Beyond chronic migraine: a systematic review and expert opinion on the off-label use of botulinum neurotoxin type-A in other primary headache disorders

Expert Rev Neurother. 2021 Aug;21(8):923-944. doi: 10.1080/14737175.2021.1958677. Epub 2021 Aug 18.


Introduction: Botulinum neurotoxin type-A (BoNTA) is licensed for the treatment of chronic migraine (CM), but it has been tested off-label as a therapeutic choice in other primary headaches (PHs). We aimed to provide a systematic review and expert opinion on BoNTA use in PHs, beyond CM.Areas covered: After providing an overview on PHs and mechanism of BoNTA action, we report the results of a systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, of BoNTA therapeutic trials in PHs beyond CM. Studies and results were reviewed and discussed, and levels of evidence were graded. We also collected data on relevant ongoing trials.Expert opinion: Although there are contradictory findings on PHs other than CM, BoNTA may represent a therapeutic option for patients who do not respond to conventional prophylactic treatments. Based on limited available evidence, BoNTA may be considered in refractory tension-type headache, trigeminal autonomic cephalalgias, primary stabbing headache, nummular headache, hypnic headache, and new daily persistent headache, after the primary nature of cephalalgia has been documented and other drugs have failed. Experienced physicians in BoNTA treatment are required to guide the therapeutic protocol for each patient to optimize good and safe outcomes.

Keywords: Primary headache; botulinum neurotoxin; cluster headache; episodic migraine; hemicrania continua; hypnic headache; new daily persistent headache; nummular headache; stabbing headache; suna; sunct; tension type headache; treatment; trigeminal autonomic cephalalgias.

Publication types

  • Systematic Review

MeSH terms

  • Botulinum Toxins, Type A* / therapeutic use
  • Expert Testimony
  • Humans
  • Migraine Disorders* / drug therapy
  • Off-Label Use
  • Trigeminal Autonomic Cephalalgias* / drug therapy


  • Botulinum Toxins, Type A