, Volume 72, Issue 6, pp 825-845

OnabotulinumtoxinA (BOTOX®)

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Abstract

This article reviews the pharmacology, therapeutic efficacy and tolerability profile of intramuscularly injected onabotulinumtoxinA (onaBoNTA; BOTOX®) for headache prophylaxis in adults with chronic migraine, with a focus on UK labelling for the drug. The pharmacological actions of onaBoNTA include a direct antinociceptive (analgesic) effect; while not fully understood, the mechanism of action underlying its headache prophylaxis effect in chronic migraine is presumed to involve inhibition of peripheral and central sensitization in trigemino-vascular neurones.

Pooled findings from two large phase III studies of virtually identical design (PREEMPT [Phase III REsearch Evaluating Migraine Prophylaxis Therapy] 1 and 2) showed that treatment with up to five cycles of onaBoNTA (155–195 units/cycle) at 12-week intervals was effective in reducing headache symptoms, decreasing headache-related disability, and improving health-related quality of life (HR-QOL) in patients with chronic migraine, approximately two-thirds of whom were overusing acute headache medications at baseline. During the double-blind phase of both trials, significantly more patients treated with onaBoNTA (two cycles) than placebo experienced clinically meaningful improvements in the monthly frequencies of headache days, moderate to severe headache days and migraine days, and in the cumulative hours of headache on headache days/month. OnaBoNTA therapy also resulted in statistically significant and clinically meaningful improvements in functioning and HR-QOL compared with placebo. Notably, improvements in headache symptoms, functioning and HR-QOL favouring onaBoNTA over placebo were seen regardless of whether or not patients were medication overusers and irrespective of whether or not they were naive to (oral) prophylactic therapy. Further improvements relative to baseline in headache symptoms, functioning and HR-QOL were observed during the open-label extension phase of both trials (all patients received three cycles of onaBoNTA).

Treatment with up to five cycles of onaBoNTA was generally well tolerated in the PREEMPT trials. Treatment-related adverse events reported by onaBoNTA recipients (e.g. neck pain, facial paresis and eyelid ptosis) were consistent with the well established tolerability profile of the neurotoxin when injected into head and neck muscles; no new safety events were observed.

Debate surrounding the PREEMPT studies has centred on the small treatment effect of onaBoNTA relative to placebo, the possibility that blinding was inadequate and the relevance of the evaluated population. Nonetheless, the totality of the data showed that onaBoNTA therapy produced clinically meaningful improvements in headache symptoms, functioning and HR-QOL; on the basis of these trials, it has become the first (and so far only) headache prophylactic therapy to be specifically approved for chronic migraine in the UK and US. Overall, onaBoNTA offers a beneficial, acceptably tolerated and potentially convenient option for the management of this highly disabling condition, for example in patients who are refractory to oral medications used for prophylaxis.

Various sections of the manuscript reviewed by: R.K. Cady, Headache Care Center, Springfield, MO, USA; H.C. Diener, Department of Neurology and Headache Center, University Hospital Essen, Essen, Germany; F.G. Freitag, Comprehensive Headache Center, Baylor University Medical Center, Dallas, TX, USA; P. Gazerani, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada; W.W. Schulte-Mattler, Neurologische Klinik und Poliklinik, Universität Regensburg, Regensburg, Germany.
Data Selection Sources: Medical literature (including published and unpublished data) on ‘botulinum toxin A’ was identified by searching databases (including MEDLINE and EMBASE) for articles published since 1996, bibliographies from published literature, clinical trial registries/databases and websites (including those of regional regulatory agencies and the manufacturer). Additional information (including contributory unpublished data) was also requested from the company developing the drug. Search strategy: MEDLINE and EMBASE search terms were (‘botulinum toxin A’ or ‘onabotulinumtoxinA’) and (‘migraine’ or ‘headache’). Searches were last updated 27 March 2012. Selection: Studies in patients with chronic migraine who received onabotulinumtoxinA (BOTOX®). Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: OnabotulinumtoxinA, BOTOX®, Botulinum toxin A, chronic migraine, headache prophylaxis, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.