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Evidence-Based Reviews

Antipsychotics for migraines, cluster headaches, and nausea

Evidence of efficacy for these conditions is limited, and risk of side effects may inhibit use

Vol. 12, No. 02 / February 2013

Most evidence supporting antipsychotics as a treatment for migraine headaches and cluster headaches is based on small studies and chart reviews. Some research suggests antipsychotics may effectively treat nausea but side effects such as akathisia may limit their use.

Migraine headaches

Antipsychotic treatment of migraines is supported by the theory that dopaminergic hyperactivity leads to migraine headaches (Table 1). Antipsychotics have been used off-label in migraine patients who do not tolerate triptans or have status migrainosus—intense, debilitating migraine lasting >72 hours.1 Primarily a result of D2 receptor blockade, the serotonergic effects of some second-generation antipsychotics (SGAs) may prevent migraine recurrence. The first-generation antipsychotics (FGAs) prochlorperazine, droperidol, haloperidol, and chlorpromazine have been used for migraine headaches (Table 2).1-27

Prochlorperazine may be an effective treatment of acute headaches9 and refractory chronic daily headache.10 Studies show that buccal prochlorperazine is more effective than oral ergotamine tartrate11 and IV prochlorperazine is more effective than IV ketorolac12 or valproate28 for treating acute headache.

Evidence suggests that chlorpromazine administered IM2 or IV3 is better than placebo for managing migraine pain. In a study comparing IV chlorpromazine, lidocaine, and dihydroergotamine, patients treated with chlorpromazine showed more persistent headache relief 12 to 24 hours post-dose.4 In another study, IV chlorpromazine, 25 mg, was as effective as IM ketorolac, 60 mg.5

Droperidol has been shown to be effective for managing headache, specifically status migrainosus.6 Patients with “benign headache”—headache not caused by an underlying medical disorder—who received droperidol reported greater reduction in visual analog pain scores within 1 hour of dosing compared with those taking prochlorperazine.7 In a randomized trial comparing IM droperidol and IM meperidine, patients with an acute migraine who received droperidol had improved scores on the visual pain analog scale and required less “rescue medication” for breakthrough pain.8 The FDA has issued a “black-box” warning of QTc prolongation with droperidol.

In a double blind, placebo-controlled trial, IV haloperidol, 5 mg, effectively treated migraine headache in 80% of patients compared with 15% of those who received placebo. However, 16% of patients considered the side effects—mainly sedation and akathisia—intolerable and 7% had symptom relapse.13 In an open-label trial of 6 patients with migraine headache, all patients achieved complete or substantial headache relief 25 to 65 minutes after receiving IV haloperidol, 5 mg.14

SGAs often antagonize 5-HT1D receptors and theoretically can render triptan therapy—which stimulates pre-synaptic 5-HT1D receptors—ineffective. This has not been seen clinically and instead, dose-related, non-specific headaches are a common adverse event with SGAs.29,30 A retrospective chart review found olanzapine provided relief for refractory headaches in patients who had failed ≥4 preventive medications. Olanzapine significantly decreased headache days, from 27.5±4.9 before treatment to 21.1±10.7 after treatment. Olanzapine also improved headache severity (measured on a 0 to 10 scale) from 8.7±1.6 before treatment to 2.2±2.1 after treatment.16 Researchers found that 2.5 or 5 mg of olanzapine relieved acute migraines for most patients, with repeat dosing as needed up to 20 mg/d. For prophylactic treatment, 5 or 10 mg of olanzapine was used. Olanzapine’s antinociceptive effect may be related to its action on α-2 adrenoreceptors and to a lesser extent on involvement of opioid and serotonergic receptors.17

