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Three Part Question

Is [Haloperidol] use in [acute migraine] [effective as pain relief]

Clinical Scenario

42 year old lady presented with acute onset of migraine headache in the ED similar to her previous episodes but unresponsive to her usual triptan and amitryptiline medications; you have tried NSAIDs and metoclopramide after ruling out other etiology (like SAH) but hasn't made a lot of difference; your colleague mentions opioids but you are not very keen as you think it doesn't help much but you want to consider Haloperidol because you have read somewhere about its anti-migraine and anti-emesis effects; you look up the evidence

Search Strategy

MEDLINE
EMBASE
Cochrane Library
[butyrophenone.mp. or exp Butyrophenones/ or haloperidol.mp. or exp Haloperidol/ or droperidol.mp. or exp Droperidol/] and [migraine.mp. or exp Migraine Disorders/ or headache.mp. or exp Headache/ or exp Headache Disorders/] limit to humans

Search Outcome

75 articles found out of which 9 were relevant to the topic

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Honkaniemi 2006 Finland	40 randomized into 2 groups receiving intravenously either 5 mg haloperidol in 500 mL of normal saline or 500 mL of normal saline alone. Pain was assessed by visual analogue scale (VAS) before and 1 to 3 hours after the infusion	PDBRCT	VAS values pre and post haloperidol use	7.7 in the haloperidol and 7.2 in the placebo group. After the infusion the VAS values were 2.2 in the haloperidol and 6.3 in the placebo group (P < .0001)	Small study, high number of side-effects
			pain relief	80% of the patients treated with haloperidol, whereas only 3 patients (15%) responded to placebo (P < .0001).
			open trial of those who had placebo and no response after 3 hrs(17) and those who refused(7)	VAS declined from 6.7 to 2.4 and 79% of these patients felt significant pain relief
			relapse	7%
			side-effects	sedation, akathisia (16%)
Monzillo 2004 Brazil	29 patients with migraine as per IHS guidelines, had dexamethasone(14) (4 mg) and haloperidol(15) (5 mg) in the treatment of migraine in the emergency room.	prospective intervention study using 2 drugs	pain intensity at 30, 60, 90, 120 mins	pain releif achieved earlier with haloperidol;at 30 mins and at 120 mins there was no difference between two drugs	Poor quality of study, no randomisation, no blinding, small numbers, confounding effect of use of intravenous dipyrone
Weaver 2004 USA	Ninety-six patients (48 in each group) in the ED were randomized to receive droperidol 2.5 mg i.v. or prochlorperazine 10 mg i.v.	randomized, controlled, blinded study	pain relief	83.3% in the droperidol group and 72.3% in the prochlorperazine group reported 50% pain reduction at 30 min (p <.01; one-sided test of equivalence)	small study, baseline characteristics similar, side effects inlcuded akathisia
			mean decrease in headache intensity	79.1% (SD 28.5%) in the droperidol group and 72.1% (SD 28.0%) in the prochlorperazine group (p =.23)
Silberstein 2003 Neurology	331 patients enrolled to assess efficacy and tolerability of droperidol 0.1 mg, 2.75 mg, 5.5 mg, and 8.25 mg for the acute treatment of moderate to severe migraine headache in adults.	randomized, double-blind, placebo-controlled, dose-ranging, multicenter study	headache response at 2hrs	better (p < 0.002) in the treatment groups receiving droperidol IM at doses of 2.75 mg (87%), 5.5 mg (81%), and 8.25 mg (85%) compared with placebo (57%).	Effectiveness seen but multitude of side-effects
			pain free at 2hrs	greater than placebo for the droperidol 2.75-mg, 5.5-mg, and 8.25-mg dose groups
			Frequency of recurrence (24hrs)	lower in droperidol group but non-significant
			side-effects	droperidol 2.75 mg group reported the elimination of migraine-associated symptoms (nausea, vomiting, photophobia, and phonophobia) than those who received placebo, 30% severe symptoms of akathisia, no QT prolongation
Richman 2002 USA	29 patients randomized to receive either 2.5 mg droperidol (15)intramuscularly; the other group received 1.5 mg/kg meperidine(14) intramuscularly	Randomized, double blind clinical trial	mean initial VAS score	88 v 76 mm; P =.03	small study, non-significant difference with opioids, high incidence of side-effects
			mean change in VAS score and Likert	VAS score (47 v 37 mm; P =.33), average Likert score (1.1 v 1.9; P =.85)
			Declining rescue medications	67% v 57%; P =.61
			Sedation	6.7 v 14.3%
			Side-effects	Akathisia in 13.3% in droperidol group
Miner 2001 USA	168 pts out of which Eighty-two (48.8%) of the patients received droperidol; 86 (51.2%) received prochlorperazine. In the droperidol group, 49 (59.6%) received IM administration and 33 (40.4%) IV. In the prochlorperazine group, 57 (66.3%) received IM administration and 29 (33.7%) IV	Prospective, randomized clinical trial	60 mins after medication VAS score	mean decrease in the VAS scores was 81.4% for droperidol and 66.9% for prochlorperazine (p = 0.001)	well-conducted study, incidence of side-effects high
			At 30 mins pain score	60.9% of the patients receiving droperidol and 44.2% of the patients receiving prochlorperazine had obtained at least a 50% reduction in their VAS scores (p = 0.09)
			60 mins pain score	90.2% of the patients receiving droperidol and 68.6% of the patients receiving prochlorperazine had at least a 50% reduction in their VAS scores (p = 0.017)
			Side-effects	dystonia, akathisia, and decreased level of consciousness, were seen in 15.2% of the patients receiving droperidol and 9.61% of the patients receiving prochlorperazine
Richman 1999 USA	37 patients with a discharge diagnosis of migraine headache who were treated with i.m. droperidol during a consecutive 5-month period	retrospective case series	30 mins after droperidol use	30 (81%) patients had symptomatic relief, 2 (5%) felt partial relief but required rescue medication, and 5 (14%) had no relief of symptoms	small case series, side effects
			Side-effects	Drowsiness (14%) and mild akathisia (8%)
Wang 1997 Taiwan	35 patients (32 women and 3 men; mean age 43 years) with status migrainosus (n = 25) or refractory migraine (n = 10) in an ambulatory infusion center. Droperidol (2.5 mg) was given intravenously every 30 minutes until either three doses were given or the patient was completely or almost headache-free prior to the next dose. Seven patients received one dose, 12 received two doses, and 16, three doses (mean 5.6 mg).	Pilot study	Headache relief	88% (22 of 25) in patients with status migrainosus and 100% (10 of 10) in patients with refractory migraine	Pilot study, small number, side-effects
			Time to improvement	40 minutes (n = 35), to mild headache--60 minutes (n = 32), and to headache-free--105 minutes (n = 28).
			Side-effects	Four patients had an asymptomatic systolic blood pressure drop > or = 20 mm Hg. Most patients were sedated (34 of 35). Five patients developed akathisia and 1 dystonia
			Relapse at 24	23% in status migrainosus and 10% in refractory migraine.

