Abstract
Background
Methysergide has been as an effective treatment for migraine and cluster headache for over 50 years but has recently been investigated by the European Medicines Agency due to safety concerns.
Methods
To assess the need for continuing availability of methysergide, the International Headache Society performed an electronic survey among their members.
Results
The survey revealed that 71.3% of all respondents had ever prescribed methysergide and 79.8% would prescribe it if it were to become available. Respondents used it more in cluster headache than migraine, and reserved it for use in refractory patients.
Conclusion
The vast majority of headache experts in this survey regarded methysergide a unique treatment option for specific populations for which there are no alternatives, with an urgent need to continue its availability. This position was supported by the International Headache Society.
Methysergide is indicated for the prophylaxis of migraine and cluster headache. Following Sicuteri’s first open-label trial in 1959 (1), results from randomized, double-blind placebo-controlled trials have confirmed its efficacy (2,3). Significant fibrotic complications were first reported by Graham within 5 years of its introduction (4). Nonetheless, its remarkable efficacy, coupled with the use of a regular drug holiday to minimize adverse effects meant that methysergide remained an important option for patients in whom other medical options had failed. It has been recommended in national and multi-national guidelines for the treatment of migraine and cluster headache (5–10). USA and Canadian guidelines had included methysergide until the drug was withdrawn (11,12).
In 2011, concerns raised in a French pharmacovigilance review regarding serious cases of fibrosis in methysergide users triggered an extensive review by the European Medicines Agency.
While the review process was underway, concern that the drug would be withdrawn led to an incentive within the headache field to retain methysergide for headache indications. To identify the extent of interest, the International Headache Society (IHS) surveyed its members in 2014 on their use of methysergide in the treatment of migraine and cluster headache. The aim of the survey was to enforce the production and distribution of methysergide for those patients whose headaches required the drug to achieve effective management.
In July 2014, all IHS members who had a valid email address were invited to respond to a simple questionnaire survey. The questionnaire asked for the nationality, previous prescription of methysergide and numbers of patients, and future prescription of methysergide (if available). They were also invited to provide additional comments. The data are presented as percentages. We did not perform a formal statistical analysis.
Regions from which eligible responses were received (n = 376).
In total, 268 (71.3%) of all respondents stated that they had ever prescribed methysergide and 108 (28.7%) had not. Of those who had prescribed methysergide, 174 (64.9%) prescribed it to 1–10 patients per year, 75 (28.0%) prescribed it to 11–50 patients per year and 19 (7.1%) prescribed it to more than 50 patients per year.
If methysergide were to become available in the future, 300 (79.8%) of all respondents stated that they would prescribe it, 25 (6.6%) would not prescribe it, 45 (12.0%) were undecided and six (1.6%) provided no answer. Regarding numbers of patients, 194 (56.2%) of the respondents willing or possibly willing to prescribe methysergide (total n = 345) would prescribe it to 1–10 patients per year, 121 (35.1%) would prescribe it to 11–50 patients per year and 28 (8.1%) would prescribe it to more than 50 patients per year; two (0.6%) provided no answer to this question.
Frequent comments made by the respondents (n = 199 in total) as structured by the authors (multiple comments were possible).
The main finding from this study is that a significant number of IHS members who responded favour methysergide for a specific group of difficult-to-treat patients, particularly patients with cluster headache. With respect to significant adverse effects, these were relevant only for a small minority of respondents.
It may be argued that the efficacy data is questionable, as the trials are old and were not conducted with the rigor of current research. However, the American Headache Society and American Academy of Neurology guidelines graded the data as being from ‘well-designed randomized clinical trials, directly relevant to the recommendation, yielded a consistent pattern of findings’ (11).
With respect to the safety of methysergide, fibrosis can be life-threatening and strategies to monitor patients and minimize risk are imperative. Two respondents noted that methysergide was useful for suicidal patients, while several respondents reported that lack of methysergide has been a significant problem for patients in whom methysergide had been the only treatment effective for migraine or cluster headache. It is also notable that during the review process, the EMA received a number of third-party testimonials from patients, patient organizations and healthcare professionals in support of the retention of methysergide. This highlights the necessity of ongoing availability of methysergide, for which there is no substitute. The IHS, by decision of its Board, supported the ongoing approval of methysergide and reported accordingly to the EMA.
The EMA recommendations, published in 2014, confirmed that methysergide was effective for the prophylaxis of migraine and cluster headache and provided much needed guidance regarding the target population and monitoring (13). Despite this reprieve, pharmaceutical companies have ceased production of methysergide and it has ceased to be marketed.
Our survey data provide evidence that methysergide is a unique and urgently needed drug for a highly selected population of patients with intractable migraine or cluster headache, and should be available worldwide. However, it should be considered that IHS has only few members in Africa and Asia, so that the results are not representative for all parts of the world.
Article highlights
Methysergide is regarded as an urgently needed drug for a highly specific population. Methysergide is primarily used in refractory cluster headache patients. The use of methysergide has to be carefully monitored.
Footnotes
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Professor Evers has no conflicts of interest to declare. Professor MacGregor acted as a consultant to Amdipharm during the EMA review.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.