Are Butyrophenones Effective for the Treatment of Primary Headache in the Emergency Department?

STATE OF THE ART N A` LA FINE POINTE

Review Article Are butyrophenones effective for the treatment of primary headache in the emergency department?

Lim Beng Leong, MBBS, MRCS (A&E)*; Anne-Maree Kelly, MD, FACEM3

ABSTRACT RE´SUME´ Objectives: Butyrophenones have been reported to provide Objectif : Il a e´te´ signale´ que les butyrophe´ nones soulageai- effective migraine relief in the emergency department (ED). ent les migraines dans les services d’urgence. Nous avons We conducted a systematic review of the evidence for their proce´deá` une analyse syste´ matique sur leur utilisation a` use in the ED. l’urgence. Data source: We searched the Cochrane, Medline, Embase, Source des donneés : Nous avons interroge´ les bases de and CINAHL databases. donneés Cochrane, Medline, Embase et CINAHL. Study selection: Included studies were randomized trials of Se´ lection des e´tudes : Nous avons retenu les essais a parenteral butyrophenone (droperidol, haloperidol) ver- randomise´ s d’un butyrophe´ none parente´ral (drope´ridol, sus placebo or a comparator in migraine or benign halope´ ridol) contre un placebo ou un comparateur en cas headache with results available in English. Study quality de migraine ou de ce´ phaleé be´ nigne. Les re´ sultats devaient was determined using the Jadad score. Six articles were eˆ tre disponibles en anglais. Nous avons e´ value´ la qualite´ des included. essais selon le score de Jadad. Six articles ont e´te´ retenus. Data extraction: Primary outcomes were subjective or Extraction des donneés:Les principaux crite` res d’e´ valuation objective headache relief (. 50% improvement in visual e´ taient le soulagement subjectif ou objectif de maux de teˆte analogue scale scores). Secondary outcomes included side (. 50 % d’ame´ lioration selon l’e´ chelle visuelle analogique). effects. We reported pooled odds ratios (ORs) with their Les crite` res secondaires d’e´ valuation e´ taient entre autres les 95% confidence intervals (CIs) for subjective or objective effets secondaires. Nous avons inclus les rapports de cotes headache relief for butyrophenones versus placebo or combine´ s (RC) avec intervalle de confiance a` 95 % (IC) pour le comparator agents. soulagement subjectif ou objectif de maux de teˆ te pour le Data synthesis: Three studies reported subjective head- groupe butyrophe´ nones par rapport au groupe placebo ou ache relief with a butyrophenone versus placebo or autres comparateurs. meperidine in migraine. Two studies reported objective Synthe` se des donneés : Trois e´ tudes ont signaleún headache relief with droperidol versus prochlorperazine, soulagement subjectif de maux de teˆ te avec un butyrophe´- whereas one study compared droperidol versus olanza- none par rapport au groupe placebo ou a`lame´pe´ ridine pour pine in benign headache. The pooled OR for subjective les cas de migraine. Deux e´ tudes ont fait e´tat d’une headache relief was 8.08 (95% CI 1.54–42.30) for a ame´ lioration objective de ce´ phale´ es avec le drope´ ridol par butyrophenone versus placebo, whereas it was 1.50 rapport au prochlorpe´ razine tandis qu’une autre e´ tude (95% CI 0.33–6.77) for droperidol versus meperidine in comparait le drope´ ridol a` l’olanzapine pour les ce´ phaleés migraine. The pooled OR for objective headache relief be´ nignes. Le RC combine´ pour le soulagement subjectif de was 2.96 (95% CI 1.36–6.43) for droperidol versus maux de teˆtee´ tait de 8,08 (IC a` 95 %, de 1,54 a` 42,30) pour un prochlorperazine in benign headache. Rates of side butyrophe´ none contre un placebo alors qu’il e´ tait de 1,50 (IC effects were 10 to 45%; akathesia and sedation were a` 95 %, de 0,33 a` 6,77) pour le drope´ ridol par rapport a`la the most common. me´pe´ ridine pour les cas de migraine. Le RC combine´ pour le Conclusions: Butyrophenones are effective for the relief soulagement objectif de maux de teˆtee´ tait de 2,96 (IC a`95%, of migraine or benign headache. However, adverse de 1,36 a` 6,43) pour le drope´ ridol par rapport a`la effects make it difficult to recommend butyrophenones prochlorpe´ razine pour les cas de ce´ phaleés be´ nignes. Les above agents with similar effectiveness and fewer taux d’effets secondaires e´ taient de 10 a` 45 %, l’akathe´ sie et problems. la se´ dation e´ tant les re´ actions les plus courantes.

