Medications for the treatment of headaches

Medications used for headache

Alkaloids of ergot

For more than half a century, ergot alkaloids have been widely used both for cupping and for preventing migraine attacks and cluster headaches. The use of these drugs is based mainly on long-term clinical experience, rather than on the results of controlled trials. Side effects in all alkaloids of ergot are similar, but with dihydroergotamine they are more rare 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 lesions, history of thrombophlebitis, Raynaud phenomenon, uncontrolled arterial hypertension, severe impairment of liver and kidney function.

Ergotamine tartrate is a classic remedy for relieving migraine attacks and cluster headaches. Ergotamine is often released in combination with other agents - caffeine, phenobarbital or alkaloids of belladonna in forms for ingestion, under the tongue or in the form of candles. In the treatment of migraine, the effective dose ranges from 0.25 to 2 mg, depending on the route of administration. The efficacy of ergotamine is significantly higher when taken at the onset of a migraine attack. When using ergotamine, there is a risk of developing abuse, which can contribute to the transformation of episodic migraine attacks into a chronic daily headache. Very rarely, the 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, necrosis of the fingers, and infarctions of various organs.

When stopping an attack of cluster headache, taking the drug under the tongue (1-2 mg) is preferable to ingestion because of a faster onset of action. For many years, ergotamine was the only prophylactic for cluster headaches and was used in a dose of 2-4 mg (inside or in candles). As a rule, patients with cluster headache are well tolerated by ergotamine. However, like any vasoconstrictor, ergotamine should be administered with caution to men over the age of 40.

Dihydroergotamine (DHE) is a restored form of ergot alkaloid, available in injectable form and has a weaker vasoconstrictor effect on peripheral arteries than ergotamine. Until recently, DGE was the main non-opioid remedy for severe migraine attacks. Unlike ergotamine, DHE can have an effect even if it is injected against a background of a developed migraine attack. With intravenous injection, the DHE causes less nausea than ergotamine, nevertheless, the injection of DHE is recommended to be preceded by the administration of an anti-emetic.

To stop a migraine attack (not migraine status), DHE is prescribed as follows:

1. at the beginning of an attack - 1-2 mg DHE intramuscularly or subcutaneously, you can re-enter no more than 3 mg within 24 hours;
2. on the background of a developed severe attack - 5 mg prochlorperazine or 10 mg metoclopramide intravenously, after 10-15 minutes intravenously injected DHE in a dose of 0.75-1 mg for 2-3 minutes;
3. if the attack did not stop within 30 minutes, 0.5 mg of DHE can be re-injected intravenously.

The most frequent side effect of DHE is diarrhea, it can be eliminated by ingestion of diphenoxylate. Contraindications to intravenous injection of DHE: variant angina pectoris, pregnancy, ischemic heart disease, uncontrolled arterial hypertension, peripheral vascular injury, severe liver and kidney damage.

DGE is also used to stop an attack of cluster headache (in a dose of 0.5-1.0 mg). According to a double-blind cross-over study, intranasal administration of DHE decreased the severity of the attack, but not its duration.

Metisergide was introduced into clinical practice in the 1960s. He was one of the first drugs to prevent migraine attacks and cluster headaches. The ability of metisergid to reduce the frequency, severity and duration of migraine attacks was proven in double-blind controlled trials. The recommended dose is from 2 to 8 mg / day. Unfortunately, metisergide can cause serious complications in the form of retroperitoneal, pericardial or pleural fibrosis. Since these complications can lead to death, metisergide is usually used in the most severe cases of migraine with ineffectiveness of other prophylactic agents. Fibrotic complications are reversible at an early stage, therefore every 6 months of treatment with metisergide is recommended to take breaks for 6-8 weeks. Early symptoms of retroperitoneal fibrosis include decreased diuresis and pain in the back or lower limbs.

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

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

[1], [2], [3], [4], [5], [6], [7], [8],

Calcium channel antagonists (calcium antagonists)

Calcium channel antagonists (calcium antagonists) are used mainly for the treatment of hypertension and vasospasm. Initially, they were proposed for the treatment of migraine attacks as a means of inhibiting the development of the vasospastic phase. Of calcium antagonists with migraine, flunarizine is most effective, but it is not approved for use in the US. Several clinical trials of nimodipine in migraine have produced mixed results. Of the other calcium antagonists, only verapamil has proven to be quite effective in double-blind clinical trials and can be used to prevent attacks of headache.

