Treatment of Acute Migraine: The British Experience

Marcia Wilkinson, M.D.

The City of London Migraine Clinic.

Reprint requests to: Dr. Marcia Wilkinson, The City of London Migraine Clinic, 22 CharterhouseSquare, London ECIM 6DX, England.

INTRODUCTION

In the UK there has been considerable interest in migraine over the years, and in the late 1960's acommittee headed by the late Russell Brain was set up to discuss the problems of migraine and its treatmentand how further research could best be done. One of the main difficulties in research into migraine is thatvery few if any headache specialists actually see their patients in an attack. The suggestion was made thatthe way to deal with this problem was to have a clinic devoted to the treatment of research into migraine andheadache which should be open during working hours and to which patients could come as an emergency ifthey had a headache. The next difficulty was where this clinic should be sited. After some discussion it wasagreed that it must be where there was maximum concentration of the population during working hours. Forthe United Kingdom this meant the City of London because although only about 25,000 people live in thesquare mile, over three-quarters of a million come there to work every day. Stress is one of the precipitatingfactors in migraine and a long journey to work, as many Londoners have, a full working day with a short lunchhour and a snack lunch, form the kind of stressful conditions under which migraine might be expected todevelop.

Premises were found in what had been an old tailor's shop in property belonging to St. Bartholomew'sHospital. Barts is one of the oldest London hospitals, having had it's 850th Anniversary in 1975, and they owna lot of property in the City. This association of the City of London Migraine Clinic with Barts has been veryimportant. Although the Clinic is a small charity organization, because of its links with Barts (for which we areall very grateful), the doctors and other researchers at the Clinic have access to all the facilities of a modernhospital. In 1973 the Clinic moved to its present premises, a Georgian house dated 1785 which used to bethe residence of the vicar of St. Bartholomews the Great. Any of you coming to London are welcome to visitthe Clinic which has a particularly fine oval staircase and some original paintings on the ceiling of the waitingroom. Unusual attributes for a migraine clinic!

The next question was how the Clinic should be set up and staffed. It was decided to open it from8:30-5:00, Monday to Fridays, as these were the times that working people were most likely to wantemergency treatment. Any patient coming with a headache received this treatment and for this they did notrequire either a doctor's letter or an appointment. In addition, patients were referred by their family doctor inthe usual way and given appointments. The staff consisted of a Consultant, two junior doctors, a NursingSister and a secretary.

During the first five years between two and three hundred emergency patients were seen each year,about 60% of whom were suffering from migraine. This meant that over the years the doctors and nurses atthe Clinic have seen several thousand people with acute headaches and have been able to make carefulobservations on them.

This number of patients have given those of us who work at the Clinic a unique opportunity for researchand provide the basis for the treatment of the acute attacks that we recommend. Acute treatment has beenso successful that the regimen instigated here is now used with great success by many Occupational Healthcentres in the City and also other clinics. Since the City of London Migraine Clinic opened in 1970 severalsimilar clinics have been started throughout the world, notably those in Copenhagen and at Charing Cross.

Migraine attacks vary in frequency and intensity, some people having attacks only once or twice a yearwhile others may have as many as one or two a week. Patients who have less than two attacks per month willusually only require treatment for the acute attack. Many forms of non-drug treatment have been usedincluding rest, relaxation therapy, biofeedback, acupuncture etc., but once the attack has become establishedsome form of drug treatment is usually necessary. Rest or sleep is an essential part of any treatment, and inaddition four main type of drugs are used in the treatment of an acute attack although many others havebeen tried. These

are sedatives or anxiolytics, anti-nauseants, pain killers and if necessary a small dose of ergotamine tartrate.1

REST AND SLEEP

Sleep is part of the natural process of recovery and patients who can go to sleep recover better than those whoonly rest or doze.2 Although most patients can go to sleep naturally in an attack if they are tense or anxious it maybe necessary to give them a sedative; a single dose of one of the short acting benzodiazepines should be used,such as 10 mg diazepam. At the City of London Migraine Clinic we have a special quiet room where patients canlie down and go to sleep.

ANTIEMETICS

The majority of migraine patients suffer from gastro-intestinal symptoms. Volans3 found that 95% of thepatients he studied had gastro-intestinal symptoms, 26% had nausea only, 48% nausea and vomiting and 21%nausea, vomiting and diarrhea. These symptoms, especially nausea and anorexia, may occur in the prodromalphase and treatment for them should be given as early as possible in the attack. Waelkens4 was the first torecommend domperidone in the prevention of complete migraine and migraine with aura and Amery5 andWaelkens found that in a double blind cross-over study a single high (30mg) oral dose of domperidone (Motilium)taken at the very first appearance of warning signals was clearly superior (p<0.001) to placebo in preventingattacks.