From the *Emergency Department, Tan Tock Seng Hospital, Singapore; and 3Joseph Epstein Centre for Emergency Medicine Research at Western Health and The University of Melbourne, Melbourne, Australia.

Correspondence to: Dr. Lim Beng Leong, Tan Tock Seng Emergency Department, 11, Jalan Tan Tock Seng, Singapore 308433; Beng_Leong_ [email protected].

This article has been peer reviewed.

ß Canadian Association of Emergency PhysiciansCJEM 2011;13(2):96-104 DOI 10.2310/8000.2011.100301

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Conclusion : Les butyrophe´ nones sont efficaces pour le d’agents offrant une efficacite´ similaire et ayant moins soulagement de migraines ou de ce´phale´es be´ nignes. d’effets ne´ fastes. Toutefois, vu les effets inde´ sirables, il est difficile de privile´ gier l’utilisation des butyrophe´ nones plutoˆ t que celle Keywords: butyrophenones, emergency, migraine

Migraine is a common complaint in the emergency physicians to differentiate migraine from other benign department (ED) and accounts for up to 5% of visits.1 headache, such as tension headache, in the ED setting. The goals of treatment include pain relief, rehydration, In addition, the differentiation between the types of and alleviation of associated symptoms such as nausea benign headaches in the ED setting does not appear to and vomiting.2 Wide variation in the agents used in the be important in their subsequent treatment, as reported ED to treat acute migraine has been reported.1,3 In by Trainor and Miner.10 They reported in their addition, some of the known therapies for treatment of prospective observational study in the ED setting that acute migraine headache have been reported to have there was no difference in the treatment used and rates significant adverse effects. Opioids have been reported of pain relief across agents, including sumatriptan, to produce rebound headache following their use in droperidol, narcotics, and nonsteroidal antiinflamma- 3,4 acute migraine and progression to chronic migraine tory drugs (NSAIDs) in migraine and migrainous and 5 with repeated use. Triptans, although widely used in tension-type headaches. acute migraine, have a very small risk of adverse Titles and abstracts were reviewed to identify papers 6 cardiovascular effects. potentially addressing the research question. The full It has been suggested that the butyrophenone class texts of these were obtained and reviewed. A hand of drugs (droperidol and haloperidol) might be search of the reference lists of published papers was effective in acute migraine.7,8 Butyrophenones are also conducted. thought to act by effecting the dopamine 2 (D ) 2 Studies were selected for inclusion if they were receptor in the brain.9 The D receptors are relatively 2 randomized and blinded trials of a parenterally abundant in the brainstem nuclei and sympathetic administered butyrophenone (droperidol, haloperidol) ganglia and nerves, through which they may regulate versus placebo or a parenterally administered com- autonomic visceral, gastrointestinal, and hemodynamic parator for the treatment of acute migraine or benign responses frequently associated with migraine.9 headache in adults with results available in English. The aim of this evidence-based report is to identify Study quality was measured by calculation of the Jadad and summarize the relevant evidence for the effective- 11 ness of butyrophenones in the treatment of acute score. Two independent reviewers independently migraine headache in the ED. screened suitable articles using our inclusion criteria. They discussed and decided on the articles finally QUESTION included in the study. The Jadad score for each of these was assigned after discussion between the reviewers. In adult patients with moderate to severe migraine The primary outcome of interest was relief of headache, are butyrophenones effective for headache headache within 2 hours of treatment for a single relief? bolus or up to 3 hours for an infusion of the studied medication. We selected the 2-hour duration for pain METHODS relief for a bolus dose as it was clinically relevant and practical in the ED and recommended by the We identified relevant studies by searching the Cochrane International Headache Society (IHS) committee on Library, Medline, Embase,andCINAHL databases using clinical trials on migraine.12 We decided on the 3-hour the search expression [Exp butyrophenones OR halo- limit for pain relief for an infusion as we felt that it peridol OR droperidol] AND [migraine OR migraine would likely have a slower onset of action and response disorders OR migraine AND disorders] OR [benign time. Secondary outcomes included relief of associated headache]. We included studies involving benign head- symptoms, mean change in visual analogue scale (VAS) ache as they likely included migraine headache as well in scores, use of rescue medications within 24 hours, and their samples, and it can be challenging for emergency side effects.

