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Three Part Question

In [patients with migraine headache] is [chlorpromazine as effective as standard treatments] at [resolving pain]

Clinical Scenario

A 38 year old female with a history of regular migraine headache since her teenage years presents to your Emergency Department with a classic history of migraine symptoms. She has tried simple over the counter analgesia, as well as her prescription medication, a triptan, with no effect. You have heard of Chlorpromazine being used in the abolition of migraine attacks, but are unsure of its relative efficacy compared to other standard treatments.

Search Strategy

Medline OVID interface. 1966–30th Jan 2007
Cochrane Database of Systematic Reviews. 4th Quarter 2006
Cochrane Central Register of Controlled Trials. 1st Quarter 2007-01-31
CINAHL. 1982- December Week 2 2006
ACP Journal Club. 1991-January/February 2007
EMBASE. 1966-30th Jan 2007-01-31
[phenothiazines OR chlorpromazine] AND [migraine OR vascular headache]
LIMIT to English Language and Human

Search Outcome

A total 81 papers were found in Medline, of which eight are directly relevant to the question. No further papers were obtained by searching Cochrane, CINAHL, EMbase or ACPJC

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Iserson KV 1983 USA	100 patients with symptoms and signs from predefined "Vascular Cephalgia" presenting to an ED 1mg/kg IM Chlorpromazine (Max 100mg) to all patients	Non Blinded Non Randomised Uncontrolled Trial	Complete resolution of headache, nausea and vomiting	96 Patients (96%)	Non blinded Open label study Exact number of exclusions unclear
			Mean time to symptom relief	35mins (Range 20-55mins)
			Headache recurrence within 48hrs	4 patients (4%)
			Symptomatic orthostatic hypotension	11 patients (11%)
McEwen et al 1987 Canada	36 patients under 60 years meeting proprietary migraine definition criteria presenting to an ED 1mg/kg IM Chlorpromazine vs. Placebo	Double blinded randomised controlled trial	Proprietary scale of symptomatic relief		Straw Man Comparison Subsequently indulges in post hoc analysis
			Not improved enough to return to activities of daily living	10 patients 953%) Chlorpromazine vs 13 patients (76%) placebo. p=0.187
			Improved enough to return to activities of daily living	9 patients (47%) Chlorpromazine vs 4 patients (24%) placebo. p=0.187
			At least some improvement in Headache	16 Patients (84%) Chlorpromazine vs 6 Patients (35%) Placebo p=0.004
			Improvement in Nausea	15 Patients (88%) Chlorpromazine vs 4 Patients (29%) Placebo p<0.001
			Side Effects
			Drowsiness	15 Patients (88%) p=0.009
			Asymptomatic Postural Hypotension	10 Patients (53%) p=0.032
Lane PL et al 1989 Canada	46 Patients diagnosed by ED physician with common or classic migraine 25mg IV Chlorpromazine and 10ml Normal Saline plus up to 2 repeat doses of 0.1mg/kg IV Chlorpromazine vs. 100mg Pethidine and 50mg dimenhydrinate plus up to 2 repeat doses of 0.4mg/kg Pethidine Other study drug used for rescue analgesia if treatment failure at 45 mins	Double blind Randomised Comparison Trial	Mean decrease in 10cm Visual Analogue Pain Score	-7.06 (SD 2.18) Chlorpromazine vs -4.45 (SD 2.62) Pethidine/Dimehydrinate p<0.001	Relatively small sample size
			Requirement for rescue analgesia	2 Patients (8%) Chlorpromazine group vs 10 Patients (45%) Pethidine/Dinmehydrinate group p<0.01
Bell et al 1990 Canada	76 adult patients under 60 years meeting proprietory migraine definition criteria presenting to 2 ED's IV Dihydroergotamine 1mg repeated if necessary at 30mins vs IV Lignocaine 50mg at 20 min intervals (max 3 times) vs IV Chlorpromazine 12.5 mg at 20 min intervals (max 3 doses) All patients pretreated with 500ml IV Normal Saline	Single Blinded Randomised Comparison Trial	Reduction in median headache intensity (Verbal 1-10 scale)	2.75 (36.7%) Dihydroergotamine vs 4.00 (50%) Lignocaine vs 6.75 (79.5%) Chlorpromazine p<0.005	Single blinded study
			Persistent relief at 24 hr telephone follow up	10 Patients (52.6%) Dihydroergotamine vs 5 Patients (29.4%) Lignocaine vs 16 Pateints (88.9%) Chlorpromazine
Cameron JD et al 1994 Canada	91 adult patients under age 60 yrs diagnosed with migraine headache by ED Physician 0.1mg/kg IV Chlorpromazine vs 0.1mg.kg IV Metoclopramide, both to max. 3 doses 5ml/kg IV Normal Saline to all patients	Double Blinded Randomised Comparison Trial	Mean change in 10cm Visual Analogue Score at discharge	4.87 +/- 2.46 Chlorpromazine vs 4.34 +/- 2.85 p=0.35	2 protocol violations in a non intention to treat study No formal entry criteria, simply clinical diagnosis of migraine
			Treatment Failure requiring second drug	9 (19%) Chlorpromazine vs 11 (25%) Metoclopramide p=0.50
			Recurrence within 48hrs at telephone follow up	21 (66%) Chlorpromazine vs 16 (55%) Metoclopramide p=0.28
Shrestha et al 1996 USA	30 adult patients under 65 years attending ED with headache meeting International Headache Association Criteria for Migraine without aura 25mg IV Chlorpromazine vs 60mg IM Ketorolac 500ml IV Normal Saline for every patient	Double Blinded Randomised Comparison Trial	Mean (+/- SEM) Pain Score (Pictographic 0-5 Scale) decrease at 2 hrs	3.6 +/- 0.4 (79% +/- 9%) Chlorpromazine vs 3.33 +/-0.3 (80% +/- 7%) Ketorolac p=0.36	Patients already taking NSAID not excluded
Kelly A-M et al 1997 Australia	43 adult patients under 65 years, features typical of migraine headache, past history of migraine and no impairment of conscious level 12.5mg IV Chlorpromazine increments to max 37.5mg vs 6mg IM Sumatriptan All patients pretreated with 10mg IV Metoclopramide and 1000ml IV Normal Saline Patient crossover at 2 hrs if Visual Analogue pain score still >3	Prospective randomised unblinded crossover trial	Percentage pain free at 1 hour	4 (18%) Chlorpromazine vs 2 (10%) Sumatriptan
			Percentage pain free at 2 hours	9 (41%) Chlorpromazine vs 8 (42%) Sumatriptan
			Percentage with relief of pain to patient's satisfaction	22 (95%) Chlorpromazine vs 19 (95%) Sumatriptan
			Mild adverse events reported	3 (13%) Chlorpromazine vs 3 (15%) Sumatriptan
Bigal ME et al 2002 Brazil	68 adult patients diagnosed by International Headache Society criteria for Migraine with aura or Migraine without aura presenting to 2 ED's	Double blind Randomised Placebo Controlled Trial	Migraine without Aura		Straw man comparison Double blinding fatally flawed Postural hypotension undefined
			Absence of pain at 30 minutes	8 (21.1%) Chlorpromazine vs 1 (3.3%) placebo. P<0.01
			Absence of pain at 60 minutes	24 (63.2%) Chlorpromazine vs 3 (10%) placebo. P<0.01
			Absence of pain at 24 hours	28 (73.7%) Chlorpromazine vs 14 (46.7%) placebo. P<0.01
			Migraine with Aura
			Absence of pain at 30 minutes	11 (36.7%) Chlorpromazine vs 0 (0%) placebo. P<0.01
			Absence of pain at 60 minutes	20 (66.7%) Chlorpromazine vs 2 (6.7%) placebo. P<0.01
			Absence of pain at 24 hours	27 (90%) Chlorpromazine vs 22 (73.3%) placebo. P<0.05
			Adverse events
			Nausea	1 (1.4%) Chlorpromazine vs 10 (16.7%) placebo. P<0.05
			Postural hypotension	9 (13.2%) Chlorpromazine vs 1 (1.6%) placebo. P<0.05
			Drowsiness	24 (35.2%) Chlorpromazine vs 10 (16.7%) placebo. P<0.05
			Dyspepsia	1 (1.4%) Chlorpromazine vs 10 (16.7%) placebo. P<0.05

