacological methods and molecular cloning. Since migraine-stopping and migraine-preventing drugs likely have different mechanisms of action, they are considered separately.

Antimigraine drugs. The efficacy of ergot preparations in migraine was established in the 1920s, but their ability to interact with 5-HT receptors was not known until the 1950s. Pharmacologically, these drugs are highly nonselective and interact with virtually all monoamine receptors. Their effect in migraine was initially thought to be due to increased sympathetic activity. Graham and Wolff (1938) suggested that the efficacy of ergotamine was due to its vasoconstrictor action on extracranial vessels. Sumatriptan was developed relatively recently as a result of a systematic search for a drug capable of activating vasoconstrictor 5-HT receptors. However, the role of vasoconstriction in the antimigraine effect of sumatriptan and ergot alkaloids remains unclear. It is possible that activation of receptors of neurons of the trigeminal ganglion or the trigeminal brainstem nucleus is no less, and perhaps even more, important.

Neurogenic inflammation is thought to play an important role in the pathogenesis of vascular headache and the mechanism of action of antimigraine drugs. This process is accompanied by vasodilation, extravasation of plasma proteins and is mediated by the release of vasoactive peptides such as substance P, neurokinin A, CGRP from trigeminovascular sensory fibers. Tachykinins induce both endothelium-dependent vasodilation and increased vascular permeability by acting on endothelial receptors. CGRP induces vasodilation by activating receptors on vascular smooth muscle cells. There is some evidence indicating the importance of neurogenic inflammation in the pathogenesis of a migraine attack. In particular, it has been shown that ergotamine and sumatriptan in doses comparable to those used to stop migraine attacks block the inflammation process in the dura mater of rats caused by electrical stimulation of trigeminal neurons. These drugs inhibit the inflammatory reaction even when they are administered 45 minutes after electrical stimulation. Moreover, other drugs that are effective in migraine attacks, such as opioids, valproic acid, aspirin, but do not affect 5-HT receptors, also block the extravasation of plasma proteins.