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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 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 , lignocaine clude altered electrical activity (“cortical (lidocaine), ketorolac, the alkaloids, spreading depression”2), a failure of brain ion , the “”, 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 , chlor- receptors are implicated in this process.3 and , 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 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: 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 , dopamin- 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 , 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 , 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) 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 study), metoclopramide (one receptor trigger zone reducing nausea and 18 15 study) and sumatriptan (one study). vomiting. It is an antagonist of the central None of the trials have reported any cases of eVects of dopamine and is relatively selective dystonia resulting from the use of chlorpro- for the D2 . It is also a mod- mazine in this way. erate á antagonist peripherally and has anti- 5-HT eVects. It is less sedating than chlorpro- mazine and results in less orthostatic Table 1 Success rates with the use of chlorpromazine for the treatment of migraine hypotension. Dystonic reactions are haloperi- dol’s principal side eVect.9 It is postulated that Study Year Design Patients (n) Success rate (%) haloperidol is eVective in migraine because of its anti-dopamine and/or anti 5-HT eVects. Lane et al11 1985 IV 52 94 Iserson12 1983 IM 100 96 McEwen13 1987 IM 36 47 The evidence regarding haloperidol Bell et al14 1990 IV 76 (3 arms) 89 No controlled or comparative trials of the use Kelly15 1997 IV 42 95 of haloperidol in migraine have been pub- Migraine: pharmacotherapy in the emergency department 243

lished. Recently, a case series of six cases of Side eVects of metoclopramide include drowsi- J Accid Emerg Med: first published as 10.1136/emj.17.4.241 on 1 July 2000. Downloaded from migraine treated with 5 mg of haloperidol IV ness and dystonia.9 after a 500 to 1000 ml bolus of IV fluids reported complete or substantial relief within The evidence regarding metoclopramide 25 to 65 minutes. Side eVects were reported as Uncontrolled studies have reported successful “minimal”.32 relief of migraine with metoclopramide of 75%.39 In a placebo controlled trail, metoclo- KETOROLAC pramide 10 mg orally was found not to be Ketorolac is a non-steroidal anti-inflammatory superior to placebo in the relief of headache agent (NSAID) that inhibits prostaglandin pain from migraine.40 However, studies of IV synthesis, platelet aggregation and serotonin metoclopramide report benefit over release from platelets.9 It is thought that placebo38 41 and in one a success rate of 67%.38 NSAIDs may act in migraine by reducing the In comparative studies, metoclopramide in a role of prostaglandins in increasing the sensi- dose of 10 mg IM or IV has been reported to tivity of blood vessel walls to pain and in regu- be less eVective than prochlorperazine (two lating smooth muscle tone and reactivity as studies).20 21 High dose metoclopramide (0.1 well as decreasing changes in vascular mg/kg/dose IV to a total of three doses; average permeability.33 dose 16 mg) was found to be of similar eVectiveness to chlorpromazine (one study).18 The evidence about ketorolac The doses used in studies have been 30–60 mg PETHIDINE intramuscularly (IM). The reported success Pethidine is a synthetic narcotic that rate is 60%.33 exerts its pharmacological activity principally In comparative studies, ketorolac (at a dose by binding to opioid receptors. The main side of 60 mg) has been reported to be similar in eVects of pethidine are nausea and vomiting, eVectiveness to pethidine (two studies)33 34 but respiratory depression, drowsiness and smooth at a dose of 30 mg IM was less eVective than muscle spasm, particularly in the biliary tree.9 pethidine (one study).35 Ketorolac has been A major concern with the use of pethidine is reported to be less eVective than prochlorpera- the possibility of the development of zine (one study).23 A very small study com- dependence.9 This concern is supported by the pared ketorolac 60 mg IM with chlorpro- findings of a study of 1900 suVerers of chronic mazine 25 mg IV and found no diVerence in headache, which found that 5% were narcotic eYcacy between the agents at two hours.17 abusers.42 However, important methodological problems It has been hypothesised that opioids are make the value of this study questionable. incapable of providing lasting, eVective analge- sia in migraine as they depend for their eVect LIGNOCAINE on projections and patients suVer- Lignocaine is a class 1b anti-arrhythmic agent ing migraine have been shown to have central 43