Comment(s)

Fear of significant side effects from chlorpromazine appear to be unfounded. There was no incidence of symptomatic postural hypotension in studies which patients received prophylatic intravenous normal saline prior to chlorpromazine administration, and no dystonic reactions were reported in any study. Drowsiness is, however, frequently reported. Chlorpromazine also seems to be efficacious whether given via the intramuscular or intravenous route.

Clinical Bottom Line

A regime of prophylactic intravenous normal saline and intramuscular or intravenous chlorpromazine appears to have superior efficacy to pethidine, lignocaine or ergot derivatives, and similar efficacy to ketorolac, metoclopramide or sumatriptan for the abolition of migraine headache.

References

1. Iserson KV Parenteral chlorpromazine treatment of migraine Annals of Emergency Medicine 12(12):756-8, 1983 Dec
2. McEwen JI. O'Connor HM. Dinsdale HB. Treatment of migraine with intramuscular chlorpromazine. Annals of Emergency Medicine 16(7):758-63, 1987 Jul
3. Lane PL. McLellan BA. Baggoley CJ Comparative efficacy of chlorpromazine and meperidine with dimenhydrinate in migraine headache Annals of Emergency Medicine 18(4):360-5, 1989 Apr
4. Bell R. Montoya D. Shuaib A. Lee MA A comparative trial of three agents in the treatment of acute migraine headache Annals of Emergency Medicine 19(10):1079-82, 1990 Oct
5. Cameron JD. Lane PL. Speechley M Intravenous chlorpromazine vs intravenous metoclopramide in acute migraine headache Academic Emergency Medicine 2(7):597-602, 1995 Jul
6. Shrestha M. Singh R. Moreden J. Hayes JE Ketorolac vs chlorpromazine in the treatment of acute migraine without aura. A prospective, randomized, double-blind trial. Archives of Internal Medicine 156(15):1725-8, 1996 Aug 12-26
7. Kelly AM. Ardagh M. Curry C. D'Antonio J. Zebic S Intravenous chlorpromazine versus intramuscular sumatriptan for acute migraine Journal of Accident & Emergency Medicine 14(4):209-11, 1997 Jul
8. Bigal ME. Bordini CA. Speciali JG Intravenous chlorpromazine in the emergency department treatment of migraines: a randomized controlled trial Journal of Emergency Medicine 23(2):141-8, 2002 Aug.