Evidence-Based Physiatry: Cochrane Corner
The aim of this commentary is to discuss in a rehabilitation perspective the published Cochrane Review “Botulinum toxins for the prevention of migraine in adults” by Herd et al.,1 (https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011616.pub2/full) which was developed by the Cochrane Pain, Palliative and Supportive Care Group. This Cochrane Corner is produced in agreement with the AJPM&R by Cochrane Rehabilitation.
Migraine is a chronic and debilitating condition, which can be characterized as either chronic or episodic. Global migraine prevalence was reported as 11.6%2 and migraine was reported as the third most disabling disease among people aged 15 to 49 years globally.3 Various attempts to reduce frequency and severity of migraine yielded mixed results.1 One proposed intervention is botulinum toxin. A Cochrane Review addresses efficacy and safety of all serotypes of botulinum toxin versus placebo or active treatment for the prevention of chronic or episodic migraine in adults.1
BOTULINUM TOXIN FOR THE PREVENTION OF MIGRAINE IN ADULTS
What Is the Aim of the Cochrane Review?
The aim of this Cochrane Review was to analyze benefits and harms of botulinum toxin as an intervention for the prevention of migraine in adults.
What Was Studied in the Cochrane Review?
The population addressed in this review was adults 18 years or older, experiencing chronic or episodic migraine. The intervention studied was any serotype of botulinum toxin administered via injections, in various doses, into head and neck muscles in comparison with placebo injections, active preventative agent, or the same drug treatment with a different dose. Trials allowing the use of concomitant preventative or rescue treatment were eligible. Primary outcome studied was number of migraine days per month.
What Were the Main Results of the Cochrane Review?
The review included 28 trials, with 4190 participants available up to December 7, 2017. The average age of participants was 42 years with 85% being women and the ratio of chronic/episodic migraine was 1872/1928. Most trials were small (<50 participants per trial arm).
Botulinum toxin versus placebo (23 trials):
- - Botulinum toxin may reduce the mean number of migraine days per month in chronic migraine by 3.1 days (low quality evidence), which was reduced to 2 days when small trials were removed (moderate quality evidence). Cochrane authors indicate that it is difficult to determine whether this result is clinically meaningful, but that the result is in keeping with previous trials about prophylactic agents.
- - No difference between botulinum toxin and placebo for the number of migraine days per month in episodic migraine (1 trial) (low quality evidence).
- - Botulinum toxin may reduce the severity of migraines (very low quality of evidence).
- - Risk of adverse events was higher with botulinum toxin than with placebo.
Botulinum toxin versus oral prophylactic medications (sodium valproate and topiramate) (3 trials):
- - The majority of participants in these three trials had chronic migraine; 14 of the 59 participants involved in one trial had episodic migraine, and all the other participants across all three trials suffered from chronic migraine.
- - There was no difference in number of migraine days or headache days between the groups (very low quality evidence for both outcomes).
- - Inconsistent results were found for headache intensity (very low quality evidence). There was no difference between groups in headache index, use of rescue medication, patient and clinician global impression (very low quality evidence). None of the trials analyzed duration of migraine or cost effectiveness.
- - There was no difference in adverse events between botulinum toxin and oral treatments.
What Were the Authors’ Conclusions?
The authors concluded that in adults with chronic migraine, botulinum toxin type A may reduce the number of migraine days per month by 2 days compared with placebo (moderate quality evidence) when small trials were removed from analysis. For adults experiencing episodic migraine, it is unclear whether botulinum toxin is effective because of low quality evidence.
What Are the Implications of the Cochrane Evidence for Practice?
The Cochrane review indicates that there is some effect of botulinum toxin on prevention of chronic migraine, but only seen in studies where botulinum toxin was compared to placebo and not when compared to oral agents, which are much cheaper. Secondary outcome measures analyzed in this review did not show a consistent treatment effect. Furthermore, none of the included trials reported data for headache index, duration of migraine, or use of rescue medication data to be used for meta-analyses. Patient and clinician-reported global assessment scales and quality of life were seldom and/or poorly reported, which precluded meta-analysis.
Trials reported few adverse events of botulinum toxin which were transient and not serious. Risk of adverse events was higher in botulinum toxin group compared to placebo. There was no difference between groups taking botulinum toxin and those taking topiramate or sodium valproate based on low quality evidence.
Regarding costs, data from two large PREEMPT trials4,5 estimated a treatment cost of £18 per one avoided headache day. Based on the currently available data, other oral preventative strategies are currently much cheaper.
Cochrane authors concluded that their findings are in line with current clinical guidelines. It was not possible to draw conclusions about the order in which botulinum toxin and other prophylactic interventions should be used to treat chronic and episodic migraine due to insufficient evidence on their comparative efficacy and safety.
Botulinum toxin injections are widely used by physicians including pain specialists, rehabilitation physicians6 and others as an intervention in a large variety of health conditions. It seems that chronic migraine can be a new area of practice for botulinum toxin when the patient is refractory to standard agents. The actual low or very low evidence on its benefits urges future research because the likelihood of changes in quality or certainty of evidence is high with further trials.
Meta-analyses could not have been made in the review regarding disability and quality of life outcomes, which are quite significant from a rehabilitation perspective. Furthermore, functioning of patients was not analyzed as one of the primary outcomes in this review. Conclusive evidence on the effects of botulinum toxin on functioning remains to be investigated.
The author thanks Cochrane Rehabilitation and Cochrane Pain, Palliative and Supportive Care Group for reviewing the contents of the Cochrane Corner.
1. Herd CP, Tomlinson CL, Rick C, et al: Botulinum toxins for the prevention of migraine in adults. Cochrane Database Syst Rev
2. Woldeamanuel YW, Cowan RP: Migraine affects 1 in 10 people worldwide featuring recent rise: a systematic review and meta-analysis of community-based studies involving 6 million participants. J Neurol Sci
3. Saylor D, Steiner TJ: The global burden of headache. Semin Neurol
4. Aurora SK, Dodick DW, Turkel CC, et al: OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia
5. Diener HC, Dodick DW, Aurora SK, et al: OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia
6. European Physical and Rehabilitation Medicine Bodies Alliance: White Book on Physical and Rehabilitation Medicine (PRM) in Europe. Chapter 7. The clinical field of competence: PRM in practice. Eur J Phys Rehabil Med