Review Article

Treatment of the acute migraine attack current status

Marcia Wilkinson

CEPHALALGIA

Wilkinson, Marcia 1983 03 01" Treatment of the acute migraine attack -current status. Cephalalgia, Vol. 3,pp. 61-7. Oslo. ISSN 0333-1024.

The main treatment of the acute migraine attack remains sleep, sedation, an anti-nauseant and analgesics,and in some patients 1 or 2 mg of ergotamine tartrate. Drugs containing large amounts of caffeine should notbe used. Absorption of drugs may be impaired in a migraine attack. Metoclopramide is probably theanti-emetic of choice because it is an effective anti-nauseant and promotes normal gastrointestinal activity.Domperidone has a similar action but is said not to go through the blood-brain harrier, so is less likely tocause extrapyramidal reactions. All drugs, including analgesics such as aspirin and paracetamol, are bestgiven in a soluble or effervescent form. Where vomiting occurs early in the attack, suppositories may beindicated. Ergotamine tartrate is necessary in about one third of attacks and is best given by suppository or byinhalation. Doses higher than 2 mg per attack or 6 mg in one week may cause toxic symptoms, the earlysigns of which are headache, nausea, vomiting and a feeling of not being very well. The non-drug treatmentsof an acute attack include pressing on the temporal artery, hot and cold compresses and relaxation. •

Marcia Wilkinson, City of London Migraine Clinic, 22 Charterhouse Square, London EC1M 6DX; Accepted1982 12 05.

Introduction

Migraine attacks vary in frequency but the majority of people who suffer from either common or classicalmigraine have between one and four attacks a month and some may have as few as one or two a year. Forthese people an effective treatment of the acute attack is probably all that is necessary. There are manyforms of treatment which have been recommended including relaxation therapy, biofeedback, acupuncture,etc., but once an attack has started it is likely that the patient will require some form of drug treatment inaddition to rest.

Four main groups of drugs are used in the treatment of an acute attack-anti-nauseants, pain-killers,ergotamine tartrate and sedatives. In many cases the combination of an anti-nauseant and a simpleanalgesic is sufficient. Most patients get over their headaches more quickly if they rest, and this is anotherimportant factor in the treatment.

It is interesting how the management of a migraine attack varies from country to country. In the UnitedKingdom, for instance, the minimun amount of potentially toxic drugs is used in order that there should be notoxic or hangover effects, and the patient is encouraged to sleep for a few hours, because it is felt that atemporary absence from work of 2-6 h is better than feeling headachy and unwell for 2-3 days. This point ofview, however, does not suit the American temperament, as some of our colleagues tell us that their patientsinsist on carrying on and that the treatment should be designed to help them do this-hence the use ofrelatively large doses of caffeine and ergotamine.

In 1970 the City Migraine Clinic, now the City of London Migraine Clinic, was opened. One of its main aimswas to treat patients when they had an acute attack of migraine and in this way to find out more about theacute attack and its treatment (1). In the twelve years the clinic has been in existence, over 4,500 patients withsevere headaches have attended the clinic for treatment and about 60% of them have had migraine. Basedon the results in these patients, the following treatment has been developed.

Rest

The natural inclination of a patient with a severe headache is to lie down and go to sleep and this should beencouraged where

possible, as this seems to be part of the natural recovery process. There is little doubt that if a patient can liedown, and preferably go to sleep, he may have a few hours off work in the first instance but will regain hisnormal efficiency more quickly.

When a patient comes to the clinic with an acute attack of migraine he is registered and then taken to thequiet room where there are comfortable beds. The history is then taken and he is examined by the doctor.

The treatment given consists of anti-nauseant, metoclopramide, an analgesic (either aspirin orparacetamol) and if necessary 1 or 2 mg of ergotamine tartrate (2) by mouth or by suppository. If the patientis anxious or upset, one of the short acting benzodiazepines such as potassium chlorazepate 15 mg(Tranxene) may be given. With this treatment, over 90% of patients with migraine are much improved and areable to go home in 3-4 h (3). Those who sleep soundly recover more quickly than do those who only rest ordoze (4).