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Table 1. Papers investigating a butyrophenone versus placebo in migraine

Author, date, and Study type (level of Jadad country Patient group evidence) Outcomes Key results Study weaknesses score

Honkaniemi J et al, 40 adult PRCT (double blind) Total or almost total More patients with total or Small sample size and 4/5 2006, Finland13 patients with comparing IV pain relief leading almost total pain relief in did not look at other migraine infusion of 5 mg to discharge haloperidol group (16/20 important side using IHS haloperidol in 1–3 hr post- vs 3/20; p , .0001); effects of definitions 500 mL normal treatment clinical success rate 80%; haloperidol, such as saline over 30 ARR 65%; NNT 1.5 (95% prolonged QTc min vs placebo CI 1.1–2.4) Improvement in Lower mean VAS post- VAS values haloperidol vs placebo 1–3 hr post- (2.3 vs 6.2; p , .0001) treatment Side effects More patients in haloperidol group developed side effects (9/20 for motor agitation or sedation vs 1/20 for visual disturbance in placebo group) Silberstein SD et 305 adult PRCT Headache relief 2 hr More patients had headache No mention regarding 4/5 al, 2003, United patients with (multicentred, post-treatment relief at 2 hr with the relative States14 moderate to double blind) potentially therapeutic contribution to the severe comparing doses of droperidol (2.75– sample size by each migraine various doses of 8.75 mg) than placebo: centre, ie, whether using IHS IM droperidol 153/181 vs 35/61; there is definitions (0.1, 2.75, 5.5, p , .002); clinical success overrepresentation 8.25 mg) with rate 84.5%; ARR 27.1%; by one centre placebo NNT 3.7 (95% CI 2.5–7.3) Use of rescue Less patients required medications rescue medications at within 24 hr post- 24 hr compared to treatment placebo group (38/181 vs 27/61; p , .05) Relief of associated Droperidol 2.75 mg reduced symptoms nausea for 4 hr, (nausea, photophobia and vomiting, phonophobia for 12 hr photophobia, compared to placebo phonophobia) (p value , .05) post-treatment Droperidol 8.25 mg reduced all associated symptoms for 48 hr compared to placebo (p value , .05) Side effects 92/305 patients had adverse effects; most commonly anxiety, akathesia, or somnolence No prolonged QTc or hypotension noted Side effects did not show linear dose dependence

ARR 5 absolute risk reduction; IHS5 International Headache Society; IV 5 intravenous; NNT 5 number needed to treat; PRCT 5 prospective randomized controlled trial; VAS 5 visual analogue scale.

For the analysis, we calculated the weighted rate of butyrophenone versus placebo or comparator in each headache relief, absolute risk reduction (ARR), number study. We weighted each study according to the needed to treat (NNT), odds ratio (OR), and 95% number of subjects enrolled. We chose to take the confidence interval (CIs) for headache relief by each more conservative approach of pooling studies with a

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Table 2. Papers of droperidol versus comparator in migraine or benign headache

Author, date, and Study type (level of Jadad country Patient group evidence) Outcomes Key results Study weaknesses score