Verapamil is used in the prophylactic treatment of migraine and cluster headache in a dose of 160-480 mg / day. In two small controlled double-blind trials, he more effectively prevented migraine attacks than placebo. In an open study, it was shown that verapamil reduced the likelihood of cluster headache attacks in 69% of cases. In another double-blind study, verapamil for cluster headache was not inferior to lithium in effectiveness. Side effects: arterial hypotension, edema, fatigue, nausea, constipation, occasionally headache. The drug is contraindicated in bradycardia, conduction disorders of the heart, weakness syndrome of the sinus node, if necessary, take beta-blockers.

[9], [10], [11], [12],

Antidepressants

Aids depressants of various pharmacological groups are widely used in the prophylactic treatment of migraine, chronic tension headache, post-traumatic and chronic daily headache. For the prevention of migraine use such heterocyclic drugs as amitriptyline, imipramine, nortriptyline, clomipramine, doxepin and trazodone. The most weighty evidence of the effectiveness of amitriptyline. Although there are many advocates of the use of selective serotonin reuptake inhibitors, such as fluoxetine, sertraline and paroxetine, there is no conclusive evidence supporting their effectiveness.

Amitriptyline is a tertiary amine, whose effectiveness in headache has been proven in double-blind, placebo-controlled studies. In addition, amitriptyline is one of the most effective treatments for post-traumatic headache and a drug of choice for chronic tension headaches and mixed headaches with migraine traits and tension headaches. With migraine, amitriptyline is used at a dose of 10 to 150 mg / day and higher (with good tolerability). With 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 cholinolytic side effects - dry mouth, tachycardia, constipation and urinary retention. Other possible side effects are a decrease in the threshold of epileptic activity, increased appetite, increased photosensitivity of the skin, and a sedative effect, which is observed especially often. To reduce the sedative effect, amitriptyline is prescribed once, 1-2 hours before sleep, and treatment starts with a low dose (for example, with 10 mg / day), and then the dose is slowly increased over several weeks (for example, by 10 mg every 1- 2 weeks). Contraindications - a recently transferred myocardial infarction, simultaneous administration of other tricyclic antidepressants or MAO inhibitors, angle-closure glaucoma, urinary retention, pregnancy, diseases of the cardiovascular system, kidneys or liver.

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

Maprotiline is a tetracyclic antidepressant, which can be useful in chronic tension headaches. In a small double-blind, placebo-controlled study, maprotiline at a dose of 75 mg / day reduced the severity of headache by 25% and increased the number of days without a headache by 40%. In a dose of 25-150 mg / day the drug is used to treat depression. In patients with a headache, Maprotiline should be tested at a low dose. Side effects - drowsiness, tachycardia, lowering the threshold of epileptic activity. Contraindications - the recently transferred myocardial infarction, the need for simultaneous administration of MAO inhibitors, epilepsy.

Fluoxetine is a selective serotonin reuptake inhibitor, which, according to some reports, at a dose of 20-40 mg / day reduces the severity of migraine. However, in a large placebo-controlled study, the drug at a dose of 20 mg / day had no effect on migraine, but caused significant improvement in patients with chronic daily headache. Fluoxetine is sometimes used empirically for chronic tension headaches. Side effects - insomnia, abdominal pain, tremor. Contraindications: hypersensitivity to the drug, the need for taking MAO inhibitors, liver disease.

[13], [14], [15]

Anticonvulsants

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

Valproic acid is a drug that has been relatively recently used to prevent migraine. 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. In small open trials, the effectiveness of these drugs is shown in cluster headache and chronic daily headache. Treatment with divalproexom sodium begins with a dose of 125-250 mg / day, then the dose is increased by 125 mg every 1-2 weeks until the headache frequency is significantly reduced. Effective dose ranges from 750 to 2000 mg / day in 3 divided doses. The goal is to obtain the maximum therapeutic effect with minimal tolerated side effects. Side effects of valproic acid include nausea, drowsiness, tremor, transient hair loss, weight gain, inhibition of platelet aggregation, minimal changes in liver function. In children, valproic acid can 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 in 1-2% of cases, children with neural tube defects are born. Contraindications to the appointment of valproic acid: liver disease, the proposed surgical intervention, pregnancy, coagulation disorders.