(membrane stabiliser) used for the treatment nervous system serotonin depletion. http://emj.bmj.com/ of ventricular arrhythmia. It is also a potent local anaesthetic agent.9 It was hypothesised The evidence with respect to pethidine that lignocaine might act in migraine by its The usual dose of pethidine is 75 mg IM/IV. A membrane stabilising eVect inhibiting the literature search covering the years 1976–1997 release of vasoactive substances from platelets failed to identify any placebo controlled studies thus inhibiting the sterile inflammatory of the eVectiveness of pethidine for the relief of response.14 migraine headache. Clinical success rates of 16 28 22% and 50% have been reported. on September 27, 2021 by guest. Protected copyright. The evidence about lignocaine In comparative trials pethidine, either alone The usual dose used in reported studies is of or in combination with hydroxyzine and the order of 100 mg. A randomised, prospec- dimenhydramine, has been reported to be less tive, double blind trial comparing IV ligno- eVective than DHE (one study)28 and chlorpro- caine (1 mg/kg) with placebo failed to demon- mazine (one study)16 and of similar eVective- strate a diVerence between the two for the relief ness to DHE (one study).29 With respect to of the head pain of migraine.36 In comparative ketorolac, pethidine was found to give better studies lignocaine has been shown to be less migraine relief than ketorolac in a dose of 30 eVective than chlorpromazine (one study)14 mg IM (1 study)35 but when the ketorolac dose and DHE (one study).14 was 60 mg IM the agents had similar eVective- Recently, nasal lignocaine spray at a concen- ness (two studies).33 34 tration of 4% has been trialled. A success rate of 55% has been reported however the early SUMATRIPTAN AND OTHER “TRIPTANS” relapse rate was 42%.37 Sumatriptan is a specific and selective 5-HT (subtype 1D) that has no eVect on METOCLOPRAMIDE other 5-HT receptor subtypes. This receptor is Metoclopramide is a non- cen- found predominantly in cranial blood vessels tral dopamine antagonist and a peripheral and produces constriction of large blood muscarinic agonist. It increases gastric empty- vessels that may be dilated during episodes of ing and is anti-emetic at the chemoreceptor migraine.44 Sumatriptan may be administered trigger zone.9 It is postulated that metoclopra- orally, SC or by . Adverse eVects mide acts in migraine by anti-emetic eVects include drowsiness, weakness, dizziness, flush- combined with central anti-dopamine eVects.38 ing, rash, pruritis, increase in blood pressure, 244 Kelly

chest pain or chest tightness. Importantly, use in acute migraine. Haloperidol and magne- J Accid Emerg Med: first published as 10.1136/emj.17.4.241 on 1 July 2000. Downloaded from sumatriptan is contraindicated in patients with sium need to be studied in appropriate trials a history of ischaemic heart disease, uncon- before conclusions can be drawn. Ketorolac, trolled hypertension or the concomitant use of metoclopramide and pethidine perform a little ergot preparations. There are also a significant better but each has been shown to be inferior number of non-responders for which no to other treatments. The potential for depend- clinical, pharmacokinetic or genetic explana- ence and abuse must also be considered with tion has been found.45 pethidine. The data on DHE are diYcult to The anti-migraine eVect of sumatriptan is interpret because it is often used in combina- thought to be attributable to its eVect on the tion with other agents, for example, metoclo- 5-HT subtype 1D receptors in cranial blood pramide, however it also has been shown to be vessels.25 44 Sumatriptan and ergot alkaloids less eVective than chlorpromazine and su- block neurogenic inflammation by acting at matriptan in acute treatment and has a high pre-junctional 5-HT receptors on trigemino- rate of unpleasant side eVects. At this time, the vascular fibres.6 most eVective agents seem to be prochlorpera- zine, chlorpromazine and sumatriptan, each of The evidence regarding “the triptans” which have achieved greater then 70% eYcacy Three large double blind studies have com- in a number of studies. pared the eYcacy of sumatriptan in doses of either 6 mg or 8 mg subcutaneously with 1 Headache Classification Committee of the International placebo. Clinical success rates were 70%,46 Headache Society. Classification and diagnostic criteria for 47 48 headache disorders, cranial neuralgias and facial pain. 75–80% and 70% respectively. In each study Cephalgia 1988; 8 (suppl 7):1–96. about half the sumatriptan treated group 2 Zagami AS. Pathophysiology of migraine and tension-type headache. Curr Opin Neurol 1994;7:272–7. reported mild adverse eVects including injec- 3 Lauritzen M. Pathophysiology of the migraine aura. The tion site reactions, nausea, flushing and chest spreading depression theory. Brain 1994;117:199–210. 4 Cailliett R. Pain: mechanisms and management. Philedelphia: heaviness. Thirty four to 60 per cent of patients FA Davis, 1993. successfully treated with sumatriptan reported 5 Goadsby PJ, Edvinsson L. The trigeminovascular system 47 and migraine: studies characterising cerebrovascular and recurrent headache within 24 hours. neuropeptide changes seen in humans and cats. Ann Neurol In comparative studies, sumatriptan when 1993;33:48–56. 6 Moskowitz MA. Neurogenic inflammation n the patho- compared with DHE IV had a significantly physiology and treatment of migraine. Neurology 1993;43 higher rate of relief of headache at two hours, (suppl 3):16–20. but there was no di erence in rate of relief at 7 Vanmhoutte PM, Cohen RA, Van Neueten JM. Serotonin V and the arterial vessels. J Cardiovasc Pharmacol 1984;6 three or four hours.27 Sumatriptan has reported (suppl 2):422–8. 31 8 Mauskop A, Altura BT, Cracco RQ, et al. Intravenous mag- to be more eVective than DHE nasal spray. It nesium sulphate rapidly alleviates headaches of various has also been reported to be of similar types. Headache 1996;36:154–60. eVectiveness to chlorpromazine (one study)15 9 Gilman AG, Rall TW, Nies AS, et al. The pharmacological basis of therapeutics. 8th ed. New York: McGraw-Hill, and less eVective than prochlorperazine (one 1991. study).22 Sumatriptan treated patients reported 10 Lance JW. The pathophysiology of migraine: A tentative synthesis. Pathol Biol (Paris) 1992;40:355–60.

