Although botulinum toxin A (Botox®) injections are approved in the United States, Canada, the UK, and other countries for the preventive treatment of severe headache conditions, a recent review and meta-analysis of clinical trials found only small benefits in patients with chronic migraine or chronic daily headaches. At the same time, botulinum toxin A injections were no more beneficial than placebo for preventing episodic migraine or tension-type headaches.
According to background information in the article, botulinum toxin A injections were first proposed as a headache therapy when it was observed that patients with chronic headaches receiving those injections for cosmetic purposes experienced headache improvement. This prompted exploratory studies and clinical trials that suggested benefit; however, the medical literature demonstrating the efficacy of botulinum toxin A for headaches still appears to be conflicted and inadequate.
Reporting in the Journal of the American Medical Association, Jeffrey L. Jackson, MD, MPH — of the Medical College of Wisconsin, Milwaukee — and colleagues describe a systematic review and meta-analysis to assess the association of botulinum toxin A with reducing headache frequency when used for preventive treatment of migraine, tension, or daily headaches in adults [Jackson et al. 2012]. For analysis purposes, headache types were categorized as being either episodic (<15/month) or chronic (≥15/month). In their literature search, covering 1966 to March 2012, the researchers identified 27 randomized placebo-controlled trials that included 5,313 study participants, and 4 randomized trials comparing botulinum toxin A with other medications.
Pooled analyses of the data from placebo-controlled trials suggested that botulinum toxin A was associated with significantly fewer headaches per month among patients with chronic daily headaches (n=1,115, reduction of 2.06 headaches per month, 3 trials) and in those with chronic migraine headaches (n=1,508, reduction of 2.30 headaches per month, 5 trials). At the same time, there was no statistically significant benefit of botulinum toxin A for reducing the frequency per month of episodic migraine or chronic tension-type headaches.
Compared with placebo, botulinum toxin A was associated with a greater frequency of blepharoptosis (upper eyelid drooping), skin tightness, paresthesias (prickly, tingling sensations), neck stiffness, muscle weakness, and neck pain. However, the researchers note that additional harms might have been missed due to the short-term design of most trials.
In individual trials comparing botulinum toxin A with other treatment modalities, botulinum did not produce statistically significant reductions in migraine headaches per month compared with topiramate or amitriptyline, or with valproate for tension-type headache. However, in a very small single trial (n=20), botulinum toxin A appeared more effective than methylprednisolone for reducing chronic tension-type headaches. Comparative adverse events for any of these trials were not reported by Jackson et al.
The authors conclude that botulinum toxin A may be associated with improvement in the frequency of chronic migraine and chronic daily headaches; however, clinical benefits were small: botulinum reduced the average number of chronic migraines per month from 19.5 to 17.2, and chronic daily headaches from 17.5 to 15.4/month. Botulinum toxin A demonstrated no significant improvement in the frequency of episodic migraine or chronic tension-type headaches.
COMMENTARY: Botulinum toxin A was originally welcomed into the therapeutic milieu for headache prophylaxis because it was perceived as a nonsystemic treatment that might have a more favorable benefit-to-risk profile than current pharmacotherapy. However, as in many areas of pain management, research on botulinum toxin A for various headache types has been hampered by insufficient and/or deficient evidence.
Jackson and colleagues note that, for nearly all headache types examined in their analyses, there were relatively few studies and many were small and underpowered, among other serious limitations. The authors concede that their results “could be spurious,” since they used statistical assumptions that might have conferred more favorable results than were justified. In fact, they observe that a more rigorous analytical approach could find that “botulinum toxin A may not be associated with benefit for any headache types.”
In a previous UPDATE [here], we noted that botulinum toxin A as a treatment for chronic migraine requires up to 39 injections into head and neck muscles, which must be repeated every 12 weeks for maximum clinical effectiveness. The cost is substantial at about $450 USD per treatment. At the time botulinum toxin A was approved in England for chronic migraine, some headache specialists contested the evidence favoring this treatment, and the Drug and Therapeutics Bulletin [abstract here] published by the British Medical Journal declined to recommend botulinum toxin A.
In their meta-analysis paper, Jackson et al. comment that the available studies appeared to underdose botulinum toxin A therapy, and it is unclear whether a higher dosing strategy, as usually recommended, might be associated with greater benefits without added risks. They conclude that more and much better trials are needed, including further comparisons with currently approved prophylactic medications for headache.
REFERENCE: Jackson JL, Kuriyama A, Hayashino Y. Botulinum Toxin A for Prophylactic Treatment of Migraine and Tension Headaches in Adults: A Meta-analysis. JAMA. 2012(Apr);307(16):1736-1745 [abstract].
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