Richman 29 adult PRCT (double blind) Proportion of patients in No significant difference (10/15 Small sample size, 3/5 PB et al, patients with comparing IM each arm who felt in droperidol arm vs 8/14 in no follow-up of 2002, migraine 2.5 mg droperidol well and were meperidine am; p 5 .61); patients post United using IHS vs IM 1.5 mg/kg discharged 30 min clinical success 67%; ARR discharge and did States15 definitions meperidine post-treatment 9.6%; NNT 11 (95% CI: not not look at other reported as the two important side treatments not significantly effects of different) droperidol such as Mean change in VAS No significant difference (47 vs prolonged QTc and 30 min post- 37 mm; p 5 .33) hypotension treatment Side effects at 30 min 1/15 vs 2/14 had sedation in post-treatment droperidol vs meperidine arms; 2/15 in droperidol arm had akathesia Miner JR et 168 adult PRCT, single blind; Proportion of patients in Significant difference (74/82 in Convenient sample 3/5 al, 2001, patients with comparing each arm who droperidol arm vs 59/86 in groups; United benign parenteral reported . 50% prochlorperazine arm; investigators not States16 headache as droperidol (IM change in VAS at p 5 .017); ARR 21.6%; NNT 5 blinded to the drug judged by 5 mg or IV 2.5 60 min post- (95% CI 3.0–10.1) used and IV or IM their EP mg) vs treatment formulations not prochlorperazine Mean change in VAS Significant difference (81.4% in randomized within (10 mg IM or IV) 60 min post- droperidol arm vs 66.9% in the 2 arms; larger treatment prochlorperazine arm; dose of IM 5 mg p 5 .001) droperidol used in the study instead Proportion of patients No significant difference (13/82 of IM 2.5 mg requiring rescue in droperidol arm vs 18/86 in medications at 60 min prochlorperazine arm; p 5 .12) post-treatment Proportion of patients No significant difference (13/82 with side effects at in droperidol arm vs 8/86 in 60 min post- prochlorperazine arm; p 5 .19) treatment Akathesia was the most common reported side effect Weaver CS 95 adult PRCT, double blind Proportion of patients in Significant difference (40/48 in Convenient sample 5/5 et al, patients with at 2 centres; each arm who droperidol arm vs 34/47 in group, the relative 2004, benign comparing IV 2.5 reported . 50% prochlorperazine arm; contribution at United headache as mg droperidol vs change in VAS at p , .01); ARR 11.0%; NNT 10 each centre not States17 judged by IV 10 mg 30 min post- (95% CI 218 to 4) reported, their EP prochlorperazine treatment premature Mean percentage No significant difference (79.1% termination of decrease in VAS in in droperidol arm vs 72.1% in study before each arm at 30 min prochlorperazine arm; calculated sample post-treatment p 5 .23) size of 460 Proportion of patients in No significant difference (6/48 in patients was each arm requiring droperidol arm vs 6/47 in reached owing to shortages of IV rescue medications prochlorperazine arm; p 5 1.0) at 30 min post- prochlorperazine treatment and the FDA ‘‘black box’’ Proportion of patients No significant difference in warning of with side effects at akathesia (5/48 in droperidol torsades de 60 min post- arm vs 9/47 in pointes with treatment prochlorperazine arm; p 5 .25) droperidol No other side effects reported in each arm

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Table 2. Continued Author, date, and Study type (level of Jadad country Patient group evidence) Outcomes Key results Study weaknesses score

Hill CH et 87 adult PRCT, single blind; Mean percentage No significant difference (52.2% Convenient sample 3/5 al, 2008, patients with comparing IM improvement in VAS vs 46.8%; p 5 .53) group; physicians United benign 5 mg droperidol after 30 min post- not blinded to States18 headache as vs IM 10 mg treatment medication used; judged by olanzapine Mean percentage No significant difference (58.7% sample size too their EPs improvement in VAS vs 63.9%; p 5 .30) small to after 60 min post- demonstrate treatment difference in Proportions of patients No significant difference (6/42 in serious side receiving rescue droperidol arm vs 4/45 in effects such as prolonged QTc medications at 60 min olanzapine arm; p 5 .43) post-treatment Side effects No significant difference in 9-point median AMS and BAS scores between the 2 arms at 30 and 60 min Median AMS scores at 30 min were 0 in droperidol arm vs 21 in olanzapine arm (p 5 .21), and at 60 min, they were 0 in both arms (p 5 .86) Median BAS scores were 0 for both arms at 30 min (p 5 .28) and at 60 min (p 5 .43) No patients with prolonged QTc or other serious side effects

