Objective.âTo assess the efficacy and safety of IV haloperidol in treatment of acute migraine headache in a double-blind, randomized, placebo-controlled study ...
Headache C 2006 by American Headache Society Published by Blackwell Publishing
ISSN 0017-8748 doi: 10.1111/j.1526-4610.2006.00438.x
Research Submission CME
Haloperidol in the Acute Treatment of Migraine: A Randomized, Double-Blind, Placebo-Controlled Study
Jari Honkaniemi, MD, PhD; Suvi Liimatainen, MD; Sirpa Rainesalo, MD, PhD; Sari Sulavuori, MD
Objective.—To assess the efficacy and safety of IV haloperidol in treatment of acute migraine headache in a double-blind, randomized, placebo-controlled study design. Background.—Neuroleptics are mainly used as antiemetics in acute migraine. In a previous open trial haloperidol was effective in relieving migraine pain. Design.—Patients were 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. If the patient felt no relief in pain intensity 1 to 3 hours after the infusion and had received placebo, he/she then received haloperidol infusion as an open trial. The open trial also included 7 patients who refused from the placebo-controlled trial. About 1 month after the infusion the patients were contacted by telephone and interviewed about the side effects of the treatment. Results.—Forty patients were enrolled into the double-blind, placebo-controlled study. Before the infusion the VAS values were 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). Significant pain relief was achieved in 80% of the patients treated with haloperidol, whereas only 3 patients (15%) responded to placebo (P < .0001). Seventeen patients treated with placebo without response together with 7 patients who refused from the placebo-controlled study participated in the open trial. In this group VAS declined from 6.7 to 2.4 and 79% of these patients felt significant pain relief. The most common side effects caused by haloperidol were sedation and akathisia, the latter being more troublesome. These effects were very common in patients participating in the double-blind (80%) and open (88%) trials. Sixteen percent of the patients considered the side effects intolerable and would not like the migraine attacks to be treated with haloperidol in the future. Three patients (7%) returned to the emergency ward because of a relapse. Conclusions.—This study shows that IV haloperidol is very effective in relieving migraine-associated pain. Because the majority of the patients had taken other medication without response, haloperidol appears to be an effective rescue medication even when other types of treatment have failed. Relapses are rare, but side effects are common, limiting the use of haloperidol in some patients. Key words: neuroleptic, dopamine, D2 receptor, haloperidol, hemicrania, headache (Headache 2006;46:781-787)
For CME, visit http://www.headachejournal.org From the Departments of Neurology, University of Tampere, and Tampere University Hospital, Tampere; and Vaasa Central Hospital, Vaasa, Finland. Address all correspondence to Dr. Jari Honkaniemi, University of Tampere, Department of Neurology, Biokatu 10, 33014, Tampere, Finland. Accepted for publication December 5, 2005.
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782 Migraine patients who have been taking maximal doses of regular analgetics and triptans without response are a common problem in neurology emergency wards. Usually these patients are treated with various combinations of analgetics and steroids, which may cause problems, such as gastrointestinal irritation, especially if the patients use NSAID-type analgetics frequently. Neuroleptics have traditionally been used to treat nausea and vomiting in acute migraine attack, but their effect appears to exceed those of classical antiemetics. The effect of neuroleptics on migraine is mediated via dopamine receptors. Dopamine receptors are divided into 2 main subclasses, the D1 group consisting of D1 and D5 receptors and the D2 group consisting of D2, D3, and D4 receptors. The D2 receptors have especially been associated with migraine. They are relatively abundant in the brainstem nuclei and sympathetic ganglia and nerves, through which they may regulate autonomic visceral, gastrointestinal, and hemodynamic responses frequently affected by migraine.1 The D1 receptors are located in the blood vessels including cerebral vessels in which they can induce vasodilatation and thereby contributing to the development of migraine headache. Thus, the anatomic distribution and the physiological role of the dopamine receptors provide an excellent theoretical background why dopamine blocking agents, such as neuroleptics, might be effective in relieving all the central symptoms of migraine. Haloperidol (chemical name 4-[4-(4-Chlorophenyl)-4-hydroxypiperidino]-4-fluorobutyrophenone) is a butyrophenone derivate, which elicits its effects mainly by blocking D2 dopamine receptor. It can bind to D1 dopamine, 5-HT2 serotonin, H1 histamine, and α2 adrenergic receptors in the brain.2 The anticholinergic and antihistamine effects are, however, clinically insignificant. Elimination half-time is variable, usually about 20 hours,3,4 but it may take up to 28 days to eliminate a single oral dose.2 About 90% of haloperidol is bound to plasma proteins. Haloperidol is metabolized via (i) oxidative dealkylation utilizing cytochrome P452D6,5 (ii) reduction of the ketone groups to form the active metabolite reduced haloperidol, and (iii) conjugation of haloperidol and reduced haloperidol forming inactive metabolites.6,7