In a case series, 3 migraine patients who met criteria for chronic daily headache and migraines but did not have a psychiatric disorder reported significant and sustained headache improvement when treated with risperidone.19 In a case series of 3 migraine patients with co-occurring psychiatric disorders, aripiprazole decreased migraine frequency and severity.15 Although limited data support quetiapine’s efficacy in treating acute migraines, in an open-label, pilot study, patients taking quetiapine, 25 to 75 mg/d, demonstrated a decrease in mean frequency of migraine days from 10.2 to 6.2 and decreased use of rescue medications from 2.3 to 1.2 days per week.18

Table 1

Possible rationale for antipsychotic use for headaches and nausea


Possible rationale


Patients are hypersensitive to dopamine agonists or dopamine transporter dysfunction. Some evidence that the dopamine D2 (DRD2) gene is involved

Cluster headache

Pain alleviation possibly related to dopamine receptor antagonism


D2 and H1 receptor blockage

Table 2

Antipsychotics for headache and nausea: Strength of the evidence


Strength of evidencea


Intermediate: Chlorpromazine,2-5 droperidol,6-8 prochlorperazine1,10-12

Weak: Haloperidol13,14

Very weak: Aripiprazole,15 olanzapine,16,17 quetiapine,18 ziprasidone19

Cluster headache

Weak: Chlorpromazine20

Very weak: Clozapine,21 olanzapine22


Intermediate: Droperidol,23 metoclopramide,24 prochlorperazine,25 promethazine25

Weak: Olanzapine26,27

aStrong: Multiple, well-designed RCTs directly relevant to the recommendation, yielding consistent findings
Intermediate: Some evidence from RCTs that support the recommendation, but the scientific support was not optimal
Weak: Consensus recommendation in the absence of relevant randomized controlled trials and better evidence than case report or series
Very weak: Case reports or case series or preliminary studies RCTs: randomized controlled trials

Cluster headaches

Subcutaneous sumatriptan and inhaled oxygen are first-line treatments for cluster headaches.31 A single, small study20 reported that chlorpromazine may prevent cluster headaches, which suggests that D2 receptor blockade may treat such headaches. However, limited supporting evidence relegates its use to a second- or third-line therapy.

In an open-label study (N = 5), olanzapine provided some relief of pain associated with cluster headache within 20 minutes of administration.22 In another study, patients with schizophrenia and comorbid cluster headaches improved with olanzapine.21

Because evidence is limited to small prospective studies, antipsychotic treatment of cluster headache is not well established.20-22 However, olanzapine may benefit patients with comorbid cluster headaches and schizophrenia.


The signaling pathways that mediate emesis involve 5-HT3, D2, muscarinic, and histamine receptors.32 Before 5-HT3 antagonists were available, the FGAs metoclopramide, droperidol, prochlorperazine, and promethazine were used to manage acute emesis in emergency departments.23 A double-blind, placebo-controlled trial found IV droperidol, 1.25 mg, was more effective than metoclopramide, 10 mg, or prochlorperazine, 10 mg, for relieving moderate to severe nausea in adult patients.23 However, droperidol and prochlorperazine were associated with akathisia. In addition, this trial did not find a clinically significant difference between groups—including placebo—in anxiety, sedation, or need for rescue medications.23 Use of droperidol to treat nausea decreased after the drug received a “black-box” warning for QT prolongation and torsades de pointes.

Metoclopramide is effective for treating acute migraine and associated nausea24 and has been used to treat gastroparesis because of its effect on upper GI motility. Phenothiazines have been used to treat nausea and studies have shown prochlorperazine to be more effective than promethazine.25 Some studies of prochlorperazine have reported a 44% incidence of akathisia, which limits the drug’s use in patients who may be sensitive to such effects.33 Promethazine can cause sedation and risk of tissue necrosis at the injection site.34

Among SGAs, olanzapine effectively prevented acute and delayed chemotherapy-induced nausea and vomiting in a proof-of-concept study of patients receiving high and moderate emetogenic therapies.26,27 National Comprehensive Cancer Network guidelines cite olanzapine as a potential option for treating refractory and breakthrough emesis.35 In a small study (N = 50), olanzapine showed comparable anti-nausea effect to aprepitant—a neurokinin 1 receptor antagonist—and effectively prevented chemotherapy-induced nausea and vomiting in highly emetogenic chemotherapy.36

Related Resources

  • Kelley NE, Tepper DE. Rescue therapy for acute migraine, part 2: neuroleptics, antihistamines, and others. Headache. 2012;52(2):292-306.
  • Dusitanond P, Young WB. Neuroleptics and migraine. Cent Nerv Syst Agents Med Chem. 2009;9(1):63-70.