AMS 5 Altered Mental Status; ARR 5 absolute risk reduction; BAS 5 Barnes Akathesia Scale; EP 5 emergency physician, FDA 5 Food and Drug Administration; IHS 5 International Headache Society; IM 5 intramuscular; IV 5 intravenous; NNT 5 number needed to treat; PRCT 5 prospective randomized controlled trial; VAS 5 visual analogue scale.

random-effects analysis. We performed all analyses treatment following a bolus dose or from 1 to 3 hours using RevMan version 5 (Cochrane Collaboration, following an infusion of a butyrophenone. Objective Copenhagen, Denmark). headache relief was defined as . 50% improvement in VAS scores. Three studies reported proportions of RESULTS patients with subjective headache relief 1 to 3 hours post administration of a butyrophenone compared to We identified 36 papers, of which 6 met the inclusion placebo or meperidine in the treatment of migraine.13–15 criteria. Two of these studies compared a butyrophe- The weighted average rate of subjective headache relief none to placebo in the treatment of migraine.13,14 One 1 to 3 hours after treatment by a butyrophenone in compared intravenous (IV) haloperidol to placebo,13 these three trials was 82.8% (n 5 216). whereas the other compared intramuscular (IM) Two studies reported proportions of patients with droperidol to placebo using four different dosage objective headache relief within 30 to 60 minutes after regimens.14 The remaining four studies compared administration of droperidol compared to prochlor- parenteral droperidol to a comparator drug in the perazine in the treatment of benign headache.16,17 The treatment of migraine or benign headache.15–18 The weighted average proportion of patients with objective comparator drugs were meperidine, prochlorperazine, headache relief at this interval was 87.7% (n 5 130) in or olanzapine. The details of these papers are shown in the two trials. The remaining study reported mean Table 1 and Table 2. percentage improvement in VAS scores of 52.2% and The most common primary outcome studied in 58.7% 30 and 60 minutes post-treatment with IM these trials was subjective or objective relief of head- droperidol, respectively, when compared to IM olan- ache at intervals from 30 minutes to 2 hours after zapine in the treatment of benign headache.18

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Figure 1. Forest plot for subjective headache relief for each butyrophenone versus placebo or comparator. Event 5 subjective headache relief within 3 hours post-treatment.

There were statistically significant differences for 65% and 27.1% for haloperidol and droperidol, subjective or objective headache relief for haloperidol respectively, compared to placebo. The ARR for and droperidol versus placebo and droperidol versus droperidol compared to meperidine was 9.6%. When prochlorperazine in the treatment of migraine or compared to placebo, the NNT for subjective head- benign headache. There were no statistically signifi- ache relief was 1.5 (95% CI 1.1–2.4) and 3.7 (95% CI cant differences for subjective headache relief for 2.5–7.3) for haloperidol and droperidol, respectively. droperidol versus meperidine in migraine treatment When compared to meperidine, the NNT for sub- and for mean percentage improvement in VAS scores jective headache relief was 10.4 (95% CIs were not for droperidol versus olanzapine in the treatment of reported as the two treatments were not significantly benign headache. different). The pooled OR for subjective headache relief within The pooled OR for objective headache relief within 3 hours of treatment was 8.08 (95% CI 1.54–42.30) for 1 hour of treatment was 2.96 (95% CI 1.36–6.43) for a butyrophenone versus placebo in migraine treatment. droperidol versus prochlorperazine in the treatment of The OR for subjective headache relief within 30 benign headache. These are demonstrated in the forest minutes of treatment was 1.50 (95% CI 0.33–6.77) plot in Figure 2. The pooled ARR and NNT for for droperidol versus meperidine in migraine treat- objective headache relief for droperidol versus pro- ment. These are demonstrated in the forest plot in chlorperazine was 17.8% and 5.6 (95% CI 3.7–12.3), Figure 1. The ARR for subjective headache relief was respectively.

Figure 2. Forest plot for objective headache relief for droperidol versus prochlorperazine. Event 5 objective headache relief within 1 hour post-treatment.