a significantly higher rate of headache recur- 11 Lane PL, Ross R. Intravenous chlorpromazine: preliminary http://emj.bmj.com/ rence within 24 hours. results in acute migraine. Headache 1985;25:302–4. 12 Iserson KV. Parenteral chlorpromazine treatment in mi- Newer “triptans” such as (10 mg graine. Ann Emerg Med 1983;12:756–8. orally) have reported success rates of the order 13 McEwen JI, O’Connor HM, Dinsdale HB. Treatment of 49 migraine with intramuscular chlorpromazine. Ann Emerg of 75–80%. Med 1987;16:758–63. Sumatriptan is also now available as a nasal 14 Bell R, Montoya D, Shuaib A, et al. A comparative trial of three agents in the treatment of acute migraine headache. spray (20 mg) and has a reported clinical suc- Ann Emerg Med 1990;19:1079–82. cess rate of 63–78%.50 51 15 Kelly AM, Ardagh M, Curry C, et al. Intravenous chlorpro- mazine versus intramuscular sumatriptan for acute mi- graine. J Accid Emerg Med 1997;14:209–11. on September 27, 2021 by guest. Protected copyright. MAGNESIUM 16 Lane PL, McLellan BA, Baggoley CJ. Comparative eYcacy of chlorpromazine and meperidine with dimenhydramine In migraine patients, magnesium has been in migraine headache. Ann Emerg Med 1989;18:360–5. shown to play an important part as a regulator 17 Shrestha M, Singh R, Moreden J, et al. Ketorolac versus chlorpromazine in the treatment of acute migraine without of neuronal excitability and therefore hypo- aura: A prospective randomised double-blind trail. Arch Int thetically of headache.52 Magnesium concen- Med 1996;156:1725–8. 18 Cameron JD, Lane PL, Speechley M. Intravenous chlorpro- trations may also have eVects on serotonin mazine versus intravenous metoclopramide in acute receptors, NMDA receptors and migraine headache. Ann Emerg Med 1995;2:597–602. 53 19 Jones J, Sklar D, Dougherty J, et al. Randomised, synthesis and release. Evidence suggests that double-blind trial of IV prochlorperazine for the treatment about 50% of migraine suVerers have reduced of acute headache. JAMA 1989;261:1174–6. 53 20 Jones J, Pack S, Chun E. Intramuscular prochlorperazine concentrations of ionised magnesium. versus metoclopramide as single-agent therapy for the treatment of acute migraine headache. Am J Emerg Med 1996;14:262–4. The evidence about magnesium 21 Coppola M, Yealy DM, Leibold RA. Randomised, placebo- A preliminary study reports clinical success in controlled evaluation of prochlorperazine versus metoclo- pramide for emergency department treatment of migraine 35 of 40 patients after infusion of1gof headache. Ann Emerg Med 1995;26:541–6. magnesium sulphate.54 Response was more 22 Donohue C, Thomas SH, Benson N, et al. Prochlorperazine versus sumatriptan for the emergency department therapy likely in those with low ionised magnesium of migraine. [Abstract]. Ann Emerg Med 1995;25:154–5. concentrations. 23 Seim MB, March JA, Dunn KA. Intravenous ketorolac ver- sus intravenous prochlorperazine for the treatment of migraine headache. Acad Emerg Med 1998;5:573–6. Summary 24 Jones EB, Gonzalez ER, Boggs JG, et al. Safety and eYcacy of rectal prochlorperazine for the treatment of migraine in Review of the evidence has some clear implica- the emergency department. Ann Emerg Med 1994;24:237– tions for the management of migraine in ED. 41. 25 Buzzi MG, Moskowitz MA. Evidence for 5-HT-1B / 1D Lignocaine fails to reach acceptable eYcacy receptors mediating antimigraine eVect of sumatriptan and standards and as such is not recommended for dihydroergotamine. Cephalgia 1991;11:165–8. Migraine: pharmacotherapy in the emergency department 245

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