In all migraine attacks an antinauseant should be taken preferably 10-15 minutes before the analgesic and/orergotamine. Metoclopramide or domperi-done are the drugs of choice. Metoclopramide can be given by mouth orby intramuscular injection in a dose of 10 mgs; it promotes gastric emptying and normal peristalsis and helps toclose the lower oesophageal sphincter. It may give rise to severe extrapyramidal reactions including musclespasms and oculogyric crises and should be used with caution, particularly in children. These reactions generallyoccur within 36 hours of starting treatment and usually disappear within 24 hours of withdrawing the drug. Allpatients should be warned of the possibility of these side effects. Oral analgesic preparations containingmetoclopramide which are available in the UK are Migravess (aspirin and metoclopramide) and Paramax(paracetamol and metoclopramide). Domperidone (Motilium) has a similar action to metoclopramide but as it issaid not to cross the blood-brain barrier it is less likely to cause central effects such as sleepiness and dystonicreactions.

Metoclopramide was first used for the treatment of migraine in the early seventies and Volans3 showed thatpatients in an acute migraine attack were much improved if they were given an intramuscular injection of 10 mgs ofmetoclopramide fifteen minutes before taking aspirin. He studied the absorption of effervescent aspirin in 42patients and found that 19 showed impaired absorption in an attack when compared with normal controls and withthemselves between attacks. He also noted that impairment of absorption seemed to correlate with the severity ofthe headache and the gastro-intestinal symptoms but not with the duration of the attack or the type of migraine.After an injection of intra-muscular metoclopramide, aspirin absorption was restored to the normal level. Somedoubt has been cast on the efficacy of metoclopramide if it is used by mouth.6 These workers found that a 10 mgoral dose of metoclopramide did not give blood levels which were sufficient for gastro-kinetic effects in normalvolunteers. This work leaves some questions unanswered as the subjects were healthy volunteers, not migrainesufferers, and the marker used was alcohol. In a more recent paper Bateman et al7 found that after 10 mgmetoclopramide was given orally to healthy volunteers there was a wide variation in the bio-availability of the drug(20-100%). They concluded that this might contribute to the unpredictable results of therapy when the drug is givenby mouth and the occurrence of side effects in some patients.

Thus the evidence for the effectiveness of metoclopramide taken orally for migraine is clinical, as so far therehave been few drug trials which have given the plasma levels of metoclopramide and aspirin in a migraineur duringan attack. A double blind study of 150 patients in an acute attack by Tfelt-Hansen and his colleagues8 showed thatmetoclopramide by itself did not reduce the pain but that it did enhance the effect of analgesic or sedativemedication. This effect just failed to be statistically significant. Ross-Lee et al9 measured the plasma aspirin andsalicylate levels over a two hour period during migraine attacks in 10 subjects given 900 mg aspirin alone, in 10subjects given 900 mg oral aspirin plus 10 mgs oral metoclopramide, and in 10 subjects given 900 mg oral aspirinplus an intramuscular injection of 10 mg metoclopramide. Higher peak aspirin and salicylate levels occurred inpatients given aspirin with metoclopramide. In their study aspirin tended to appear in plasma earlier in patientsgiven aspirin with oral metoclopramide than in patients given aspirin alone or aspirin with intramuscularmetoclopramide. This group obtained better early pain relief than the other two treatment groups.

Other antinauseants may be used but none have the same gastro-kinetic actions as metoclopramide anddomperidone and are on the whole less effective in migraine. Prochlorperazine maleate (Stemetil) 5mg or cyclizinehydrochloride (Valoid) 50 mg are sometimes used; a single dose should be given at the onset of symptoms.Antiemetics should never be used prophylactically in migraine.

ANALGESICS

The non-narcotic drugs aspirin and paracetamol

(acetaminophen) are particularly suited to the relief of pain in migraine, and recently there has been an increaseduse of the non-steroidal anti-inflammatory drugs. In treating several thousand patients in an acute attack ofmigraine at the City of London Migraine Clinic it has not been necessary to use narcotic analgesics.

Aspirin. Aspirin is the analgesic of choice for migraine, in a dose of 600-900 mgs. If, after taking the originaldose with metoclopramide, the headache still persists the metoclopramide and aspirin can be repeated in 4-6hours. Effervescent or soluble preparations of aspirin give higher blood levels within a shorter time than do solidtablets10,11 and the same is true of paracetamol.12

Aspirin has been used extensively for the treat-merit of headache for over fifty years and is generally available'over the counter'. It is not possible to estimate the number of people who take aspirin but it is probably true to saythat more migrainous headaches are improved by aspirin than by any other drug. The main disadvantage to theuse of aspirin is bleeding from the gastro-intestinal tract so this drug should not be used by those with a history ofindigestion or by those who are on anticoagulants or similar drugs. Bronchospasm and skin reactions may occur inhypersensitive patients. Prolonged administration may cause tinnitus or deafness.

