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• Botulinum toxin for treatment of migraine: randomized controlled trials versus basic sciences
  Vinod K Gupta, M.D.
  Published on: 12 July 2004

• Published on: 12 July 2004

  Botulinum toxin for treatment of migraine: randomized controlled trials versus basic sciences

  • Vinod K Gupta, M.D., Physician

  Dear Editor

  Jankovic reviews the expanding list of approved and off-label indications for therapeutic use of botulinum toxin (BT). [1]. One of the prominent off-label indications for use of BT is migraine, the advent of which therapy was serendipitous.

  Use of BT for migraine prevention is gaining momentum through the results of randomized controlled trials (RCT) – both completed and ongoing – and, in th...

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  Dear Editor

  Jankovic reviews the expanding list of approved and off-label indications for therapeutic use of botulinum toxin (BT). [1]. One of the prominent off-label indications for use of BT is migraine, the advent of which therapy was serendipitous.

  Use of BT for migraine prevention is gaining momentum through the results of randomized controlled trials (RCT) – both completed and ongoing – and, in the effort to evolve a broad consensus, certain clinical reservations have been recently addressed [2].

  In this period of elucidation of anti-migraine mechanisms of BT that would eventually lead towards formal approval of its use for clinical practice, it is important to maintain an open, cautious, and critical approach to the literature.

  A direct skeletal muscle-spasmolysis independent prolonged analgesic action is believed to underlie efficacy of BT in preventing migraine attacks for three months or more [2-4]. The following facts do not sustain this theoretical premise: (i) Three RCTs in human volunteers do not support a direct or genuine analgesic action of BT [5-7]. (ii) Dose-dependent modification of analgesia-related behaviour in rats lasts only for two weeks with the higher (medium) dose tested [8]. (iii) In clinical trials in migraine patients, neither a predictable nor a dose-dependent response has been seen [9]. (iv) Peak responses to BT-A in migraine patients are seen at 8 -12 weeks2,3,4 whereas BT-A affected nerve endings in mice fully recover function between 63-91 days [10]. (v) BT does not cross the blood-brain barrier [8]. and cannot influence either meningeal pain receptors or dural inflammation believed to underlie migraine headache [11]. or the aura [3].

  While BT cannot influence central sensitization, blocking of peripheral sensitization through suppression of release of substance P does not contribute to analgesia in humans [6]. and is limited to 15 days in cultured embryonic rat dorsal root ganglia [12]. (vi) Donepezil – that exerts central and peripheral cholinergic activity opposite to that of BT -- remits migraine with aura or migraine without aura, an effect comparable to propranolol in controlled conditions [13]. (vii)

  The clinical utility of BT in migraine has not been compared with other established prophylactic agents. (vii) Approximately 1% of patients receiving BT-A injections develop severe, debilitating headaches that may persist for 2-4 weeks [14].

  The placebo effect cannot be reliably excluded in RCT, particularly with soft end points that hamper migraine research; RCT with BT in off- label indications such as migraine can misguide clinicians if undertaken without sufficient conceptual clarity [15]. Without a defensible core research vision to direct it, migraine remains a loosely-connected chain of assumptions and is in its infancy; great care should be taken before making further pathophysiological assumptions as well as therapeutic recommendations [16].

  References

  (1). Jankovic J. Botulinum toxin in clinical practice. J Neurol Neurosurg Psychiatry 2004;75:951-7.

  (2). Silberstein SD, Aoki KR. Botulinum toxin type A: myths, facts, and current research. Headache 2003;43(supplement 1): 1.

  (3). Evans RW, Blumenfeld A. Botulinum toxin injections for headache. Headache 2003;43:682-5.

  (4). Dodick DW. Botulinum neurotoxin for the treatment of migraine and other primary headache disorders: from bench to bedside. Headache 2003; 43: (supplement 1):25-33.

  (5). Voller B, Sycha T, Gustorff B, Schmetterer L, Lehr S, Eichler HG, Auff E, Schnider P. A randomized, double-blind, placebo controlled study on analgesic effects of botulinum toxin A. Neurology 2003;61:940-4.

  (6). Kramer HH, Angerer C, Erbguth F, Schmelz M, Birklein F. Botulinum Toxin A reduces neurogenic flare but has almost no effect on pain and hyperalgesia in human skin. J Neurol 2003;250:188-93.

  (7). Blersch W, Schulte-Mattler WJ, Przywara S, May A, Bigalke H, Wohlfarth K. Botulinum toxin A and the cutaneous nociception in humans: a prospective, double-blind, placebo-controlled, randomized study. J Neurol Sci 2002;205:59-63.

  (8). Cui M, Khanijou S, Rubino J, Kei Roger Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 2004;107:125-33.

  (9). Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. Headache 2000;40:445-50.

  (10). de Paiva A, Meunier FA, Molgo J, et al. Functional repair of motor endplates after botulinum toxin-A poisoning: bi-phasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci (USA). 1999;96:3200-5.

  (11). Silberstein SD. Neurotoxins in the neurobiology of pain. Headache 2003;43(suppl 1):2-8.

  (12). Welch MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon 2000;38:245-58.

  (13). Nicolodi M, Galeotti N, Ghelardini C, Bartolini A, Sicuteri F. Central cholinergic challenging of migraine by testing second-generation anticholinesterase drugs. Headache 2002;42:596-602.

  (14). Alam M, Arndt KA, Dover JS. Severe, intractable headache after injection with botulinum A exotoxin: report of 5 cases. J Am Acad Dermatol 2002;46:62-5.

  (15). Gupta VK. Randomized controlled trials: the hijacking of basic sciences by mathematical logic. BMJ Online (6 July 2004). Available at: http://bmj.bmjjournals.com/cgi/eletters/329/7456/2#65969

  (16). Gupta VK. Bureaucratisation of migraine. Lancet Neurol 2004;3:396.

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  Conflict of Interest:
  None declared.

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