Gabapentin is an anticonvulsant, which, according to a small double-blind and open-label study, is able to prevent migraine attacks. Side effects include only transient drowsiness and mild dizziness. Due to relatively benign side effects, gabapentin is a promising drug, but its antimigraine effect needs to be investigated more thoroughly.

Acetazolamide is an inhibitor of carbonic anhydrase prescribed in a dose of 500-1000 mg 2 times a day for the treatment of benign intracranial hypertension. The effect of the drug is associated with inhibition of cerebrospinal fluid production. Acetazolamide is also sometimes used in a dose of 250 mg 2 times a day to prevent acute mountain sickness, one of the main manifestations of which is headache. Side effects include paresthesia, nephrolithiasis, anorexia, gastrointestinal disorders, transient myopia, drowsiness and fatigue. There are isolated reports of the development of kidney dysfunction, reminiscent of sulfonamide nephropathy. The drug is contraindicated in patients with nephrolithiasis, hepatic or renal insufficiency.

Acetaminophen is a preparation with an analgesic and antipyretic effect, which at a dose of 650-1000 mg is often very effective in treating mild migraine and tension headache. In severe headache, the use of acetaminophen often does not give the desired effect, but in combination with barbiturates, caffeine or opioids, its effectiveness can be significantly increased. Attacks of mild or moderate headache during pregnancy should be treated with acetaminophen. Side effects from the stomach with the use of acetaminophen are much less pronounced than when using NSAIDs. In general, when taking the drug in therapeutic doses, side effects are rare. Toxic doses of the drug may cause liver necrosis.

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

Beta-blockers

Beta-blockers are widely used as antihypertensive agents. In clinical trials antimigrenous effect was detected in five drugs, including non-selective beta-adrenoblockers propranolol in a dose of 40-200 mg / day, nadolol in a dose of 20-80 mg / day, timolol in a dose of 20-60 mg / day, and also atenolol beta-adrenoreceptor blockers 25-150 mg / day and metoprolol 50-250 mg / day. Side effects of these drugs include a decrease in the 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, impaired conduction of the heart, peripheral vascular damage, diabetes mellitus with unstable blood sugar level.

Buspheron is an azapyrone anxiolytic, a partial agonist of 5-HT _1A receptors. It was reported that, at a dose of 30 mg / day, it is equally effective in the preventive treatment of chronic tension headaches, like 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, which, along with caffeine (50 mg), aspirin (325 mg) or acetaminophen (325-500 mg), is part of several combined analgesic drugs commonly used to treat migraine and tension headaches. Codeine is also included in some preparations. The recommended dose is 2 tablets every 4 hours, but not more than 6 tablets per day. These combinations are suitable for rare episodes of moderate or severe headache. However, if these drugs are used more than once a week, there is a risk of abuse and the occurrence of a ricochet headache. When using butalbital, both physicians and patients should consider the risk of developing abuse. Side effects: drowsiness, dizziness, shortness of breath, gastrointestinal disorders. Combined analgesics are contraindicated in hypersensitivity to any of their components, the presence in the history of indications of drug dependence, as well as in the pathology of the kidneys and liver.

Isometateene mucate is a remedy with a slight vasoconstrictive action (65 mg in capsule), used in combination with acetaminophen (325 mg) and soft sedative dichloralphenazone (100 mg). It is used to relieve mild headache and migraine pain. If you have a headache, take 2 capsules, then you can take 1 capsule every hour, but not more than 5 capsules in 12 hours. Side effects: dizziness, tachycardia, occasionally - skin rashes. Experience shows that this remedy is less likely to cause ricochet headache than other combined analgesics, but it, like any other analgesic, is not recommended for daily use. Contraindications: glaucoma, severe damage to the liver, kidney or heart, hypertension, the need to take MAO inhibitors.