Drug Brand Names

  • Aprepitant • Emend
  • Aripiprazole • Abilify
  • Chlorpromazine • Thorazine
  • Dihydroergotamine • D.H.E 45
  • Droperidol • Inapsine
  • Ergotamine tartrate • Ergostat
  • Haloperidol • Haldol
  • Ketorolac • Toradol
  • Lidocaine • Xylocaine, Lidoderm
  • Meperidine • Demerol
  • Metoclopramide • Reglan
  • Olanzapine • Zyprexa
  • Prochlorperazine • Compazine
  • Promethazine • Phenergan
  • Quetiapine • Seroquel
  • Risperidone • Risperdal
  • Sumatriptan • Imitrex
  • Valproate • Depakote


Dr. Macaluso has received grant or research support from EnVivo Pharmaceuticals, Janssen L.P., and Pfizer, Inc.

Dr. Tripathi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.


1. Dusitanond P, Young WB. Neuroleptics and migraine. Cent Nerv Syst Agents Med Chem. 2009;9(1):63-70.

2. McEwen JI, O’Connor HM, Dinsdale HB. Treatment of migraine with intramuscular chlorpromazine. Ann Emerg Med. 1987;16(7):758-763.

3. Bigal M, Bordini CA, Speciali JG. Intravenous chlorpromazine in the emergency department treatment of migraines: a randomized controlled trial. J Emerg Med. 2002;23(2):141-148.

4. Bell R, Montoya D, Shuaib A, et al. A comparative trial of three agents in the treatment of acute migraine headache. Ann Emerg Med. 1990;19(10):1079-1082.

5. Shrestha M, Singh R, Moreden J, et al. Ketorolac vs chlorpromazine in the treatment of acute migraine without aura. A prospective, randomized, double-blind trial. Arch Intern Med. 1996;156(15):1725-1728.

6. Wang SJ, Silberstein SD, Young WB. Droperidol treatment of status migrainosus and refractory migraine. Headache. 1997;37(6):377-382.

7. Miner JR, Fish SJ, Smith SW, et al. Droperidol vs. prochlorperazine for benign headaches in the emergency department. Acad Emerg Med. 2001;8(9):873-879.

8. Richman PB, Allegra J, Eskin B, et al. A randomized clinical trial to assess the efficacy of intramuscular droperidol for the treatment of acute migraine headache. Am J Emerg Med. 2002;20(1):39-42.

9. Jones J, Sklar D, Dougherty J, et al. Randomized double blind trial of intravenous prochlorperazine for the treatment of acute headache. JAMA. 1989;261(8):1174-1176.

10. Lu SR, Fuh JL, Juang KD, et al. Repetitive intravenous prochlorperazine treatment of patients with refractory chronic daily headache. Headache. 2000;40(9):724-729.

11. Sharma S, Prasad A, Nehru R, et al. Efficacy and tolerability of prochlorperazine buccal tablets in treatment of acute migraine. Headache. 2002;42(9):896-902.

12. Seim MB, March JA, Dunn KA. Intravenous ketorolac vs intravenous prochlorperazine for the treatment of migraine headaches. Acad Emerg Med. 1998;5(6):573-576.

13. Honkaniemi J, Liimatainen S, Rainesalo S, et al. Haloperidol in the acute treatment of migraine: a randomized, double-blind, placebo-controlled study. Headache. 2006;46(5):781-787.