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Rates of side effects to butyrophenone were flaws in the methodologies of these trials and concerns reported to be 10 to 45%. Akathesia and sedation over the optimal dosage of droperidol and the safety of were the most commonly reported side effects. In butyrophenones. only one article did the authors specifically state in The total sample sizes in some of the trials were the study protocol that subjects underwent cardiac relatively small (, 100),13,15,17 and this might have monitoring during droperidol treatment in the ED.18 contributed to selection bias. In addition, there were No patients with prolonged QTc were reported in concerns regarding blinding in some trials.16,18 In these their study following droperidol treatment. These are trials, the physicians were not blinded to the type of shown in Table 1 and Table 2. medications used to treat the benign headache, and in the trial by Miner and colleagues, blinding was also not DISCUSSION achieved to the formulation of droperidol or prochlorperazine.16 These would potentially add bias to These studies demonstrated that butyrophenones are the report, assessment, and analysis of data. Another effective for the relief of moderate to severe migraine important issue in the methology of these trials was in the ED when compared to placebo or meperidine. that none were designed to specifically investigate They also showed that droperidol may be as effective serious cardiovascular side effects of butyrophenones, as prochlorperazine or olanzapine in the relief of including prolonged QTc. All of them excluded benign headache in the ED. Our findings are patients with existing cardiac conditions who might consistent with reported success rates of 85% for be more susceptible to serious cardiovascular adverse chlorpromazine, 71% for sumatriptan, and 61% for effects, and only one trial specified that recruited metoclopramide.19 Side effects, although minor, were patients underwent cardiac monitoring while they were relatively common (10–45%), and most frequently treated with droperidol.18 Although these studies included akathesia and sedation. Serious side effects reported no serious adverse cardiovascular side effects, such as hypotension or prolonged QTc were rarely the above concerns with their methodology might have reported in the selected studies. masked their true prevalence in the diversified patient Although three of the six studies included used the populations in the ‘‘real ED world’’ treated with classification by the International Headache Society20 to butyrophenones for their benign headache. define migraine,13–15 we included three studies that The concern about serious adverse effects of investigated the use of droperidol in benign head- butyrophenones, particularly prolonged QTc, remains ache.16–18 We included them as we wanted to reflect the the major limitation toward their widespread use in ‘‘real world’’ of the ED. We believed that differentiating treating headache. the various types of benign headache, including migraine There have been mixed reports on the cardiovascular and tension headache, is challenging, and the studies side effects of butyrophenones. A ‘‘black box’’ warning with benign headache probably included a disproportio- was placed on droperidol with regard to the risks of nately large number of patients with migraine. Further, prolonged QTc and torsades de pointes by the Food and Trainor and Miner also reported that there was no Drug Administration (FDA) of the United States.21 difference in treatment success rates for various agents, Other studies, however, seemed to report that droper- such as sumatriptan, droperidol, and NSAIDs, in idol was safe in this aspect.22–24 Nuttall and colleagues and migraine and migrainous and tension-type headaches. Fortney and colleagues reported that IV droperidol up It was difficult to perform subgroup analysis for to 1.25 mg was safe in adult surgical patients.22,23 Chase headache relief between the studies on migraine13–15 and and Biros also reported, in their retrospective study, that those on benign headache.16–18 The former studies IV or IM droperidol 2.5 to 5 mg produced very few reported subjective headache relief, whereas the latter adverse effects in ED patients with head injury, alcohol reported objective headache relief or mean percentage or cocaine intoxication, and/or recent seizures.24 We improvement in VAS scores. identified some limitations to these studies. The dosages Although the selected studies suggested promising used for droperidol in the surgical patients22,23 were results on the effectiveness of butyrophenones, we relatively lower than the dosages used in the studies identified several limitations that prevented their identified in this review, which used up to 8.25 mg widespread use in clinical practice. These included droperidol. In addition, the ED study, although using a