Corticosteroids are often administered intravenously in the treatment of migraineal status and cluster-resistant headache-resistant treatment. In these situations, more often used dexamethasone, which is administered at 12-20 mg intravenously. In chronic and episodic forms of cluster headache, as well as with migraine status after intravenous dexamethasone or from the very beginning of treatment, prednisolone is administered internally in a gradually decreasing dose. 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 canceled within 2-4 weeks. Doses should be selected individually. Side effects: hypernatremia, hypokalemia, osteoporosis, aseptic necrosis of the thigh, stomach ulcer, gastrointestinal bleeding, hyperglycemia, hypertension, mental disorders, weight gain. Corticosteroids are contraindicated in the mycobacterial or systemic fungal infection, ocular herpes, and also in the history of hypersensitivity to these drugs.

Lithium carbonate is used for the prophylactic treatment of episodic and chronic cluster headaches. Its effectiveness is shown in more than 20 open clinical trials. Since the drug has a narrow therapeutic window, during treatment it is recommended to examine the lithium content in serum 12 hours after its administration. The therapeutic concentration in the blood is 0.3 to 0.8 mmol / l. With cluster pain, lithium has a therapeutic effect at low concentrations in the blood. With the simultaneous administration of NSAIDs and thiazide diuretics, an increase in the concentration of lithium in the serum is possible. 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 tremors, polyuria, thirst, nausea, diarrhea, muscle weakness, ataxia, accommodation disorder, dizziness. Contraindications: severe exhaustion, kidney and heart disease, dehydration, gynatraemia, the need for diuretics or angiotensin-converting enzyme inhibitors.

Metoclopramide is a benzamide derivative, often combined with NSAIDs or DHE in the management of severe migraine attacks. In a double-blind study, it has been shown that even with isolated use of metoclopramind (10 mg intravenously) is superior to placebo in the management of a severe migraine attack in an emergency department. This is somewhat surprising, since in other studies, the use of metoclopramide failed to demonstrate an additional weakening of nausea or an increase in the analgesic effect when added to ergotamine. Recommended dose: 5-10 mg intravenously. Side effects: akathisia, drowsiness, dystonic reaction. Contraindications: the need for neuroleptics, pregnancy, breastfeeding, pheochromocytoma.

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

Chlorpromazine is a neuroleptic, a phenothiazine derivative, sometimes used in severe migraine attacks, if vasoactive drugs or opioids are contraindicated or ineffective. In a small, double-blind, parallel study, the relief from pain under the influence of chlorpromazine was statistically not significant. In a larger, blind, comparative study, chlorpromazine was significantly more effective than intravenously administered meperidine or dihydroergotamine. The need for intravenous administration, the possibility of developing arterial hypotension, drowsiness, akathisia limit the use of chlorpromazine. Before introducing chlorpromazine, it is necessary to establish a system for intravenous infusion and introduce 500 ml of isotonic sodium chloride solution. Only after that, 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 regularly check blood pressure and the patient should remain in bed for an hour. Instead of chlorpromazine, prochlorperazine can be administered, 10 mg intravenously, without the need for a preliminary infusion of an isotonic solution. If necessary, the drug is injected again after 30 minutes. Side effects: orthostatic hypotension, drowsiness, dry mouth, dystonic reaction, malignant neuroleptic syndrome. Neuroleptics are contraindicated in cases of hypersensitivity to them, and if necessary, take other drugs that depress the central nervous system.

[22], [23], [24], [25], [26], [27], [28], [29]

Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) have analgesic, anti-inflammatory and antipyretic effects, inhibiting the activity of cyclooxygenase. The inhibition of cyclooxygenase blocks the formation of pro-inflammatory prostaglandins and the aggregation of platelets. These drugs can be used both for arresting a migraine attack and tension headache, and for short-term prophylactic therapy for migraine and some other types of headache. In this regard, it is difficult to correlate the preventive efficacy of drugs with their ability to inhibit the function of platelets. There is no data on the comparative efficacy of various NSAIDs that would have been obtained in adequate clinical trials.

NSAIDs, which are most often used to relieve a primary headache, such as migraine or tension headache.

Preparations	Initial dose (mg)	Dose for repeated administration (mg)
Aspirin	900-1000	975
Ibuprofen	600-800	600
Ketoprofen	50-75	50
Napprosin	500-825	500
Naproxen	550	275
Ketorolac (inside)	20	10
Indomethacin (candles)	50	-

In addition, some NSAIDs are effective in preventing migraine. These include aspirin in a dose of 675 mg 2 times a day, naprosin at a dose of 250 mg 2 times a day, naproxen 550 mg twice daily, ketoprofen 50 mg 3 times a day, mefenamic acid 500 mg 3 times a day. In controlled trials, the effectiveness of naproxen in the treatment of menstrual migraines is shown, which is particularly difficult to treat.

