Original Article
Treatment of Acute Cluster Headache with Sumatriptan — The Sumatriptan Cluster Headache Study Group*
N Engl J Med 1991; 325:322-326August 1, 1991
- Abstract
- Abstract
Background.
Attacks of cluster headache are difficult to treat. Sumatriptan, an agonist of 5-hydroxy-tryptamine1—like receptors, has proved effective in the treatment of migraine. The clinical similarities between migraine and cluster headache and positive results from an open pilot study in patients with cluster headache indicated that sumatriptan should be evaluated more rigorously in the treatment of this condition.
Methods.
We conducted a randomized, double-blind, placebo-controlled crossover study to assess the efficacy and tolerability of sumatriptan in 49 patients with cluster headache. The patients received, in random order, a subcutaneous injection of 6 mg of sumatriptan for one cluster-headache attack and placebo for another attack. The results for the two attacks could be fully evaluated for 39 patients. A response to treatment was defined as complete or almost complete relief of headache (no pain or mild pain) within 15 minutes after the injection.
Results.
In the 39 patients, the severity of headache decreased in 74 percent of the attacks within 15 minutes of treatment with sumatriptan, as compared with 26 percent of the attacks for which placebo was given (P<0.001). Thirty-six percent of the patients were free of pain within 10 minutes after the administration of sumatriptan, as compared with 3 percent after placebo (P<0.001); by 15 minutes these numbers had increased to 46 percent and 10 percent, respectively (P<0.001). Thirteen percent of the patients required oxygen as an additional treatment 15 minutes after receiving sumatriptan, as compared with 49 percent of those who received placebo. The severity of functional disability and the incidence of ipsilateral conjunctival injection also decreased more in response to sumatriptan than placebo. Sumatriptan was well tolerated, and there were no serious adverse events.
Conclusions.
Sumatriptan is an effective and well-tolerated treatment for acute attacks of cluster headache. (N Engl J Med 1991; 325:322–6.)
Media in This Article
Figure 1
Percentages of Patients with Cluster Headache Who Responded to the Administration of Sumatriptan (Open Bars) or Placebo (Hatched Bars) within 15 Minutes.Figure 2
Mean Ratings of Headache Severity and Functional Disability in the Two Groups of Patients with Cluster Headache at Various Times after the Administration of Sumatriptan (Circles) or Placebo (Squares)Article Activity
- Article
CLUSTER headache is characterized by recurrent, unilateral attacks of headache of great intensity and brief duration, often accompanied by local signs and symptoms of autonomic dysfunction.1 The attacks occur in series lasting weeks or months, so-called cluster periods. About 10 percent of patients have chronic symptoms. These headaches are difficult to treat.2 The pain is often severe and rapidly reaches maximal intensity. The brief duration of the attacks dictates that to be of any practical use, a treatment must be effective within a few minutes after its administration.
Among the treatments used for this disorder, orally administered analgesic drugs and ergotamine tartrate have limited value, but the sublingual administration of ergotamine may be beneficial.3 Inhalation of ergotamine may also give some relief, but the drug is difficult to inhale, even for regular users of an aerosolized medication. Oxygen inhalation (7 liters per minute for 15 minutes) is effective,3 proving superior to air inhalation in a double-blind comparative study,4 and many patients now use oxygen inhalation effectively outside hospital settings. Intranasal application of lidocaine5 and application of cocaine to the sphenopalatine ganglion6 may be effective but are not widely used.
The cause of cluster headache is unknown, but there are clinical similarities to migraine. It is therefore possible that serotonin (5-hydroxytryptamine) plays a part, as it does in migraine.7 Sumatriptan (3-[2-(dimethylamino)ethyl]-N-methylindole-5-methanesulfonamide) is a highly selective agonist of 5-hydroxytryptamine1—like receptors that relieves the symptoms of migraine when administered subcutaneously.8 9 10 In a pilot study of patients with cluster headache, four of six patients had marked relief within 8 to 17 minutes after the subcutaneous injection of either 3 or 6 mg of sumatriptan.11
We carried out this study to evaluate the efficacy of 6 mg of sumatriptan in rapidly relieving the pain of cluster headache and to determine its tolerability. The study was placebo-controlled because the extent of the response to placebo in cluster headache has not previously been established.