May 2006 Thirty percent of haloperidol is secreted into urine and 20% into bile.8 The main side effects of haloperidol are sedation, prolonged QT-interval, and extrapyramidal effects. In its mildest form these include bradykinesia, akathisia, rigidity, and tremor.9-11 More severe extrapyramidal side effects such as tardive dyskinesia, opisthotonus, torticollis, dystonia of the jaw, neck, and mouth including buccolingual dyskinesia may also develop. These side effects have been observed especially during haloperidol intoxication. Usually these acute side effects develop rapidly, but several days’ delay may also occur.12-14 In a previous open trial haloperidol was effective in relieving migraine pain.13 The present work was conducted to study the efficacy and tolerability of IV haloperidol in the treatment of acute migraine headache.
MATERIALS AND METHODS The present study was conducted as a randomized, double-blind, placebo-controlled study in the Tampere University Hospital. Subjects were recruited between January 2002 and February 2005. This study was conducted in accordance with the guidelines of the Helsinki declaration and approved by the local ethical committee for clinical research. The subjects were sent to the acute care unit of Tampere University Hospital because of acute or prolonged migraine attack. Inclusion criteria were diagnosis of migraine as defined by the criteria of the International Headache Society Classification Committee for migraine.15 Exclusion criteria were long QT-interval, usage of drugs prolonging QT-interval, hepatic disease, epilepsy or history of seizures, hyperthyreosis, parkinsonism, chronic psychiatric disease, other neuroleptic medication, and intoxication. Once the patient was found to be eligible to the study and informed consent was obtained, the patients were randomized by envelope selection. The patients were randomized into 2 groups receiving intravenously either 5 mg haloperidol in 500 mL of normal saline or 500 mL of normal saline alone as a 20 to 30 minute infusion. The treatment was carried out by an attending nurse, who prepared and blinded the infusion.
Headache Pain was estimated by a visual analogue scale (VAS) before and between 1 hour and 3 hours after the infusion. If the patient felt no significant relief in pain intensity 1 hour to 3 hours after infusion, the code was broken. If the patient had been treated with haloperidol, he/she was classified as nonresponder and the study was terminated. If the patient had received placebo, he/she then received haloperidol infusion as an open trial and 1 hour to 3 hours after the infusion pain was assessed again. If an eligible patient refused from the double-blind, placebo-controlled trial, he/she was then asked to receive the haloperidol treatment as an open trial as described above. Primary outcome measures were pain intensity as assessed by VAS and total or almost total pain relief leading to discharge. The statistical significances were determined by Student’s t-test and chi-square test for independence. A sample size of 20 subjects in both treatment groups in the double-blind study setting was calculated to be sufficient to detect 3-point change in the VAS values assuming a standard deviation of 3.0, a power of 80% and significance level 5%. Drop-out rate was estimated to be about 25%. After a follow-up period of at least 1 month the patients were contacted by telephone and interviewed about the efficacy and side effects of the treatment.
RESULTS A total of 52 migraine patients were recruited into the study. Six cases were rejected: 1 of them did not fulfill the inclusion criteria, 2 were pain free before the infusion, 2 cases were included in the study twice, and 1 suffered from cluster headache. The average age of the remaining 47 patients was 36 years. Fortyone patients (85%) were women and 6 (13%) were men. Forty subjects participated in the double-blind, placebo-controlled study and 7 in the open trial. The mean duration of the headache period before hospitalization was 75 hours. Thirty-two patients (66%) had suffered from headache in less than 72 hours. The mean duration of the headache period for these patients was 27 hours. The average duration of the headache was 8 days for the remaining 13 patients (28%) who thus suffered from status migrainosus defined as headache lasting longer than 72 hours. Data were unavailable for 2 patients.