Absorption of drugs

Absorption of drugs is normal in migrainous individuals between attacks-in the attack this may beimpaired-any abnormalities found occurring only just before or during the attack. The most easilydemonstrated effect is that of gastric stasis (5, 6). There are many stories of radiologists doing a barium mealand finding an atonic stomach. On enquiring if the patient has a headache, the radiologist is told `Yes'-hedoes have a migraine attack. It is also well known that drugs given by mouth in a migraine attack may beineffective even though the patient is not vomiting.

In a migraine attack the right drug in the right dose at the right time and in the right form must be givenand it has been shown in many studies that soluble or effervescent drugs are more easily absorbed thanthose given in sugar-coated capsules.

Effervescent preparations of aspirin give higher blood levels of the drug within a shorter time than do solidtablets (7) and the same is true of paracetamol (8). Soluble aspirin is more rapidly absorbed than ordinaryaspirin (9).

At the migraine clinic we have been interested in the method and rate of absorption of drugs and havealways used either effervescent or soluble preparations. Originally it was thought that the effervescentpreparations would be more quickly absorbed than the soluble form but it was found (10) that there was nodifference in the plasma salicylate levels after soluble and effervescent aspirin in normal volunteers. Theauthors, however, pointed out that this may not apply to clinical situations where there are different absorptionconditions, such as in a migraine attack.

Drugs given as suppositories are usually better absorbed than those given by mouth-probably two to fourtimes as efficiently-and these preparations, particularly the Cafergot suppository, have been used for a longtime in the treatment of migraine.

In 1974, Volans (11) studied the absorption of effervescent aspirin in 42 patients during acute attacks ofmigraine. He found that 19 out of the 42 patients showed impaired absorption when compared with normalcontrols and with themselves between attacks. He also noted that impairment of absorption seemed tocorrelate with the severity of the headache and the gastro-intestinal symptoms at the time of the treatment,but not with the duration of the attack or the type of migraine.

Nearly all writers agree that the earlier in the attack a patient is treated the better and it is certainly a goodidea to give early treatment because the sooner the patient has the treatment the sooner he will be free ofpain. It is, however, worth treating a migraine attack whenever the patient is seen (3).

In a group of 310 patients (4), including those with tension headache as well as migraine, the patients whoarrived early in the attack had significantly fewer headaches in the next seven days than did the others. Sixtyper cent of those coming within less than 6 h from the onset of the headache had no further headaches in thenext seven days. This compared with those who had had a headache for more than 24 h before they came,

of whom only 28% had no further headaches in seven days. On the whole, those with migraine came earlierin the attack than those with either tension headache or a combination of migraine and tension headache.Many patients seem to suffer from more than one type of headache.

In addition to aspirin or paracetamol, combinations of these drugs with other substances or other drugsmay be used. Dextropropoxyphene (12) and Midrin or Midrid (13) (isometheptone combined with paracetamoland dichloralphenazone) have been recommended.

There are many proprietary combinations of drugs, each of which has its own adherents. In the UnitedKingdom one of the most popular of these is Migraleve, which combines an anti-nauseant, buclizinedihydrochloride with paracetamol, and there are many others. As a general rule, if a patient finds a particularpreparation satisfactory he should be encouraged to stick to it.

Anti-nauseants

An anti-emetic should be given as early as possible in the attack if the patient suffers from nausea orvomiting. The drug of choice is metoclopramide 10 mg either by intra-muscular injection or by mouth.Metoclopramide was first used in the early sixties (14) and was found to depress the vomiting centre andstimulate gut motility. It increases propulsive activity in the stomach and helps to close the lower oesophagealsphincter, and it is this action which is important in migraine. Metoclopramide also acts on the brain byblocking dopamine receptors; one of its main side effects is the production of extrapyramidal symptoms and itstimulates the production of prolactin.