Methods
Patients
This study was conducted in 12 hospital neurology departments in Denmark, France, Poland, and Sweden. Men and women from 18 to 65 years of age were included if they had a history of episodic or chronic cluster headache meeting the criteria of the International Headache Society's Headache Classification Committee1 and if untreated attacks typically lasted 45 minutes or more. Cluster headache is characterized by severe unilateral orbital, supraorbital, and temporal pain (alone or in combination), lasting 15 to 180 minutes if untreated. The pain is associated with at least one of the following signs, which must be present on the same side of the head as the pain: conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis, and eyelid edema. The frequency of attacks varies from one every other day to eight per day. Episodic cluster headache occurs in periods lasting 7 days to 1 year, separated by pain-free periods of 14 days or more. In chronic cluster headache, attacks occur for more than 1 year without remission or with remission lasting less than 14 days.
Any prophylactic therapy was withdrawn at least one week before the study began. The use of preparations containing ergot or opiates was not allowed within 24 hours before the study and that of other analgesic drugs within 6 hours before the study.
Patients were excluded if they regularly used narcotic analgesic drugs or were known to abuse narcotic drugs, if they were currently abusing ergotamine or had abused it within the previous year, or if they were pregnant or nursing. Women who were not using adequate contraceptive measures were also excluded, as were patients who had any of the following: a history suggestive of ischemic heart disease; peripheral vascular disease; severe hypertension; mild-to-moderate hypertension being treated with a calcium-antagonist or β-adrenergic—antagonist drug; epilepsy; hepatic, renal, or heart disease; or serious psychiatric illness.
Study Design
The study was conducted according to a double-blind, randomized, placebo-controlled crossover design. All patients were hospitalized once they entered a cluster period, to facilitate direct observation. The period of hospitalization was generally several days. The patients were assessed clinically and randomly assigned to one of two groups for the treatment of two subsequent attacks of cluster headache. The first injection was usually given after one or two days of hospitalization. One group received 6 mg of sumatriptan for the first attack and placebo for the second attack. The other group received placebo for the first attack and 6 mg of sumatriptan for the second attack. Each 0.5-ml injection was administered subcutaneously by a physician or a trained nurse and had to be given within 10 minutes of the onset of the attack. The patient's response 5, 10, 15, 20, 25, 30, 60, 90, and 120 minutes after the injection was recorded by the physician or nurse. The administration of 100 percent oxygen (7 liters per minute for 15 minutes) was allowed as "rescue medication" after 15 minutes, and simple analgesic drugs were allowed after 120 minutes for patients whose headache had not decreased in severity to mild or no pain. The minimal interval between study injections was 24 hours, and the longest interval was 9 days. The patients who had attacks of cluster headache during the stipulated 24-hour interval between study injections were permitted to receive medications that did not contain ergotamine. If such medication was administered, then a further interval of 6 hours after simple analgesics or 24 hours after opiates was required before the second study injection was administered to treat a subsequent cluster-headache attack.
Sumatriptan was supplied in ampules containing 12 mg of sumatriptan base per milliliter as the succinate salt in an isotonic saline solution. Placebo was supplied in matching ampules containing isotonic saline solution.
Evaluation of Efficacy
The severity of headache and the global response to treatment were assessed and reported verbally by the patient. Overall functional disability, the presence or absence of ipsilateral conjunctival injection, and the presence or absence of vomiting were assessed by the physician or nurse. All assessments were then recorded in the clinical-record form by the physician or nurse. Table 1Table 1
Efficacy Rating Scales for Severity of Headache, Functional Disability, and Response to Treatment in Patients with Cluster Headache. provides details of the grading scales. The primary clinical end point of efficacy was the relief of pain, from grades 2 to 4 before treatment to grade 1 or 0 within 15 minutes after the injection. The secondary end points of efficacy were pain relief 5 and 10 minutes after injection, the need for rescue medication 15 and 120 minutes after the injection, overall functional disability, the presence or absence of vomiting and of ipsilateral conjunctival injection, and the global response to the injection up to 120 minutes later. On completion of the two trials each patient was asked to express a treatment preference.Evaluation of Safety
Heart rate and blood pressure were measured before and 120 minutes after the injection. Twelve-lead electrocardiographic recordings were made before the trial and at the end of each study day. Complete blood counts were performed, and serum total protein, glucose, sodium, potassium, calcium, urea, creatinine, bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase were measured before the trial and at the end of both study days.
