J Accid Emerg Med 2000;17:241–245 241 Migraine: pharmacotherapy in the emergency J Accid Emerg Med: first published as 10.1136/emj.17.4.241 on 1 July 2000. Downloaded from department Anne-Maree Kelly Abstract be assigned. In addition, there are a number of Migraine can be a disabling condition for uncommon variants such as ophthalmoplegic the suVerer. For the small number of and abdominal migraine. patients who fail home therapy and seek treatment in an emergency department, Pathophysiology there are a number of therapeutic options. The pathophysiology of migraine is complex This paper reviews the evidence regarding and our understanding continues to evolve. the eVectiveness and safety of the following Events implicated in migraine initiation in- therapies: the phenothiazines, lignocaine clude altered electrical activity (“cortical (lidocaine), ketorolac, the ergot alkaloids, spreading depression”2), a failure of brain ion metoclopramide, the “triptans”, haloperi- homeostasis, an eZux of excitatory amino dol, pethidine and magnesium. Based on acids from nerve cells and increased energy available evidence, the most eVective metabolism.3 N-methyl-D-aspartate (NMDA) agents seem to be prochlorperazine, chlor- receptors are implicated in this process.3 promazine and sumatriptan, each of which The headache pain of migraine seems to have achieved greater then 70% eYcacy in result from the activation of the trigeminovas- a number of studies. cular system.4–6 The triggers to the develop- (J Accid Emerg Med 2000;17:241–245) ment of migraine headache are probably Keywords: migraine chemical and are thought to originate in the brain, blood vessel walls and the blood itself. These triggers stimulate trigeminovascular Migraine headache can be a disabling condi- axons causing pain and the release of vasoac- tion for the suVerer. The patient and their gen- tive neuropeptides from perivascular axons. eral practitioner successfully manage most These neuropeptides act on mast cells, en- migraine headaches. However, a small number dothelial cells and platelets resulting in in- fail to respond and suVerers may present for creased extracellular levels of arachidonate treatment at emergency departments (ED). As metabolites, amines, peptides and ions. These most patients have tried oral medications mediators and the resultant tissue injury lead before attending the ED, other routes of to prolongation of pain and hyperalgesia.6 http://emj.bmj.com/ administration (usually parenteral) are most Serotonin has also been specifically impli- often used in ED. This review will focus on the cated in migraine. By activation of aVerents, it agents that may be used to treat migraine in causes a retrograde release of substance P. This ED and the evidence supporting their use. is turn increases capillary permeability and oedema.7 In addition, magnesium has been suggested as having a role.8 Definitions The complexity of the mechanisms involved Most of the research in the area of migraine on September 27, 2021 by guest. Protected copyright. in the genesis of migraine makes it likely that focuses on so called common migraine or there are a number of ways to interrupt the migraine without aura. The Headache Classifi- processes to provide e ective relief from cation Committee of the International Head- V migraine symptoms. A number of pharmaco- ache Society1 defines migraine without aura as logical agents and combinations of agents for an “idiopathic, recurring headache disorder the relief of migraine have been studied. manifesting in attacks lasting 4–72 hours. Typical characteristics are unilateral location, pulsating quality, moderate or severe intensity, Therapeutics aggravation by routine physical activity and Most patients who present to ED with severe association with nausea, photophobia and pho- migraine have tried to terminate their migraine nophobia.” The rarer migraine with aura is headache with oral medication before their described as an “idiopathic, recurring head- attendance. Therefore, this review will focus on Department of the agents that are appropriate for use in ED. Emergency Medicine, ache disorder manifesting with attacks of Western Hospital, neurological symptoms unequivocally localis- In considering them, the important issues to be Footscray 3011, able to the cerebral cortex or brain stem, considered are their eYcacy, the need for addi- Australia usually developing gradually over 5–20 min- tional medication and the incidence of “re- utes and lasting less than 60 minutes. Head- bound” headache. Correspondence to: Professor Kelly, Director of ache, nausea and/or photophobia usually fol- Emergency Medicine low neurological aura symptoms directly or PROBLEMS WITH THE EVIDENCE (Anne-Maree.Kelly@ after a free interval of less than an hour. The