783 Almost all patients (43; 91%) had taken some kind of medication without response to their migraine attack prior to hospitalization: 27 (57%) had taken triptans, 24 (51%) NSAID-type analgetics, 13 (28%) paracetamol, 3 (6.4%) tramadol, 5 (11%) combination preparation containing NSAID and codeine, and 3 (6.4%) metoclopramide. About half of the patients (23; 49%) had tried more than 1 type of medication before seeing a physician. In the double-blind study 20 patients received haloperidol and 20 were treated with placebo. Before the treatment the mean VAS values did not differ significantly between the 2 treatment groups: VAS was 7.7 in the haloperidol group and 7.2 in the placebo group (Fig. 1). Infusion of placebo or haloperidol caused a statistically significant reduction in the headache intensity: the VAS values dropped to 6.3 after placebo (P < .01) and 2.3 after haloperidol (P < .0001) (Fig. 3). However, the postinfusion values were significantly lower in the haloperidol group (P < .0001). Sixteen of the 20 patients (80%) who received haloperidol in the double-blind trial felt marked relief from the pain, whereas only 3 of the 20 patients (15%) responded to placebo. This difference was statistically significant (P < .0001, chi-square test for independence). The 4 nonresponders in the haloperidol group did not differ from the general study population in regard to the duration of their migraine attacks or prior medication. The 17 patients who did not respond to placebo along with 7 patients who refused from the placebo-controlled, double-blind trial participated in the open trial. The mean VAS value was 6.6 before and 2.3 after the infusion (P < .0001) (Fig. 2). Nineteen of these 24 patients (79%) were pain free after the infusion (Fig. 3). Vast majority of the patients who received haloperidol in the double blind (16; 80%) or open (21; 88%) trial complained side effects, mainly motor agitation (9 (53%) patients in the double-blind trial; 12 (50%) in the open trial) and sedation (9 (53%) patients in the double-blind trial; 8 (33%) in the open trial), the former being more troublesome. One of the 3 patients who responded to placebo complained of side effects (visual disturbances). Three patients treated with haloperidol (7%) returned to the emergency ward
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Fig 1.—The effect of IV haloperidol in migraine pain in the double-blind, placebo-controlled study as assessed by VAS. Mean VAS value was 7.7 before and 2.3 after the infusion in the haloperidol group (P < .0001). Mean in placebo group was 7.2 before and 6.3 after the infusion (P < .01). The VAS values in the haloperidol and placebo groups did not differ before the infusion. The postinfusion VAS values were significantly lower in the haloperidol group (P < .0001). n = 20 in both groups.
because of a recidive attack occurring within 2 to 3 days after the infusion. Four patients (9%) reported a recidive migraine attack, which they decided to treat at home within a few days after the haloperidol infusion. Two patients returned to the hospital because of side effects. These side effects were not, however, the anticipated extrapyramidal side effects but hyperventilation and shortness of breath. Seven of the 44 patients (16%) who received haloperidol would not like their migraine to be treated with haloperidol in the future because of these side effects. Thirteen (39%) of the 44 patients treated with haloperidol reported that the
prolonged migraine attack they had suffered from during the previous days was interrupted by haloperidol, and they had several pain-free days or weeks before the next attack.
DISCUSSION The present data demonstrate the efficacy of IV haloperidol in acute, prolonged, and treatmentresistant migraine attacks. Four out of 5 patients felt significant relief in pain intensity, even when other medications had failed. Relapses were rare, and several patients reported that haloperidol interrupted the
Fig 2.—The effect of IV haloperidol in migraine pain in the open trial. Mean = 6.6 before and 2.3 after the treatment (P < .0001). n = 24.