Metoclopramide was used in the early seventies at the City Migraine Clinic. Volans (15) showed thatpatients in an acute migraine attack did much better with this drug than without it. The plasma salicylate levelwas higher if they were given an intramuscular injection of metoclopramide 15 min before taking 900 mgaspirin.

Since then, this treatment has been used at the City of London Migraine Clinic and its predecessors andalso in other clinics throughout the world. A double blind study of metoclopramide in the treatment of 150patients in an acute migraine attack (16) showed that metoclopramide did not by itself reduce the pain, butenhanced the effect of the analgesic or sedative medication. This effect, however, just failed to be statisticallysignificant.

Metoclopramide has also been used by mouth and the evidence for this is clinical as so far no drug trialspublished have given plasma levels of metoclopramide and aspirin m a migraineur during an attack, althoughsuch trials are under way at present. It has been found to exert a beneficial influence on the nausea, but thetendency to diarrhoea and the duration and intensity of the attacks were uninfluenced (17).

Ross-Lee et al. (18) found that higher peak aspirin and salicylate levels occurred when patients weregiven aspirin with metoclopramide. Aspirin tended to appear in plasma earlier in patients given aspirin withmetoclopramide than in patients given aspirin alone or aspirin with intramuscular metoclopramide. Patientsgiven aspirin with metoclopramide tended to obtain better early pain relief than the other two treatmentgroups, although after 1 h from the start of treatment there was better pain relief if metoclopramide had beengiven by injection.

Recently there have been doubts cast on the efficacy of metoclopramide by mouth (19) as the bloodlevels of the drug which are sufficient for gastrokinetic effects had not been achieved in normal volunteersreceiving 10 mg by mouth. This work, however, still leaves some questions unanswered as the subjects werehealthy volunteers and not migraine sufferers and the marker used was alcohol. In a more recent paper (20)it was found that after an oral dose of 10 mg in healthy male volunteers there was a wide difference in thebioavailability (30-100%) and that this might contribute to the unpredictable results of therapy when the drugis given by mouth, and the occurrence of side effects in some patients. The commonest side effects ofmetoclopramide are sleepiness and

dystonic reactions. Children seem particularly susceptible to this drug. It should not be used in children underten and a 5 mg dose only should be given to children under sixteen.

Recently, another anti-emetic has come on the market. This is domperidone, a peripheraldopamine-receptor antagonist with anti-emetic and gastrokinetic properties (Motilium, Janssen, 10-20 mg).As it is said not to go through the blood brain barrier (21), it is less likely to cause extrapyramidal reactions.

Other anti-nauseants may be used but none of them has a similar gastrokinetic action. Prochlorperazinemaleate 5 mg (Stemetil) or cyclizine hydrochloride 50 mg (Valoid) are useful anti-emetics. Prochlorperazinemaleate is available by mouth, as a suppository or by injection and cyclizine by mouth or by injection.Thiethylperazene (Torecan), a phenothiazine derivative, is also available by mouth or suppository. Anyanti-emetic should be used as early as possible in the attack, but anti-emetics should not be used as regularprophylactic therapy.

Analgesics

Aspirin

Aspirin is probably the analgesic of choice in migraine in a dose of 900 mg. For those who cannot takeaspirin, paracetamol is a good alternative but does not have the same anti-prostaglandin effect as aspirin.Aspirin has been used by the general public for the treatment of headache for over fifty years and it isprobably true to say that more migraine headaches are improved by aspirin than by any other drug. The maindisadvantage to the use of aspirin is bleeding from the gastrointestinal tract, so this drug should not be usedby those with a history of indigestion or by those who are on anticoagulants or similar drugs. Neither should itbe used by those who are allergic to it and preferably soluble or effervescent forms should be used. If, aftertaking the original dose with metoclopramide and one or two milligrams of ergotamine tartrate, the headachestill persists, metoclopramide and aspirin can be repeated in 4-6 h.