Comment(s)

Haloperidol use was first reported in a few cases by Fischer in 1995 in cases with migraine headache and was found to be effective. Droperidol which belongs to the same pharmacological group(butyrophenones) was assessed subsequently as well. Both did show benefit in reduction of headache intensity in the studies reported above but were plagued by occurrence of neurological side-effects. In 2001 FDA issued a black-box warning on use of droperidol due to its cardiac side-effect of causing QT prolongation, Torades and sudden cardiac death.Since then, droperidol fell out of favour considerably while Haloperidol has been used with variable degree of success. Recently, the US FDA also advised a new Cardiovascular subsection regarding cases of sudden death, QT prolongation and Torsades de Pointes(TdP) in patients treated with haloperidol, especially when given intravenously, or at doses higher than recommended. Although injectable haloperidol is only approved for intramuscular injection, there is considerable evidence that the intravenous administration of haloperidol is a relatively common off-label clinical practice. In another study from the Mayo Clinic in Oct 2007, Nuttall et al reviewed the use of droperidol in Post-operative nausea and vomiting surgical patients in a large sample before and after the FDA warning. They concluded that the warning on use of low-dose droperidol was excessive and unnecessary. In light of the new reports and previous warnings, it would be prudent to say that although haloperidol and droperidol have shown benefits in reducing migraine intensity and anti-emesis, the side-effect profile of the medications may influence our choice and force us to exercise restraint. Other drugs with better risk-benefit profile should be considered first in acute migraine.

Clinical Bottom Line

Haloperidol and Droperidol maybe considered as a 'trade-off between benefits and harms' and ,therefore, caution exercised when contemplating its use in acute migraine

References

1. Honkaniemi J. Liimatainen S. Rainesalo S. Sulavuori S. Haloperidol in the acute treatment of migraine: a randomized, double-blind, placebo-controlled study Headache 46(5):781-7, 2006 May
2. Monzillo PH. Nemoto PH. Costa AR. Sanvito WL. [Acute treatment of migraine in emergency room: comparative study between dexametasone and haloperidol. Preliminary results Arquivos de Neuro-Psiquiatria. 62(2B):513-8, 2004 Jun.
3. Weaver CS. Jones JB. Chisholm CD. Foley MJ. Giles BK. Somerville GG. Brizendine EJ. Cordell WH. Droperidol vs prochlorperazine for the treatment of acute headache. Journal of Emergency Medicine 26(2):145-50, 2004 Feb
4. Silberstein SD. Young WB. Mendizabal JE. Rothrock JF. Alam AS. Acute migraine treatment with droperidol: A randomized, double-blind, placebo-controlled trial Neurology. 60(2):315-21, 2003 Jan 28
5. Richman PB. Allegra J. Eskin B. Doran J. Reischel U. Kaiafas C. Nashed AH. A randomized clinical trial to assess the efficacy of intramuscular droperidol for the treatment of acute migraine headache. American Journal of Emergency Medicine. 20(1):39-42, 2002 Jan.
6. Miner JR. Fish SJ. Smith SW. Biros MH. Droperidol vs. prochlorperazine for benign headaches in the emergency department Academic Emergency Medicine. 8(9):873-9, 2001 Sep.
7. Richman PB. Reischel U. Ostrow A. Irving C. Ritter A. Allegra J. Eskin B. Szucs P. Nashed AH. Droperidol for acute migraine headache American Journal of Emergency Medicine 17(4):398-400, 1999 Jul
8. Wang SJ. Silberstein SD. Young WB. Droperidol treatment of status migrainosus and refractory migraine. Headache. 37(6):377-82, 1997 Jun.