An evidence-based review of the therapeutics nwhcn.org.au) headache usually lasts less than 72 hours, but of acute migraine is compromised by the qual- Accepted for publication may be completely absent.” At least two typical ity of the evidence available. With the excep- 8 December 1999 episodes are needed before this diagnosis can tion of the drug company sponsored studies 242 Kelly investigating the “triptans”, most studies are The evidence about prochlorperazine J Accid Emerg Med: first published as 10.1136/emj.17.4.241 on 1 July 2000. Downloaded from small with less than 50 patients in each There are only a few small studies about subgroup being the norm. This means that the prochlorperazine and migraine. Success rates power of these studies to reach methodologi- of 67–92%19–22 have been reported. Most stud- cally sound conclusions is limited. In addition, ies use a dose of 10 mg IV. a variety of measures of “success of treatment” In comparative studies, prochlorperazine has are used by diVerent study groups, which been reported to give better pain relief than makes comparison diYcult. Given these limita- sumatriptan (one study),22 metoclopramide tions, this paper attempts to pull together the (two studies)20 21 and ketorolac (one study).23 available evidence to inform practice and form A preliminary report regarding the use of a basis for further research. rectal prochlorperazine suppositories reported good outcomes24 but its design makes evalua- tion diYcult. PHENOTHIAZINES: CHLORPROMAZINE AND PROCHLORPERAZINE ERGOT ALKALOIDS Phenothiazines are antipsychotic drugs. In the The pharmacological activity of ergot alkaloids central nervous system, they are powerful derives from their ability to interact to varying antagonists of the neurotransmitter action of degrees with subtypes of adrenergic, dopamin- dopamine in the basal ganglia and limbic ergic and tryptaminergic receptors.9 The ergot system. They are also potent anti-emetics via alkaloids have a number of side eVects related eVects on the chemoreceptor trigger zone and to their pharmacological actions. These in- neuroleptic actions seem to change pain clude peripheral vasoconstriction, peripheral perception. In addition, they are á adrenergic gangrene, vomiting, nausea, chest pain, pruritis antagonists (which can lead to orthostatic and headache.9 hypotension); chlorpromazine having greater á The ergot alkaloids seem to exert their anti- blocking eVect than prochlorperazine. And migraine eVect by strongly binding to 5-HT they have anti-cholinergic properties and are (Subtype 1B and 1D) receptors in the blood antagonists at both histamine and 5-HT vessels of the dura and scalp resulting in receptors.9 inhibition of the trigeminal nerve mediated Besides its hypotensive eVect, the major side neurogenic inflammation.62526 eVect of phenothiazines in short-term use is dystonia. This is an idiosyncratic reaction and The evidence regarding DHE may occur after a single dose.9 The mechanism Studies of DHE, either alone or in combina- by which phenothiazines act in migraine is tion with metoclopramide or hydroxyzine, uncertain. It is possibly the result of a report success rates of 23%,14 73%27 and 93%28 combination of actions: anti-5-HT eVect, anti- when used in the dose of 1 mg IV. dopamine eVect in the chemoreceptor trigger In comparative studies, DHE has been zone and vascular eVects via its á blocking shown to be more eVective than pethidine (one 10 28 14 action. study) or lignocaine (one study), less http://emj.bmj.com/ eVective than chlorpromazine (one study)14 and of similar eVectiveness to sumatriptan (one The evidence about chlorpromazine study)27 and pethidine (one study).29 Table 1 summarises the success rates with the Of particular note, in the only study where use of chlorpromazine. adverse events were carefully collected, 55% of Dosing regimens have varied but a dose of patients treated with DHE experienced severe 12.5 mg intravenously (IV) repeated at 20 gastrointestinal side eVects.14 minute intervals to a total dose of 37.5 mg Nasal sprays of DHE are also available. on September 27, 2021 by guest. Protected copyright. would be representative. IV fluids need to be Headache relief rates of 27% at 30 minutes and given because of the significant rate of ortho- 70% at four hours have been reported.30 One static hypotension. study suggests DHE spray to be less eVective With respect to comparative trials, chlorpro- than sumatriptan subcutaneous (SC).31 mazine has been reported to be superior to 16 pethidine (one study), lignocaine (lidocaine) HALOPERIDOL 14 (one study) and dihydroergotamine (DHE) Haloperidol is a butyrophenone, heterocyclic 14 (one study) and of similar eVectiveness to antipsychotic agent. It has e ects on the chemo- 17 V ketorolac (one