Paracetamol

Paracetamol in a dose of 1,000 mg should be used for migraineurs who for any reason cannot take aspirin.As with aspirin the dose can be repeated in 4-5 h. Like any other active drug, paracetamol can cause toxicside effects, the main effects being on the liver and kidney where excessive doses will cause papillarynecrosis. Patients who have taken an overdose of paracetamol may appear well for the first two or three daysand then succumb with liver damage. The hepatic changes produced by overdosage of paracetamolprobably result from the accumulation of a highly active intermediate metabolite in the hepatocytes.

Ergotamine tartrate

Extracts of ergot were first used for the treatment of migraine towards the end of the nineteenth century in theUnited States (22) and in Germany (23). Thomson (22) suggested that ergot should be taken as early aspossible in an attack and that if it could not be taken by mouth it should be used as an enema. In 1918ergotamine tartrate was isolated but it was not until the second half of the 1920s that ergotamine tartrate wasused for migraine. Since then ergot and its derivatives have been one of the main drugs used in migraine.

The pharmacological actions of the ergot alkaloids are complex: some actions are completely unrelated,and some are even mutually antagonistic (24).

Because of its many and varied reactions the actual role that ergotamine tartrate plays in the treatment ofmigraine is difficult to define. Originally it was thought that its vasoconstrictor action might be the mostimportant, but recent work has shown that in different circumstances ergotamine may either dilate or constrictperipheral vessels.

The effect of ergotamine depends on the pre-existing state of the vascular bed. When

the vascular resistance is increased it may cause dilatation but when the vascular resistance is low,ergotamine acts as a constricter (25).

Until recently it was not possible to measure therapeutic amounts of ergotamine in the patient but in 1976(26) a radioimmunoassay for ergotamine was devised. Since then, other workers (27) Using this techniquehave found that ergotamine is rapidly distributed to the tissues from the systemic circulation, and that itsplasma half life is 97 ± 30 min, while the urinary excretion of ergotamine is low. They also found that higherplasma levels are obtained from a suppository than from the same dose given orally and that adversereactions are relatively frequent with plasma levels greater than 1.8 µgm/ml. From these studies it wouldseem that the uptake and usage of ergot-amine may vary from person to person. Other workers (28) havesuggested that the metabolic disposition of ergotamine may occur in two phases-one with a half-life of 2 hand another with a half-life of 20 h. Ergotamine tartrate is rapidly absorbed, the half time absorption rate being30 min with peak plasma concentrations being reached 2 h after ingestion (29).

Ergotamine tartrate can be taken by mouth, by suppository or by inhalation. In most countries theinjections have been withdrawn. By mouth the dose is 1 or 2 mg per attack and the maximum dose per weekshould probably not exceed 6 mg. Early papers, such as that by Lennox (30), have shown that parenteral useof ergotamine tartrate is very effective in over 80% of patients.

Graham (31) suggests. that ergotamine should be given as early as possible in the headache phase, butthat it may still be effective even late in the attack. The dose he recommends is up to 3 mg per attack, but hegoes on to make the point that there should be at least two days a week or more in which ergot is not takenso as to prevent ergot dependency. Lance (32) recommends a dose of 1-6 mg of ergotamine at the start ofthe attack, the dose depending on the patient's weight, and the drug should be in a form which is readilyabsorbed and acceptable to the patient.

Diamond & Dalessio (33) suggest that 1-2 mg be given as soon after the onset of the attack as possible,followed by 1-2 mg every 30 min up to a total of 6 mg in 24 h, with a maximum dose in one week of 12 mg.