The physician recorded any adverse events that occurred during and after each injection. Reports of these adverse events were collected by giving the patient the opportunity to mention spontaneously any medical problems and then having the physician ask whether the patient had had any medical problems after the injections.
Power Calculations and Randomization
Calculations of sample size were based on the predicted numbers of attacks of cluster headache in which relief from headache (a grade of 0 or 1) would be attained within 15 minutes after the injection. The rate of response to sumatriptan was estimated to be 60 percent and that to placebo, 30 percent. Data for 66 patients were required to detect such a difference between sumatriptan and placebo at the 5 percent significance level (two-sided) with more than 90 percent power.
The randomization code was generated with PACT (Patient Allocation for Clinical Trials), a Glaxo Group Research software program, so that the order in which each patient received the two injections was predetermined according to the patient's identification number. Patients were randomly assigned to a group in blocks of six, each block containing an equal number allocated to the two groups. Complete blocks were allocated to centers, and patients were enrolled in ascending sequential order of patient number at each center.
Statistical Analysis
All tests of significance in the full analyses were two-sided and were considered to indicate statistical significance at a P level below 0.05. Statistical analyses were performed with the SAS package (version 6.03) on an Olivetti M380 personal computer. The numbers of patients in the two groups whose headache had decreased in severity to grade 0 or 1 within 15 minutes after injection were compared with Prescott's test performed with a log-linear model appropriate for binary crossover.12
Changes in the severity of headache and the grade of functional disability from base line to 5, 10, and 15 minutes after injection in the two groups were compared with Koch's test.13 A mean headache score and a functional-disability score were calculated at each time point. The incidence of ipsilateral conjunctival injection was compared in the two groups with Prescott's test. The frequency of vomiting was not analyzed because only one patient reported vomiting during the study.
The global response to treatment at 15 minutes and the length of time to complete resolution of headache after each injection (grouped into appropriate intervals) were compared in the two groups with Koch's test. The number of patients requiring rescue medication 15 minutes after injection was compared with Prescott's test. The rates of incidence of adverse effects after the administration of sumatriptan and placebo were compared with either the MantelHaenszel chi-square test or Fisher's exact test, as appropriate.
To review the efficacy and safety of sumatriptan and placebo, an interim analysis was scheduled to be carried out when 33 patients for whom usable data could be obtained had completed both arms of the study. The study was required to be stopped when a significance level of at least 0.5 percent (P<0.005) was obtained for the comparison between the two groups. This rule was satisfied at the interim analysis; therefore, the study was terminated.
Ethical Approval
The trial was conducted in accordance with the Declaration of Helsinki. Approval was obtained from the appropriate ethics committees, and each patient gave informed consent before the trial.
Results
Demographic Characteristics
A total of 49 patients had been assigned to a group when the study was stopped in accordance with the predefined criterion. Twenty-eight patients received sumatriptan for the first attack of cluster headache; 26 of these patients received placebo for a second attack. Twenty-one patients received placebo for the first attack and sumatriptan for the second attack. Full analyses were conducted on the 39 patients who received an injection within 10 minutes of the onset of each of two attacks in which the pretreatment severity of headache was grade 2 or higher. Of the 10 patients excluded from the efficacy analysis, 7 received an injection for attacks with a pretreatment severity of less than grade 2, 1 received an injection more than 10 minutes after the onset of the attack, and 2 did not have a second cluster-headache attack while hospitalized.
