Abstract
Article abstract The authors performed a double-blind, double-dummy study to compare the efficacy of verapamil with placebo in the prophylaxis of episodic cluster headache. After 5 days’ run-in, 15 patients received verapamil (120 mg tid) and 15 received placebo (tid) for 14 days. The authors found a significant reduction in attack frequency and abortive agents consumption in the verapamil group. Side effects were mild. These findings provide objective evidence for the effectiveness of verapamil in episodic cluster headache prophylaxis.
Cluster headache is characterized by excruciating unilateral headaches, confined to a period lasting a few weeks to several months separated by spontaneous remission phases lasting months or years. The crises last from 15 to 180 minutes and recur with a frequency of once every 2 days to eight times a day.1 Homolateral lacrymation, conjunctival injection, nasal congestion, rhinorrhea, and miosis also manifest during an attack.1 The illness produces considerable disability; it is therefore important to enlarge the therapeutic armamentarium.
In an open trial,2 69% of 48 patients with cluster headache improved more than 75% during verapamil treatment, and 15 of the 33 (73%) episodic patients improved (dosage ranged from 120 to 1200 mg/day). Since then, verapamil has been increasingly employed to prevent cluster headache,3-6 but few controlled studies have investigated its efficacy. We performed a double-blind controlled study testing verapamil against placebo as a prophylactic for episodic cluster headache, the most common form of cluster headache.
Methods.
Patients.
Thirty outpatients were enrolled (table 1; figure). All were informed of the study design and aims and gave their written consent.7 Before entry, all underwent EKG and routine blood tests. Blood pressure and heart rate were monitored daily for the entire period of the study. Inclusion criteria were age 18 to 60 years, diagnosis of episodic cluster headache according to International Headache Society criteria,1 at least one cluster period lasting at least a month before the study, being in cluster period for not more than 10 days, and expected duration of remainder of cluster period not less than 20 days (as suggested by length of past periods). Exclusion criteria were liver or kidney disease, cardiopathology contraindicating verapamil administration (second or third grade atrioventricular block, sinoatrial block, sinus node syndrome, heart rate <50/minute, or systolic pressure <90 mm Hg), psychiatric disorder or treatment with antidepressants or antipsychotics, drug or alcohol abuse, and previous adynamic ileus.
Clinical characteristics of groups
Figure. Profile of the trial.
Study design.
The study was multicentric, double-blind, double-dummy for parallel groups. After 5 days’ run-in (no prophylaxis) patients were randomized to verapamil 360 mg/day (120 mg tid) or placebo (tid) for 2 weeks. Frequency, intensity and duration of attacks, and consumption of abortive agents were reported in a headache diary. Acute treatment was allowed throughout the study. To abort attacks most patients used subcutaneous sumatriptan.
The primary endpoint was to determine if verapamil reduced attack frequency. Because of the speed of action of subcutaneous sumatriptan taken to abort crises, we did not assess changes in attack intensity or duration.
Statistical analysis.
The study was divided into run-in (5 days), first week (7 days), and second week (7 days). The median number of attacks and of abortive agents consumed per day in each of these periods were compared in the groups using the nonparametric Mann-Whitney rank sum test. Quoted p values refer to this test; however, means (±SD) are given in Results for greater intelligibility. Patients with a reduction in headache frequency of more than 50% were considered responders.
To facilitate interpretation of the magnitude of the treatment effect, we calculated effect sizes in each group as mean change in attack frequency (in first and second weeks compared with run-in) divided by the SD of the initial mean value.8 An effect size of 0.2 is regarded as small, 0.5 is moderate, and 0.8 or more is large; a positive value denotes improvement and a negative one worsening.9
Results.
The clinical characteristics (see table 1) of the two groups did not differ except that the duration of previous cluster periods was greater in the placebo arm; the difference was not significant. Post hoc analysis showed the groups were balanced for stage of cluster phase when they entered the study.