Heyck (34) is more cautious and recommends subcutaneous or intramuscular injection of 0.25-1.0 mg ofergotamine tartrate (Gynergen), and also stresses the importance of giving it early in an attack. He alsorecommends injections of dihydroergotamine mesylate (Dihydergot or DHE45). He found that a combinationof ergotamine and caffeine by mouth was much more effective than ergotamine given on its own and quotesthe double blind trials which demonstrated this (35, 36). The following is a list of preparations of ergotaminetartrate available in the United Kingdom:

CAFERGOT Ergotamine tartrate 1 mg(Wander) Caffeine 100 mg

FEMERGIN Ergotamine tartrate 1 mg(Wander)

LINGRAINE Ergotamine tartrate 2 mg(Winthrop) (to be used sublingually)

MIGRIL (Wellcome) Ergotamine tartrate 2 mgCyclizine hydrochloride 50 mgCaffeine hydrate 100 mg

EFFERGOT Ergotamine tartrate 2 mgCaffeine 50 mg(to be dissolved in water)

CAFERGOT Ergotamine tartrate 2 mgSUPPOSITORIES Caffeine 100 mg(Wander) Belladonna alkaloids 0.25 mg

Butalbital 100 mgMEDIHALER- Ergotamine tartrate 0.36 mg

Ergotamine per dose(Riker)

DIHYDERGOT Each 1 ml ampoule contains1 mg dihydroergotaminemesylate

Ergotamine tartrate preparation for intra-muscular use are no longer available in the United Kingdom.

Ergotamine tartrate overdose

The effective dose of ergotamine tartrate is not far from the toxic dose and the toxic effects have beenrecorded by many observers (37, 38, 39). Most manufacturers in their literature say that not more than 10-12mg

should be taken in any one week but this is probably too high. It is suggested that the maximum per week shouldprobably be 6 mg, and for an attack 1 or 2 mg. The early signs of ergotamine tartrate overdose are nausea,vomiting, headache as well as a feeling of not being well, all symptoms which resemble those of migraine. Thecharacteristics of the headache are that they tend to occur every day and respond only to further doses ofergotamine. Classical migraine never occurs daily though occasionally an individual may get one or two attacks aweek, each headache lasting a few hours up to 36 h. The so-called status migrainosus seems, in many cases, tobe due to the injudicious and continual use of ergotamine tartrate.

The more severe signs of ergotamine tartrate poisoning, including gangrene and other vascular lesions, are rareif therapeutic doses of ergotamine are used.

Caffeine

Many of the ergot-containing drugs also contain caffeine. Caffeine was originally added to ergotamine preparations(40) to enhance the vasoconstrictive activity of the drug. Later it was shown (41) that caffeine enhanced theintestinal absorption of ergot-amine and up to 100 mg of caffeine are present in most ergotamine-containingcompounds. Recent work has shown that patients do better if they go to sleep in an attack (4) and if possible it isbetter to give preparations containing little or no caffeine. Caffeine is a stimulant and should be avoided in peoplewishing to go to sleep.

Other methods of treatment

Some people, particularly those who are tense or anxious, find that they can abort or diminish their attacks byremedies other than drugs. These include pressing on the temporal artery, using hot or cold compresses, relaxationexercises or by use of biofeedback techniques. In a recent paper (31), physical exercise, breathing 100% oxygen,increasing CO2 by rebreathing in a bag or ingesting tiny amounts of nitroglycerine are listed as possible methods ofabating an attack.

Relaxation

Headaches are sometimes associated with tension in the muscles of the scalp, forehead and back of the neck andif this tension can be reduced the headache often improves. Patients can be taught to control their attacks and theirliability to suffer from headaches by lowering their general arousal in the form of relaxation exercises (42, 43) or byusing one of the many autogenic biofeedback training techniques (43, 44, 45). The auto-genic biofeedbacktechnique is a method of providing a conditioned stimulus along with an opportunity to respond in various ways, thedesired response then being reinforced or rewarded. After several reinforcements the stimulus serves as a signalfor the subject to perform the learned response. The techniques used are designed to teach the patient to developnew voluntary physiological control skills and often temperature biofeedback training is found most satisfactory.Other patients do well on a combination of temperature and EMG feedback training.

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