Table 2Table 2
Patients' Characteristics and History of Cluster Headache. shows the characteristics and cluster-headache history of the 39 patients who could be evaluated. This group was comparable to the total patient group in these respects. The characteristics of the cluster-headache attacks treated during the trial are shown in Table 3Table 3
Base-Line Characteristics of Patients with Cluster Headache Given 6 mg of Sumatriptan or Placebo..Clinical Efficacy
Sumatriptan was significantly more effective than placebo in reducing the severity of headache to grade 1 or 0 within 15 minutes of the injection (P<0.001). Twenty-nine of the 39 attacks treated with sumatriptan (74 percent) decreased in severity to that level within 15 minutes, whereas placebo was effective in only 26 percent of the attacks (Fig. 1Figure 1
Percentages of Patients with Cluster Headache Who Responded to the Administration of Sumatriptan (Open Bars) or Placebo (Hatched Bars) within 15 Minutes.).The reduction in the mean score for the severity of headache was significantly larger after the injection of sumatriptan than after the administration of placebo at both 10 and 15 minutes (P<0.001 for both comparisons). Even after five minutes the difference between the two groups approached significance (P = 0.086) in favor of sumatriptan (Fig. 2Figure 2
Mean Ratings of Headache Severity and Functional Disability in the Two Groups of Patients with Cluster Headache at Various Times after the Administration of Sumatriptan (Circles) or Placebo (Squares)). More patients became free of pain after sumatriptan than after placebo administration. After 10 minutes 36 percent of the patients given sumatriptan had no pain, as compared with 3 percent of those given placebo. By 15 minutes 46 percent of the sumatriptan-treated patients had no pain, as compared with 10 percent of the patients given placebo. The attacks for which sumatriptan was given were significantly shorter than those for which placebo was given (P = 0.004): 77 percent of the attacks treated with sumatriptan were completely resolved within 30 minutes of treatment, as compared with 33 percent of those in which placebo was given. Thirteen percent of patients required oxygen 15 minutes after receiving sumatriptan, as compared with 49 percent of those given placebo (P = 0.001).The decrease in functional disability 5, 10, and 15 minutes after the injection of sumatriptan was also significantly greater than after placebo (P = 0.004, P = 0.001, and P = 0.001, respectively). Most patients were able to function normally within 30 minutes after receiving sumatriptan, whereas it took up to 60 minutes when they received placebo (Fig. 2).
The incidence of ipsilateral conjunctival injection was significantly reduced after the injection of sumatriptan as compared with placebo at 5, 10, and 15 minutes (P = 0.005, P = 0.002, and P<0.001, respectively). Conjunctival injection was present in 36 percent of the patients 15 minutes after sumatriptan injection, as compared with 74 percent after placebo injection. The comparable figures 30 minutes after injection were 10 percent and 51 percent, respectively. Because of the low incidence of vomiting before treatment (one patient before placebo), no statistical analysis of the responses was possible.
Fifteen minutes after the injection of sumatriptan 67 percent of the patients reported a good or excellent response, as compared with only 18 percent who received placebo. More patients preferred sumatriptan than preferred placebo (29 vs. 8, or 74 percent vs. 21 percent); 2 patients expressed no preference.
The possibility of a treatment-order interaction was examined, but for all the analyses the tests for period effects and treatment according to period interactions were not significant.
Adverse Events
Sumatriptan was well tolerated. A total of 49 attacks of cluster headache were treated with sumatriptan, and placebo was given in 47 attacks. Adverse events were reported in association with 26 percent of the attacks in which placebo was given, as compared with 35 percent of the attacks treated with sumatriptan. The adverse events were predominantly of two types: injection-site reactions and neurologic symptoms. Injection-site reactions, which included pain (2 patients), swelling, burning, erythema, and tingling at the site of injection, were reported by 7 patients after the injection of placebo and by 11 patients after treatment with sumatriptan. Neurologic symptoms, such as dizziness, tiredness, numbness of hands, tingling, paresthesia, a feeling of paralysis in the face, and cold and hot sensations, were reported by 8 patients after the injection of placebo and by 12 patients after treatment with sumatriptan. No patients withdrew from the trial because of an adverse event after the first injection. In addition, no drug-related abnormalities were detected in the hematologic or biochemical tests, no electrocardiographic abnormalities developed after treatment with sumatriptan, and there were no significant changes from base line in heart rate or blood pressure.
Discussion
Cluster-headache attacks are relatively short-lived and resolve spontaneously within 15 to 180 minutes,1 , 14 and the rate of response to placebo has been considered low. On the other hand, the variable length of such attacks makes a comparison of a new treatment with placebo more important. To allow adequate time for the assessment of the response to sumatriptan, we recruited patients whose attacks usually lasted more than 45 minutes, and we used a crossover design in an attempt to ensure that attacks of comparable duration were treated with sumatriptan and placebo. Furthermore, if a drug is to be of value in treating the acute paroxysm, it must act very rapidly, within 10 or 15 minutes of administration. The primary end point chosen for the evaluation of efficacy was therefore the severity of headache 15 minutes after injection. Using this design we clearly demonstrated the therapeutic benefit of sumatriptan.