During run-in the patients who later received verapamil had more attacks per day (verapamil arm 1.92 ± 0.87, placebo arm 1.37 ± 0.8 (means ± SD); p < 0.008; table 2) and consumed more abortive agents per day (verapamil arm 1.8 ± 0.79, placebo 1.0 ± 0.77; p < 0.0001) than the group that later received placebo. During the first week of treatment there was no difference between the groups in terms of number of attacks (verapamil 1.1 ± 1.02, placebo 1.7 ± 1.12) or number of abortive agents consumed (verapamil 1.0 ± 0.96, placebo 1.2 ± 0.92). In the second week both the number of attacks (verapamil 0.6 ± 0.88, placebo 1.65 ± 1.01; p < 0.001) and the consumption of analgesics (verapamil 0.5 ± 0.87, placebo 1.2 ± 1.03; p < 0.004) were lower in the verapamil arm than the placebo arm.
Daily headache attacks and abortive agents consumed per/day in each patient throughout the study
Eighty percent (n = 12) of verapamil arm patients were responders. Six of these (40%) responded by the end of the first week, whereas the other 6 (40%) experienced the improvement after the first week. During the second week, 4 patients (27%) became pain free and another patient experienced only one attack. Three patients (20%) in the verapamil group were nonresponders. There were no re-sponders in the placebo group.
Three placebo patients had previously received verapamil, with benefit. Five of the 15 verapamil arm patients had received open verapamil to prevent attacks in a previous cluster period: four of these experienced marked/complete benefit and one had an uncertain response; for each of these patients a similar response type was observed during the current study.
At the end of the first week effect sizes were 1.15 in the verapamil group and −0.67 in the placebo group, and 1.9 and −0.49 at the end of the second week.
Side effects.
Side effects were mild and never required suspension of treatment (table 3). Constipation was the most frequent side effect and was considered by the patients to be the most bothersome. There was a significant reduction in blood pressure and heart rate in the verapamil group, but no symptoms clearly referable to hypotension.
Side effects in the groups
Discussion.
This is the first double-blind study comparing verapamil with placebo in the prophylaxis of episodic cluster headache. The drug significantly reduced attack frequency and analgesic consumption during the 14 days of drug administration and side effects were few and mild. The effect size values further indicate the effectiveness of verapamil in the prophylaxis of episodic cluster headache8,9 and also suggest that placebo patients worsened—a finding that reflects the usual clinical course of a cluster period. The drug’s effect appeared during the first week of administration (as shown by the percentage of responders and effect size) and this is in accord with common clinical experience,4-6 a previous open study,2 and our double-blind study against lithium.3 During run-in, the patients who later received verapamil experienced more headaches and consumed more abortive agents than the placebo group. This chance imbalance would almost certainly not have occurred if the number of patients studied had been greater. This imbalance, however, does not weaken our findings but strengthens them because the verapamil group had more severe cluster headache than the controls. This conclusion is supported by the post hoc analysis, which showed the groups were balanced for stage of cluster phase when they entered the study. It is extremely unlikely that previous experience of verapamil could have compromised blinding in the three placebo and five verapamil patients who had previously received the drug: constipation does not usually become apparent until the second week and the reductions in blood pressure were moderate and asymptomatic. A limitation of this study was the 2-week treatment period. Future studies should verify the longer term efficacy of verapamil.
Acknowledgments
Acknowledgment
The authors thank Don Ward, for translating the manuscript; Dr. Alessandra Solari (Laboratory of Epidemiology, Istituto Neurologico C. Besta), for help with the statistical analysis; Professor Peer Tfelt-Hansen, for reviewing an earlier version and providing valuable suggestions; and Dr. Susanna Usai, for editorial assistance.
Footnotes
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Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and then scroll down the Table of Contents for the March 28 issue to find the title link for this article.
- Received October 1, 1999.
- Accepted December 3, 1999.
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