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Fig 3.—After haloperidol infusion 80% of the patients in the double-blind trial and 79% in the open trial felt significant pain relief and could be discharged. Only 15% of the patients treated with placebo responded in the double-blind trial. Haloperidol was significantly more effective than placebo (P < .001). The values are expressed as mean ± SEM
prolonged, intractable migraine spiral they had suffered for days. Some patients reported a prolonged pain-free period after the infusion. Conversely, 4 out of 5 patients treated with haloperidol felt significant side effects. One out of 6 patients treated with haloperidol felt such intolerable side effects that they refuse to be treated with haloperidol in the future. In the evidence-based guidelines of migraine treatment published by the US Headache consortium, neuroleptics were not listed as a pain-relieving group of their own. In general, they were considered as antiemetics to be used as an adjunct therapy to treat migraine-associated nausea16,17 despite the fact that the use of neuroleptics has resulted in the highest responses in pain relief.18 The only neuroleptic recommended for the first-line therapy was IV prochlorperazine. The quality of evidence for the neuroleptics listed was in general considered to be grade B. Conversely, parenterally administered chlorpromazine, metoclopramide, and prochlorperazine were found usable in relieving migraine pain. In addition to drugs traditionally used as antiemetics, such as domperidone, droperidol, metoclopramide, and prochlorperazine, also classical phenothiazine neuroleptics levomepromazine and chlorpromazine have been used in migraine. The pain-relieving properties of these drugs have produced somewhat mixed results, but parenteral administration has usually yielded good responses.
Droperidole (2.75 mg IM) was significantly more effective than placebo with about 60% patients being pain free by 2 hours.19 Domperidone has not been studied in a double-blind, placebo-controlled study design, but 40 mg dose has been demonstrated to be effective when taken during the prodromal phase.20 Metoclopramide (10 mg IV) relieved migraine-associated pain in 46% to 67% of the patients when given intravenously.21-23 Prochlorperazine (20 mg IM or IV) may be slightly more effective of these traditional antiemetic drugs with good response in pain relief in 67% to 75% of the patients.24,25 In the only study of levomepromazine in acute migraine by Stiell et al,26 70% of the patients showed good response after a 3.75 mg IM dose. Finally, 73% of migraine patients treated with IV chlorpromazine (0.1 mg/kg) were pain free within 1 hour.27 Haloperidol has shown its efficacy in 1 open-label trial with 6 enrolled patients.28 The present data show that haloperidol produces significant pain relief within hours in over 80% of the migraine patients. Taken together, especially levomepromazine, haloperidol, and chlorpromazine appear to be very effective in relieving migraine headache. These classical antipsychotic neuroleptics appear to have superior analgesic properties in migraine pain compared to triptans, which in general relieve pain in only about 60% of the patients.29 In addition, the migraine patients seen in emergency rooms have usually
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786 taken triptans without response, necessitating other medication options. The adverse effects of the neuroleptics in migraineurs are usually characterized as mild to moderate and infrequent to occasional.18 Drowsiness was the major adverse effect caused by IM levomepromazine26 and IV chlorpromazine.27 Sedation is usually not considered as a problematic side effect in migraine treatment and it may, in fact, be useful in some patients.18 Postural hypotension and syncope were infrequent, but more severe adverse effects in some cases required hospitalization. Extrapyramidal side effects such as dystonia and akathisia have rarely been reported,16 although 16% to 44% of the headache patients treated with IV prochlorperazine complained akathisia.30,31 In the present work, about half of the patients treated with IV haloperidol complained significant akathisia, which seems to be more frequent than previously reported for the other neuroleptics. Some of these side effects were considered intolerable, so that the patients would not like to be treated with haloperidol any more. Symptomatic hypotension was not observed at all. Although we did not perform electrocardiogram (EKG) to the patients prior to infusion, it may be advisable to check EKG along with checking serum potassium and magnesium levels, especially if the patient is taking medication that can prolong QTintervals. In practice, we routinely give the patients 5 to 10 mg diazepam, which they are advised to take if they start feeling restless. More severe extrapyramidal side effects—which were not observed among the 44 patients treated with haloperidol in this study— should be treated with anticholinergics, such as biperiden. This study shows that haloperidol can be used as an (cost-) effective rescue medication, when other treatments options fail or cannot be used. Compared to other neuroleptics the efficacy of haloperidol seems to be among the highest reported so far. Because the majority of the patients had taken regular NSAID-type analgetics and triptans without response, haloperidol is also effective in treatment-resistant migraine attacks. Recidives are rare. Vast majority of the patients will suffer from side effects, which are generally well tolerated and reversible, but limit the use of haloperidol for some patients.
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