Paracetamol (Acetaminophen). Paracetamol in a dose of 1,000 mg is similar in efficacy to aspirin but has nodemonstrable anti-inflammatory activity and is less irritant to the stomach. It should be used by migraine suffererswho cannot take aspirin. As with any other active drug, paracetamol can cause toxic effects, and overdosage withparacetamol is particularly dangerous as it may cause hepatic damage which is sometimes not apparent for 4-6days. The hepatic changes produced by overdosage of paracetamol probably result from the accumulation of ahighly active intermediate metabolite in the hepatocytes. As with aspirin, in an acute migraine attack the dose ofparacetamol and metoclopramide can be repeated in 4-6 hours.

Non-Steroidal Anti-Inflammatory Drugs. There are now many of these compounds on the market and theyare similar in efficacy to aspirin but they have the advantage of causing fewer and less severe side effects. Theyare however very much more expensive. These side effects are generally mild and infrequent but, as with aspirin,include gastro-intestinal discomfort or occasionally bleeding, nausea, hypersensitivity reactions, headache, vertigoand tinnitus. Blood dyscrasias have been described. These drugs differ little from each other in efficacy but there isconsiderable variation in patient response and the main difference in the drugs is in the incidence and type of sideeffects.

Naproxen (Naprosyn) is one of the NSAIDS which has been used in the treatment of migraine and it combinesgood efficacy with a low incidence of side effects and needs to be taken only twice daily. In a trial in 1985 Johnsonet al13 treated seventy patients with classical or common migraine during three attacks with either naproxensodium or placebo in a double-blind parallel groups study. The initial dose of naproxen sodium was 825 mgsfollowed one hour later by a further 550 mg. The patients were studied for a maximum of ten attacks andsignificant improvement was observed in the severity and duration of headaches when the patients were onnaproxen sodium. The premonitory symptoms and photophobia improved significantly on naproxen sodium andsignificantly less rescue analgesics were required. Patients suffering from migraine without aura had less severeheadaches and photophobia when taking naproxen sodium than when taking placebo and the headaches wereshorter in duration and patients took less rescue analgesic. No significant difference was observed between thetreatment of groups in patients with migraine with aura. Ten patients in the placebo group and six in the naproxengroup reported side effects but these were possibly associated with the use of rescue medication. In this studynaproxen sodium proved safe and effective in common migraine attacks but in this study efficacy was notestablished in classical migraine.

In another trial with thirty-two patients naproxen was found to be statistically significantly superior to placebo inreducing the severity of head pain, nausea and photophobia; Pradalier and colleagues14 showed that naproxensodium was significantly more effective than an ergotamine compound (ergotamine tartrate 2 mg, caffeine 91.5 mgand cyclizine chlorhydrate 50 mg). Other NSAIDS such as mefenamic acid (Ponstan) and tolfenamic acid havebeen shown to have beneficial effects in reducing the frequency and severity of migraine attacks and trials arebeing done on these and other similar drugs. This is important as there seems to be considerable differences inpatient response to each drug.

ERGOTAMINE TARTRATE

Extracts of ergot were first used for the treatment of migraine towards the end of the 19th century but it was notuntil 1918 that ergotamine tartrate was isolated and its use for migraine really began in the 1920s. Since then ergotand its derivatives have been used extensively for migrainous patients who do not respond to an antinauseant andan analgesic. The value of ergotamine is limited by difficulties in absorption and by its side effects. Thepharmacological actions of the ergot compounds are complex and some appear mutually antagonistic.15 Becauseof these many and varied actions it is difficult to define the role that ergotamine tartrate plays in the treatment ofmigraine. Originally it was thought that its main action was that of a vesoconstrictor but studies by Olesen and hiscolleagues16,17 suggest that in an attack of migraine with aura, hypoperfusion

may persist for several hours and that there is no vasodilatory phase as postulated by Wolff.18 Recent workhas shown that in different circumstances ergotamine may either dilate or constrict vessels - the effect of theergotamine depending on the pre-existing state of the vascular bed. When the vascular resistance isincreased ergotamine may cause dilatation but when the vascular resistance is low it may act as aconstrictor.19 Until recently it was not possible to measure therapeutic amounts of ergotamine tartrate but in1976 a radio-immunoassay for ergotamine was devised.20

