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Abstract and Introduction
Abstract
Objective.— To evaluate the efficacy, safety, and optimum dose of a highly purified Clostridium botulinum type A toxin-hemagglutinin complex (Dysport) for migraine prophylaxis.
Background.— Botulinum toxin type-A has demonstrated good efficacy in several open-label studies of patients with migraine, involving either individualized or standardized protocols, although data from placebo-controlled trials have been conflicting.
Methods.— A 12-week, double-blind, randomized trial of Dysport (120 or 240 units) vs placebo was conducted in 6 centers in Thailand to evaluate the efficacy, safety, and optimum dose of botulinum toxin type-A (Dysport) for migraine prophylaxis. A total of 128 patients with migraine without aura were enrolled. The primary end point was the change in the mean number of migraine attacks per 4-week period from the pre-treatment period to 8–12 weeks post injection. Secondary efficacy measures included the change in the mean total intensity score from the pre-treatment period to 8–12 weeks, the investigator and patient global assessments of change at each visit compared with pre-treatment, and Migraine Disability Assessment and Short Form-36 scores.
Results.— Change in number of migraine attacks from pre-treatment to weeks 8–12 was not significantly different. There was a greater improvement in total intensity score at weeks 8–12 with Dysport-240 (not significant), and interim visit data showed that this was significant at weeks 0–4 (P = .03 Dysport-240 vs placebo). The mean duration of headache during weeks 0–4 was lower with Dysport-240 (P = .04 vs placebo). Improvements in patient and investigator global assessments of change between weeks 0–4 and 8–12 were significant for the Dysport-240 group (both P < .05 vs placebo).
Conclusions.— Limitations in study design and assessment tools employed may have contributed to the inconclusive nature of the primary end point data. Dysport-240 showed significant benefit over placebo at some end points and further trials with more appropriate outcome measures are required to evaluate effectively this treatment.
Introduction
Migraine is a common, primary, episodic headache disorder that is characterized by a combination of headache with one or more other neurological, gastrointestinal, and autonomic symptoms. The cause of migraine is unclear, although genetic defects are associated with certain forms. Current knowledge about its pathophysiology indicates that migraine is a neurovascular disorder.
Epidemiologic studies have documented a high prevalence of migraine worldwide and demonstrated both its high socioeconomic impact and the profound effect that the disorder can have on an individual's quality of life. In the World Health Organization's study on the global burden of disease, migraine was ranked 20th among all diseases causing worldwide disability, and the 9th leading cause of disability in women. In Western countries, migraine affects about 11% of adult populations, with a peak prevalence between the ages of 22 and 55 years – the period of highest productivity. The highest prevalence of migraine is in North America, followed by Central and South America; Europe; Asia and Africa have the lowest prevalences.
Although migraine is a highly prevalent and disabling condition, it is under-diagnosed and under-treated. Recent advances have been made in the management of migraine, but pharmacologic treatment options are still far from optimum, leaving many patients without pain-free treatment or with unpleasant side effects. Botulinum toxin type A (BoNT-A) is a potent neurotoxin that has been used to treat a variety of disorders associated with elevated muscle tension, including focal dystonias, spasticity, and achalasia. The pain-relieving effects of BoNT-A were initially noted in studies of the treatment of cervical dystonia, and several studies subsequently showed that the toxin may be effective in the treatment of both tension-type headache and migraine. Although an increase in muscle tenderness has been described in migraine, muscle relaxation and pain relief may not always be associated. Therefore, the pain-relieving capacity of BoNT-A may not be correlated with direct neuromuscular effects.
Botulinum toxin type A has demonstrated good efficacy in several open-label studies of patients with migraine, involving either individualized or standardized protocols. Data from placebo-controlled trials, however, have been conflicting. These differences in outcomes may have been due to differences in study methodology, including the number of injections and total dose given at an individual visit, study duration and position of the injection sites (which muscles were injected, where they were injected, and whether this was individualized). In addition, the assessments and end points used were different and may not have been sufficiently sensitive or specific. It should also be noted that although BoNT-A preparations are formulated as mouse median lethal dose (LD50) units, differences in assay methodology among different BoNT-A compounds mean that the units of measurement are not directly interchangeable. When comparing data among studies, a ratio of between 2 and 3 units of Dysport® (Ipsen Ltd, Slough, UK) to 1 unit of Botox® (Allergan Inc., Irvine, CA, USA) should be considered.
This study was designed to evaluate whether BoNT-A was effective in the prophylaxis of migraine without aura. We conducted a 2-dose, double-blind, randomized, placebo-controlled trial in a large cohort of patients to evaluate the efficacy, safety, and optimum dose of a highly purified Clostridium botulinum type A toxin-hemagglutinin complex (Dysport) for migraine prophylaxis.
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