Web extra Antipsychotics for migraines, cluster headaches, and nausea Evidence of efficacy for these conditions is limited, and risk of side effects may inhibit use ost evidence supporting antipsychotics as a treat- ment for migraine headaches and cluster head- Maches 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, page E2). Antipsychotics have been used off-label in migraine patients who do not tolerate triptans or have status migrainosus—intense, debilitating migraine JON KRAUSE FOR CURRENT PSYCHIATRY lasting >72 hours.1 Primarily a result of D2 receptor block- ade, the serotonergic effects of some second-generation anti- Aveekshit Tripathi, MD psychotics (SGAs) may prevent migraine recurrence. The Senior Resident Psychiatry and Behavioral Sciences first-generation antipsychotics (FGAs) prochlorperazine, droperidol, haloperidol, and chlorpromazine have been Matthew Macaluso, DO Assistant Professor, Psychiatry and Behavioral Sciences 1-27 used for migraine headaches (Table 2, page E3). Associate Director, Residency Training 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 University of Kansas School of Medicine-Wichita Wichita, KS 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 chlorproma- zine showed more persistent headache relief 12 to 24 hours post-dose.4 In another study, IV chlorpromazine, 25 mg, Current Psychiatry was as effective as IM ketorolac, 60 mg.5 Vol. 12, No. 2 E1 continued Table 1 Possible rationale for antipsychotic use for headaches and nausea Condition Possible rationale Migraine 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 Headache, nausea, Nausea D2 and H1 receptor blockage and antipsychotics Droperidol has been shown to be effec- headache severity (measured on a 0 to 10 tive for managing headache, specifically scale) from 8.7 ± 1.6 before treatment to 2.2 status migrainosus.6 Patients with “benign ± 2.1 after treatment.16 Researchers found headache”—headache not caused by an that 2.5 or 5 mg of olanzapine relieved underlying medical disorder—who re- acute migraines for most patients, with ceived droperidol reported greater reduc- repeat dosing as needed up to 20 mg/d. Clinical Point tion in visual analog pain scores within 1 For prophylactic treatment, 5 or 10 mg of Primarily a result hour of dosing compared with those tak- olanzapine was used. Olanzapine’s anti- ing prochlorperazine.7 In a randomized nociceptive effect may be related to its ac- of D2 receptor trial comparing IM droperidol and IM me- tion on α-2 adrenoreceptors and to a lesser blockade, the peridine, patients with an acute migraine extent on involvement of opioid and sero- serotonergic effects who received droperidol had improved tonergic receptors.17 of some SGAs may scores on the visual pain analog scale In a case series, 3 migraine patients who and required less “rescue medication” for met criteria for chronic daily headache and prevent migraine breakthrough pain.8 The FDA has issued a migraines but did not have a psychiatric recurrence “black-box” warning of QTc prolongation disorder reported significant and sustained with droperidol. headache improvement when treated with In a double blind, placebo-controlled risperidone.19 In a case series of 3 migraine trial, IV haloperidol, 5 mg, effectively patients with co-occurring psychiatric dis- treated migraine headache in 80% of pa- orders, aripiprazole decreased migraine tients compared with 15% of those who re- frequency and severity.15 Although limited ceived placebo. However, 16% of patients data support quetiapine’s efficacy in treat- considered the side effects—mainly seda- ing acute migraines, in an open-label, pilot tion and akathisia—intolerable and 7% study, patients taking quetiapine, 25 to 75 had symptom relapse.13 In an open-label mg/d, demonstrated a decrease in mean trial of 6 patients with migraine headache, frequency of migraine days from 10.2 to all patients achieved complete or substan- 6.2 and decreased use of rescue medica- tial headache relief 25 to 65 minutes after tions from 2.3 to 1.2 days per week.18 receiving IV haloperidol, 5 mg.14 SGAs often antagonize 5-HT1D recep- tors and theoretically can render triptan Cluster headaches therapy—which stimulates pre-synaptic Subcutaneous sumatriptan and inhaled 5-HT1D receptors—ineffective. This has oxygen are first-line treatments for clus- not been seen clinically and instead, ter headaches.31 A single, small study20 dose-related, non-specific headaches are reported that chlorpromazine may pre- a common adverse event with SGAs.29,30 vent cluster headaches, which suggests A retrospective chart review found olan- that D2 receptor blockade may treat such zapine provided relief for refractory headaches. However, limited supporting headaches in patients who had failed ≥4 evidence relegates its use to a second- or preventive medications. Olanzapine sig- third-line therapy. nificantly decreased headache days, from In an open-label study (N = 5), olanzap- 27.5 ± 4.9 before treatment to 21.1 ± 10.7 ine provided some relief of pain associated Current Psychiatry E2 February 2013 after treatment. Olanzapine also improved with cluster headache within 20 minutes of Table 2 Antipsychotics for headache and nausea: Strength of the evidence Condition Strength of evidencea Migraine 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 Nausea/vomiting 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 Clinical Point A small study reports that chlorpromazine administration.22 In another study, patients Metoclopramide is effective for treat- may prevent cluster with schizophrenia and comorbid cluster ing acute migraine and associated nausea24 headaches, which headaches improved with olanzapine.21 and has been used to treat gastroparesis suggests D2 receptor Because evidence is limited to small because of its effect on upper GI motil- blockade may treat prospective studies, antipsychotic treat- ity. Phenothiazines have been used to treat ment of cluster headache is not well es- nausea and studies have shown prochlor- such headaches tablished.20-22 However, olanzapine may perazine to be more effective than prometh- benefit patients with comorbid cluster azine.25 Some studies of prochlorperazine headaches and schizophrenia. have reported a 44% incidence of akathi- sia, which limits the drug’s use in patients who may be sensitive to such effects.33 Nausea Promethazine can cause sedation and risk The signaling pathways that mediate em- of tissue necrosis at the injection site.34 esis involve 5-HT3, D2, muscarinic, and Among SGAs, olanzapine effectively pre- histamine receptors.32 Before 5-HT3 an- vented acute and delayed chemotherapy- tagonists were available, the FGAs meto- induced nausea and vomiting in a proof- clopramide, droperidol, prochlorperazine, of-concept study of patients receiving high and promethazine were used to manage and moderate emetogenic therapies.26,27 acute emesis in emergency departments.23 National Comprehensive Cancer Network A double-blind, placebo-controlled trial guidelines cite olanzapine as a potential found IV droperidol, 1.25 mg, was more option for treating refractory and break- effective than metoclopramide, 10 mg, through emesis.35 In a small study (N = or prochlorperazine, 10 mg, for relieving 50), olanzapine showed comparable anti- moderate to severe nausea in adult pa- nausea effect to aprepitant—a neurokinin tients.23 However, droperidol and prochlor- 1 receptor antagonist—and effectively perazine were associated with akathisia. In prevented chemotherapy-induced nau- addition, this trial did not find a clinically sea and vomiting in highly emetogenic significant difference between groups—in- chemotherapy.36 cluding placebo—in anxiety, sedation, or need for rescue medications.23 Use of dro- References 1. Dusitanond P, Young WB. Neuroleptics and migraine. Cent peridol to treat nausea decreased after the Nerv Syst Agents Med Chem. 2009;9(1):63-70. drug received a “black-box” warning for 2. McEwen JI, O’Connor HM, Dinsdale HB. Treatment of migraine with intramuscular