The primary measure of efficacy was the reduction in the severity of headache pain to mild or none, since we considered this the most useful indicator of therapeutic success. Analyses were also performed on changes in the mean headache score. We assumed that the data we collected using the rating scale for the severity of headache pain could be summarized as if they were numerical without substantial distortion of the overall analysis, an assumption that is generally considered acceptable when data from subjective rating scales are being analyzed.15 , 16 We found sumatriptan to be more effective than placebo in reducing the severity of headache within 15 minutes after administration. Seventy-four percent of the patients had a decrease in the severity of headache when their attacks were treated with sumatriptan, whereas 26 percent had a decrease when they were given placebo. In addition, more patients were free of pain 15 minutes after the injection of sumatriptan than after the injection of placebo (46 percent vs. 10 percent). Furthermore, sumatriptan treatment resulted in a greater reduction in the mean headache-severity score 10 minutes after injection; even at 5 minutes the difference in the mean score between the two groups approached significance. No other pharmaceutical compound is known to provide similar relief at such an early stage. The speed of the response in these patients correlates well with the pharmacokinetic properties of sumatriptan; the peak plasma concentration occurred 14 minutes after a single subcutaneous injection of 6 mg of sumatriptan in normal subjects.17
Cluster headache, like migraine, has long been considered to involve cranial noncerebral vasodilatation, but the precise mechanisms involved are unclear. Ergotamine, the standard treatment for migraine and cluster headache, is a potent vasoconstrictor, and it may at least in part stimulate 5-hydroxytryptamine receptors.18 Studies of the pharmacology of the cranial vasculature have identified a population of 5-hydroxytryptamine1—like receptors located predominantly in these vessels. Sumatriptan was developed as a specific agonist of this type of receptor.19 Its efficacy in relieving cluster headache indicates a role for 5-hydroxytryptamine in the pathophysiology of this disease. Furthermore, in a significant number of patients, sumatriptan caused resolution of the classic sign of ipsilateral conjunctival injection that occurred during the attacks. Resolution of this autonomic disturbance associated with the disorder suggests that sumatriptan may interrupt the basic process underlying cluster headache rather than act as an analgesic agent.
We conclude that sumatriptan is an effective and well-tolerated treatment for acute attacks of cluster headache.
*The following clinical investigators and research personnel participated in the Sumatriptan Cluster Headache Study Group: K. Ekbom, M.D. (principal investigator), E. Waldenlind, M.D., and R. Levi, M.D. — Söder Hospital, Karolinska Institute, Stockholm, Sweden; B. Andersson, M.D. (deceased) — Gãvle Hospital, Gãvle, Sweden; J. Boivie, M.D., and N. Dizdar, M.D. — University Hospital, Linköping, Sweden; M.G. Bousser, M.D., A. Tehindrazanirivelo, M.D., and G. Lutz, M.D. — Hôpital St. Antoine, Paris; J. Hannerz, M.D. — Karolinska Hospital, Karolinska Institute, Stockholm, Sweden; J.E. Hardebo, M.D. — University Hospital, Lund. Sweden; P. Henry, M.D., and M. Rosazza, M.D. — Hôpital Pellegrin—Tripode, Bordeaux, France; A. Krabbe, M.D. — Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; J. Kinnman, M.D. — Halmstad Hospital, Halmstad, Sweden; L.I. Persson, M.D. — Sahlgrenska Hospital, University of Gothenburg, Gothenburg, Sweden; A. Prusinski, M.D., A. Durko, M.D., W. Kozubski, M.D., and J. Rozniecki, M.D. — Neurology Clinic, Medical Academy, Lodz, Poland; M.M. Wysocka-Bakowska, M.D. —Neurology Clinic, Medical Academy, Warsaw, Poland; and J.A. Cole, B.Sc, P. Patel, M.Sc., AJ. Pilgrim, B.M., D.Phil., P.D. O'B.Winter, Ph.D., and S. Donoghue, Ph.D. — Glaxo Group Research Ltd., Greenford, Middlesex. United Kingdom.
Address reprint requests to Dr. Karl Ekbom at the Department of Neurology, Söder Hospital, S-l1883 Stockholm, Sweden.
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