14. Fisher H. A new approach to emergency department therapy of migraine headache with intravenous haloperidol: a case series. J Emerg Med. 1995;13(1):119-122.

15. LaPorta LD. Relief from migraine headache with aripiprazole treatment. Headache. 2007;47(6):922-926.

16. Silberstein SD, Peres MF, Hopkins MM, et al. Olanzapine in the treatment of refractory migraine and chronic daily headache. Headache. 2002;42(6):515-518.

17. Schreiber S, Getslev V, Backer MM, et al. The atypical neuroleptics clozapine and olanzapine differ regarding their antinociceptive mechanisms and potency. Pharmacol Biochem Behav. 1999;64(1):75-80.

18. Krymchantowski AV, Jevoux C. Quetiapine for the prevention of migraine refractory to the combination of atenolol + nortriptyline + flunarizine: an open pilot study. Arq Neuropsiquiatr. 2008;66(3B):615-618.

19. Cahill CM, Hardiman O, Murphy KC. Treatment of refractory chronic daily headache with the atypical antipsychotic ziprasidone-a case series. Cephalalgia. 2005;25(10):822-826.

20. Caviness VS, Jr, O’Brien P. Cluster headache: response to chlorpromazine. Headache. 1980;20(3):128-131.

21. Datta SS, Kumar S. Clozapine-responsive cluster headache. Neurol India. 2006;54(2):200-201.

22. Rozen TD. Olanzapine as an abortive agent for cluster headache. Headache. 2001;41(8):813-816.

23. Braude D, Soliz T, Crandall C, et al. Antiemetics in the ED: a randomized controlled trial comparing 3 common agents. Am J Emerg Med. 2006;24(2):177-182.

24. Colman I, Brown MD, Innes GD, et al. Parenteral metoclopramide for acute migraine: meta-analysis of randomised controlled trials. BMJ. 2004;329(7479):1369-1373.

25. Ernst AA, Weiss SJ, Park S, et al. Prochlorperazine versus promethazine for uncomplicated nausea and vomiting in the emergency department: a randomized, double-blind clinical trial. Ann Emerg Med. 2000;36(2):89-94.

26. Navari RM, Einhorn LH, Loehrer PJ Sr, et al. A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study. Support Care Cancer. 2007;15(11):1285-1291.

27. Passik SD, Navari RM, Jung SH, et al. A phase I trial of olanzapine (Zyprexa) for the prevention of delayed emesis in cancer patients: a Hoosier Oncology Group study. Cancer Invest. 2004;22(3):383-388.

28. Tanen DA, Miller S, French T, et al. Intravenous sodium valproate versus prochlorperazine for the emergency department treatment of acute migraine headaches: a prospective, randomized, double-blind trial. Ann Emerg Med. 2003;41(6):847-853.

29. Caley CF, Cooper CK. Ziprasidone: the fifth atypical antipsychotic. Ann Pharmacother. 2002;36(5):839-851.

30. Geodon [package insert]. New York NY. Pfizer Inc.; 2012.

31. Kudrow L. Response of cluster headache attacks to oxygen inhalation. Headache. 1981;21(1):1-4.

32. Scuderi PE. Pharmacology of antiemetics. Int Anesthesiol Clin. 2003;41(4):41-66.

33. Drotts DL, Vinson DR. Prochlorperazine induces akathisia in emergency patients. Ann Emerg Med. 1999;34(4):469-475.

34. Institute for Safe Medication Practices. Action needed to prevent serious tissue injury with IV promethazine. Published August 10 2006. Accessed November 28, 2012.

35. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. 2010. Accessed November 29 2012.

36. Navari R, Gray SE, Carr AC. Olanzapine versus aprepitant for the prevention of chemotherapy induced nausea and vomiting (CINV): a randomized phase III trial. J Clin Oncol. 2010;28(15 suppl):9020.-

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