It has been found, using this technique, that ergotamine is rapidly distributed to the tissues from thesystemic circulation and that its plasma half-life is 97 ± 30 minutes while the urinary excretion of ergotamine islow.21 Aellig and Nuesch22 have suggested that the metabolic disposition of ergotamine may occur in twophases - one with a half-life of two hours and another with a half-life of 20 hours. Ala-Hurula et al23 foundthat ergotamine tartrate was rapidly absorbed, the half time absorption rate being 30 minutes with peakplasma concentrations being reached two hours after ingestion. Graham et al24 performed a study of thesystemic availability of ergotamine tartrate given by three different routes of administration to healthyvolunteers. They found that the serum concentrations after rectal administration were significantly higher thanthose following oral administration at all points up to 3 hours and that the serum concentration after a dosegiven by aerosol was higher than that given by mouth at most points even though the aerosol dose was onlyhalf that given by mouth. It follows from this work that ergotamine should be given either by suppository or inan aerosol form. The dose of ergotamine by suppository is 1 or 2 mg (half or 1 cafergot suppository) perattack and the aerosol dose (Riker ergotamine medihaler) two or three puffs (0.72 or 1.08 mgs ofergotamine). If ergotamine tartrate is given by mouth the dose is one or two mgs and the maximum amountthat should be taken in one week is 6 mg, preferably only used on two occasions.

Earlier workers have suggested that higher doses can be given but, if they are, symptoms of ergotamineoverdose are likely to occur.

In the IHS classification it says that status migrainosus fulfills the criteria for one form of migraine exceptthat the headache lasts for more than 72 hours whether treated or not. In my experience status migrainosusdoes not occur at the City of London Migraine Clinic as an entity. We do see patients who say that they havehad bad continuous headaches for days or weeks and who have at one time had migraine attacks. We findthat these people suffer from either chronic tension type headache with or without migraine or more likely thatthey suffer from migraine and drug abuse of either ergotamine tartrate, analgesics, opiates orbenzodiazepines. This may be a difference between the populations in the United States of America and theUK and I look forward to hearing Dr. Raskin's views on this. The treatment for those suffering from chronicdrug abuse headache is to withdraw the drug or drugs and if necessary give alternative treatment withsedatives or anxiolytics.

CAFFEINE

Caffeine is a weak stimulant which is often included in small doses in analgesic and ergotamine tartratepreparations. It does not contribute to the analgesic or anti-inflammatory effects of any of the preparations butit was originally added to egotamine preparations to enhance the vasoconstrictor activity and the intestinalabsorption of ergotamine.25 Up to 100 mgs of caffeine are present in most ergotamine compounds. Recentwork has shown that patients do better if they can go to sleep in an attack and, as caffeine is a stimulant, it isbest avoided.

THE TREATMENT OFACUTE MIGRAINE IN CHILDREN

The present recommendation in the United Kingdom is that aspirin should not be given to children underthe age of 12 unless specifically indicated for childhood rheumatic conditions. This is because of thepossibility of developing Reye's syndrome. This is a rare but severe neurological disorder complicated byhepatic dysfunction and predominantly affecting children. In a typical case of Reye's syndrome a previouslyhealthy child gets a common viral infection which is apparently taking a normal course when there is asudden onset of profuse, persistent, effortless vomiting accompanied or soon followed by alteration in thelevel of consciousness. Liver involvement is indicated by grossly elevated levels of serum aspartate andalanine transaminase, and the blood ammonia level is usually also raised. The etiology of Reye's syndrome isbelieved to be multifactorial, resulting from an abnormal reaction to a viral infection in a geneticallysusceptible host and which is modified by an exogenous toxin. Aspirin is one of the toxins that have beenimplicated. Because of this danger it is recommended that paracetamol should be used as an analgesic.Although some children are sensitive to metoclopramide and may develop extrapyramidal symptoms 5 mgsof this drug may be used if nausea and vomiting occur but the parents must always be told of the possibleside effects and told not to continue with the drug if there are extrapyramidal symptoms.

To sum up, the British Experience is that the best treatment for a migraine attack is rest combined with anantiemetic - metoclopramide or domperidone - and an analgesic - aspirin 900 mgs or paracetamol 1,000mgs. In about one third of patients ergotamine tartrate either by suppository or inhalation to a maximum of 2mgs per attack can be used. Larger doses of ergotamine may cause toxicity -

usually increased vomiting or prolongation of the attack. This simple treatment has been shown to be equally successful in thetreatment of migraine with or without aura.

Although this treatment with anti-emetics, analgesics and, if necessary, ergotamine tartrate is very successful, what we doneed are alternative treatments for acute migraine headaches. We are all looking forward to the results of the trials ofsumatriptan and of other agents acting on serotonin receptors.

REFERENCES

1. Wilkinson M: Treatment of the acute migraine attack-cur-rent status. Cephalalgia 3:61-67, 1983.

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3. Volans GN: Absorption of effervescent aspirin during migraine. Br Med J 2:256-258, 1974.

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