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similar dosing of 2.5 to 5 mg droperidol, did not excluded from systematic reviews. We did not perform investigate the rates of prolonged QTc among the a hand search of recent conference proceedings to patients.24 Hence, it is difficult to extrapolate the findings identify unpublished trials. Nevertheless, we had tried in these studies to the patients with migraine or benign to minimize such bias by doing a hand search of the headache in our identified studies. One of the studies reference lists of identified papers. included in our review was terminated prematurely because of the FDA warning.17 CONCLUSIONS Other, less serious side effects, such as akathesia and sedation, were common and occurred in 10 to 45% of Available data suggest that butyrophenones are effec- patients treated with butyrophenones for their benign tive for the relief of migraine or benign headache. headache. In addition, in the haloperidol trial, 16% of However, at this time, the lack of a clear dosing patients who responded to IV haloperidol did not wish strategy, the prevalence of adverse effects, and a small their migraine to be treated with the agent in the future risk of serious cardiovascular adverse effects make it because of these side effects.13 difficult to recommend butyrophenones above agents Another limitation is that there was little suggestion with similar effectiveness and fewer problems. by these studies of the optimal dosing of butyrophe- Competing interests: None declared. nones in the treatment of migraine or benign headache that balanced efficacy and side effects.13–18 This is REFERENCES especially important as previous studies have reported a dose-related response of prolonged QTc with droper- 1. Vinson DR. Treatment patterns of isolated benign head- idol.25,26 The chief reason for the failure to identify aches in US emergency departments. Ann Emerg Med 2002; optimal butyrophenone dosing in the treatment of 39:215-22. acute migraine or benign headache was study design. 2. Silberstein SD, Saper JR, Freitag F. Migraine: diagnosis and There was only a single study on haloperidol, and it treatment. In: Silberstein SD, Lipton RB, Dalessio DJ, editors. Wolff’s headache and other head pain. 7th ed.New compared an IV infusion of 5 mg of haloperidol in York: Oxford University Press, 2001. p. 121-237. 13 500 mL of normal saline over 30 minutes to placebo. 3. Colman I, Rothney A, Wright SC, et al. Use of narcotic Similarly, only two trials studied IV droperidol; each analgesics in the emergency department treatment of compared IV 2.5 mg droperidol to IV 10 mg migraine headache. Neurology 2004;62:1695-700. prochloperazine.16,17 No other dosages of IV droperidol 4. Friedman BW, Kapoor A, Friedman MS, et al. The relative have been studied to date to identify optimal dosing. efficacy of meperidine for the treatment of acute migraine: a meta-analysis of randomized controlled trials. Ann Emerg On the other hand, there was much variation in the Med 2008;52:705-13. dosing of IM droperidol used in the studies,14–16,18 and 5. Bigal ME, Lipton RB. Excessive acute migraine medication these ranged from 0.1 to 8.25 mg. use and migraine progression. Neurology 2008;71:1821-8. Despite the varying dosage regimens, only one study 6. Dodick D, Lipton RB, Martin V, et al. Consensus statement: investigated the optimal dosage of IM droperidol.14 In cardiovascular safety profile of triptans (5-HT1B/1D ago- that article, the authors reported no linear dose- nists) in the acute treatment of migraine. Headache 2004;44: 414-25. dependent relationship between IM droperidol and its efficacy or side effects and suggested an optimal 7. Richman PB, Reischel U, Ostrow A, et al. Droperidol for acute migraine headache. Am J Emerg Med 1999;17:398-400. dosing of 2.75 mg. 8. Fisher H. A new approach to emergency department therapy These issues challenge the broad adoption of of migraine headache with intravenous haloperidol: a case butyrophenones for the treatment of migraine or series. J Emerg Med 1995;13:119-22. benign headache. 9. Mascia A, Afra J, Schoenen J. Dopamine and migraine: a There were some limitations to our review. We only review of pharmacological, biochemical, neurophysiological, included studies in English and could have excluded and therapeutic data. Cephalalgia 1998;18:174-82. relevant studies published in other languages. In 10. Trainor A, Miner J. Pain treatment and relief among patients with primary headache subtypes in the ED. Am J Emerg Med addition, there could always be selection bias by our 2008;26:1029-34. reviewers. Finally, we were also unable to exclude 11. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality publication bias. Trials reporting negative findings are of reports of randomized clinical trials: is blinding necessary? less likely to be published and more likely to be Control Clin Trials 1996;17:1-12.

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