Side effects of NSAIDs are mainly associated with a negative effect on the gastrointestinal tract. These include dyspepsia, diarrhea, gastritis, as well as increased bleeding. With prolonged use of high doses, renal dysfunction is possible. At a toxic level of drugs in the blood there may be a noise in the ears. Contraindications: peptic ulcer, hypersensitivity to other NSAIDs, chronic anticoagulant therapy, liver or kidney disease, age younger than 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, idiopathic piercing headache.

Treatment of these forms of headache begins with a dose of 25 mg 2 times a day, then it is increased every few days until the seizures stop. For this, it is sometimes required to increase the dose to 150 mg / day. After stabilization of the condition, the dose is gradually reduced to the minimum effective value (usually from 25 to 100 mg / day). There are significant individual differences in the magnitude of the effective dose. Although after the withdrawal of the maintenance dose the headache is often renewed, nevertheless, long-term remissions are possible.

Indomethacin can cause serious gastrointestinal complications with prolonged use, including dyspepsia, gastric ulcer, gastrointestinal bleeding. Other side effects are 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 elixir or suppository, indomethacin is better tolerated than in tableted form. Contraindications: hypersensitivity to the drug, bronchial asthma, hives and rhinitis with NSAIDs, peptic ulcer.

Ketorolac Tremethamine is a potent non-steroidal anti-inflammatory agent that is available in tablet form and injection solution. The drug can be administered intramuscularly (60-90 mg) in the treatment of severe migraine attacks as an alternative to narcotic analgesics, especially in the presence of nausea and vomiting. However, in one study, this expensive treatment was less effective than the combination of DHE with metoclopramide. However, in some patients ketorolac has a good effect and can be particularly 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, with prolonged use, ketorolac can cause nephropathy. The contraindications are the same as those of other NSAIDs.

Opioid (narcotic) analgesics

Opioid (narcotic) analgesics are widely used in combination preparations for oral administration with moderate or severe migraine attacks, tension headache, cluster headache. In addition, opioids for intramuscular or intravenous administration (eg, meperedin) are often used to stop severe migraine attacks in an emergency room. Adverse reactions: drowsiness, dizziness, nausea, vomiting, constipation, ataxia, dependence. Contraindications to the use of narcotic analgesics include: hypersensitivity, the presence of drug dependence or the need to use MAO inhibitors. Ingestion or intranasal administration of opioids should be avoided in the treatment of chronic tension headaches until all other alternatives are tried. However, in certain situations, for example, in pregnancy or severe vascular disease, opioid analgesics may be the only available remedy. The group of opioid analgesics include 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 application of butorphanol, in patients with migraine very often there is a tendency to independently increase the dose of the drug.

Before prescribing opioids for chronic headache, the purpose of their use, the dose and duration of treatment should be clearly defined. With the patient should discuss in detail the possibility of developing a rebound headache and dependence.

Meperidine in combination with antiemetic is widely used in the emergency department for the treatment of severe migraine attacks, despite the absence of double-blind, placebo-controlled clinical trials that confirm its effectiveness. In one comparative study, it was shown that it is inferior in effectiveness to DHE. Meperedin should be used mainly in patients with rare severe seizures, and also if there are contraindications to other drugs (for example, in patients with severe peripheral, cerebral or coronary artery disease or during pregnancy).

Sumatriptan is a serotonin receptor agonist, which causes a narrowing of the meningeal vessels and suppresses neurogenic inflammation in them. In large-scale, double-blind clinical trials, subcutaneous administration of 6 mg of sumatriptan significantly reduced the headache for 1 hour in 80% of patients, while placebo eased headache in only 22% of cases (Moskowitz, Cutrer, 1993). After the administration of sumatriptan, there was also a decrease in nausea, vomiting, light and phobia. The effectiveness of the drug was the same if it was administered within 4 hours after the onset of the attack. When taking a tablet form (25 and 50 mg), the drug acted much more slowly. At present, the form is also available for intranasal administration of sumatriptan. Intranasal preparation is administered in a dose of 20 mg, the effect in this case is manifested for 15-20 minutes.

Subcutaneous administration of sumatriptan allows you to quickly stop an attack of cluster headache. In a double-blind, placebo-controlled trial, sumatriptan reduced pain and scleral injection in three quarters of patients within 15 minutes. Since a significant proportion of patients with a cluster headache are middle-aged men with a 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 of a transient nature and include a sensation of compression of the head, neck and chest, a sensation of tingling in the neck and on the scalp, sometimes dizziness. Contraindications: diagnosed ischemic heart disease or suspected of it, pregnancy, vasospastic angina, uncontrolled hypertension.

Fenelzin is an MAO inhibitor, sometimes used at a dose of 15 to 60 mg / day to prevent migraine attacks in patients resistant to other drugs. The only evidence of its effectiveness was obtained in an open study in 25 patients with severe migraine who did not respond to other treatments. These patients took phenelzine at a dose of 45 mg / day to 2 years. In 20 of them, there was a more than 50% reduction in the frequency of headache attacks. The combination of phenelzine with sumatriptan appears to be safe (Diamond, 1995). The possibility of developing hypertensive crises after the consumption of tyramine-containing products or the introduction of sympathomimetic drugs limits the use of phenelzine, the ion is shown mainly in cases of severe migraine resistant to other agents. Other side effects are also possible: orthostatic hypotension, urinary retention, gastrointestinal disorders, hepatotoxicity, ejaculatory impairment. Fenelzin can not be combined with sympathomimetics, including antiarrhythmic drugs, anti-asthmatic agents, anorexigens, other MAO inhibitors, antidepressant derivatives of dibenzapine. Patients taking phenelzine should limit the intake of tiram-min-containing products, including fermented cheeses, alcoholic beverages, sauerkraut, sausages, liver, beans, etc. Contraindication to the appointment of the drug is pheochromocytoma, heart failure, impaired liver function.

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

Cyproheptadine is particularly widely used as an antihistamine. In addition, at doses of 4 to 24 mg / day, it is used to prevent migraine attacks in children and adults, sometimes with a cluster headache. In an open study, cyproheptadine in a dose of 12-24 mg / day in 15 patients out of 100 completely eliminated attacks of headache, and in 31% of patients caused significant improvement. 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 the use of MAO inhibitors, peptic ulcer, prostatic hyperplasia, pyloroduodenal obstruction.

Serotonergic agents

Serotonin (5-HT) is a neurotransmitter, most commonly mentioned when discussing the pathogenesis of migraine. Nevertheless, most of the evidence for his involvement in migraine development 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 biogenic amines, causes an atypical headache in migraine sufferers, probably increasing the release of 5-HT from intracellular stores. Similarly, chlorophenyl piperazine (HFC), the main metabolite of trazodone antidepressant, is able to induce migraine-like pain in humans, activating 5-HT _2B and 5-HT _2C receptors. Probably the most convincing evidence of the involvement of 5-HT in the pathogenesis of migraine is the ability of drugs interacting with 5-HT receptors to stop migraine attacks (ergot alkaloids and sumatriptan) or to prevent them (metisergid, pisotifen, cyproheptadine).

At present, 15 different types of 5-HT receptors have been identified using pharmacological methods and molecular cloning. Since drugs that stop migraine attacks and warn them, probably have different mechanisms of action, they are treated separately.

Drugs that stop migraine attacks. Efficacy of ergot preparations for migraine was established in the 1920s, but the fact that they are able to interact with 5-HT receptors remained unknown until the 1950s. From the pharmacological point of view, these drugs are highly non-selective and interact with virtually all monoamine receptors. Initially, it was suggested that their effect on migraines is explained by the increase in sympathetic activity. Graham and Wolff (1938) suggested that the effectiveness of ergotamine is due to its vasoconstrictor action on extracranial vessels. More recently, sumatriptan was created as a result of a systematic search for a drug that can activate vasoconstrictive 5-HT receptors. However, the role of vasoconstriction in the antimigrenous effect of sumatriptan and ergot alkaloids remains unclear. Perhaps the activation of the receptors of the trigeminal nerve ganglion neurons or the trigeminal nerve stem is not less, but, perhaps, more important.

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