Onabotulinum Toxin Injection and Headaches

  • Andrew BlumenfeldEmail author
  • Stephen D. Silberstein
  • Michael L. Oshinsky


Onabotulinum toxin A (botulinum toxin type A, Botox®) is a focally acting neurotoxin that inhibits the release of neurotransmitters from presynaptic nerves. Preclinical evidence has shown that onabotulinum toxin A has anti-inflammation and antinociceptive properties. Onabotulinum toxin A is a safe and effective treatment for chronic migraine. Seven botulinum toxin serotypes are produced by Clostridium botulinum (i.e., A, B, C, D, E, F, and G). Botulinum toxins consist of a heavy chain of 100 kDa and a light chain of 50 kDa linked by a single disulfide bond and are synthesized as a relatively inactive single-chain polypeptide.


Botulinum Toxin Chronic Migraine Chronic Daily Headache Headache Frequency Cervical Dystonia 
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  1. 1.
    Cui M, Khanijou S, Rubino J, Aoki KR. Botulinum toxin A inhibits the inflammatory pain in the rat formalin model. Soc Neurosci. 2000;26:656 (Abstract).Google Scholar
  2. 2.
    Cui M, Li Z, You S, Khanijou S, Aoki K. Subcutaneous BOTOX inhibits formalin-induced local neurotransmitter release and spinal nociceptive processing. 2002. 17 Aug 2002. (GENERIC) Ref Type: Conference Proceeding.Google Scholar
  3. 3.
    Aoki KR. Physiology and pharmacology of therapeutic botulinum neurotoxins. Curr Probl Dermatol. 2002;30:107–16.PubMedCrossRefGoogle Scholar
  4. 4.
    Smuts JA, Baker MK, Smuts M, Stassen JM, Rossouw E, Barnard PW. Prophylactic treatment of chronic tension-type headache using botulinum toxin type A. Eur J Neurol. 1999;6:99–102.CrossRefGoogle Scholar
  5. 5.
    Binder WJ, Brin MF, Blitzer A, Shoenrock LD, Pogoda JM. Botulinum toxin type A (Botox) for treatment of migraine headaches: an open-label study. Otolaryngol Head Neck Surg. 2000;123:669–76.PubMedCrossRefGoogle Scholar
  6. 6.
    Freund BJ, Schwartz M. Treatment of chronic cervical-associated headache with botulinum toxin A: a pilot study. Headache. 2000;40:231–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Silberstein SD, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. Headache. 2000;40:445–50.PubMedCrossRefGoogle Scholar
  8. 8.
    Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Headache. 2005;45:293–307.PubMedCrossRefGoogle Scholar
  9. 9.
    Blumenfeld AM, Schim JD, Chippendale TJ. Botulinum toxin type A and divalproex sodium for prophylactic treatment of episodic or chronic migraine. Headache. 2008;48:210–20.PubMedCrossRefGoogle Scholar
  10. 10.
    Dodick D, Aurora S, Turkel C, et al. Botulinum toxin type A for treatment of chronic migraine; the double blind phase of the PREEMPT clinical program. Cephalalgia. 2009;29 Suppl 1:34 (Abstract).Google Scholar
  11. 11.
    Dodick DW, Turkel CC, DeGryse RE, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010;50:921–36.PubMedCrossRefGoogle Scholar
  12. 12.
    Diener H-C, 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. 2010;30:804–14.PubMedCrossRefGoogle Scholar
  13. 13.
    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. 2010;30:793–803.PubMedCrossRefGoogle Scholar
  14. 14.
    Blumenfeld A, Silberstein SD, Dodick DW, Aurora SK, Turkel CC, Binder WJ. Method of injection of onabotulinumtoxinA for chronic migraine: a safe, well-tolerated, and effective treatment paradigm based on the PREEMPT clinical program. Headache. 2010;50:1406–18.PubMedCrossRefGoogle Scholar
  15. 15.
    Rowland LP. Stroke, spasticity, and botulinum toxin. N Engl J Med. 2002;347:382–3.PubMedCrossRefGoogle Scholar
  16. 16.
    Dolly O. Synaptic transmission: inhibition of neurotransmitter release by botulinum toxins. Headache. 2003;43 Suppl 1:S16–24.PubMedCrossRefGoogle Scholar
  17. 17.
    Aoki KR, Guyer B. Botulinum toxin type A and other botulinum toxin serotypes; a comparative review of biochemical and pharmacological actions. Eur J Neurol. 2001;8 suppl 5:21–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Foran PG, Mohammed N, Lisk GO, et al. Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A. Basis for distinct durations of inhibition of exocytosis in central neurons. J Biol Chem. 2003;278:1363–71.PubMedCrossRefGoogle Scholar
  19. 19.
    de Paiva A, Meunier FA, Molgo J, Aoki KR, Dolly JO. Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci U S A. 1999;96:3200–5.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Meunier FA, Lisk G, Sesardic D, Dolly JO. Dynamics of motor nerve terminal remodeling unveiled using SNARE-cleaving botulinum toxins: the extent and duration are dictated by the sites of SNAP-25 truncation. Mol Cell Neurosci. 2003;22:454–66.PubMedCrossRefGoogle Scholar
  21. 21.
    Naumann M, Yakoleff A, Durif F. A randomized, double-masked, crossover comparison of the efficacy and safety of botulinum toxin type A produced from the original bulk toxin source and current bulk toxin source for the treatment of cervical dystonia. J Neurol. 2002;249:57–63.PubMedCrossRefGoogle Scholar
  22. 22.
    Brashear A, Gordon MF, Elovic E, et al. Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med. 2002;347:395–400.PubMedCrossRefGoogle Scholar
  23. 23.
    Jankovic J, Schwartz KS. Longitudinal experience with botulinum toxin injections for treatment of blepharospasm and cervical dystonia. Neurology. 1993;43:834–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Lew MF, Adornato BT, Duane D, et al. Botulinum toxin type B: a double-blind, placebo-controlled, safety and efficacy study in cervical dystonia. Neurology. 1997;49:701–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Brashear A, Lew MF, Dykstra DD, et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-responsive cervical dystonia. Neurology. 1999;53:1439–46.PubMedCrossRefGoogle Scholar
  26. 26.
    Brin MF, Lew MF, Adler CH, et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia. Neurology. 1999;53:1431–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Jankovic J, Brin MF. Therapeutic uses of botulinum toxin. N Engl J Med. 1991;324:1186–94.PubMedCrossRefGoogle Scholar
  28. 28.
    Jankovic J. Medical therapy and botulinum toxin in dystonia. Adv Neurol. 1998;78:169–83.PubMedGoogle Scholar
  29. 29.
    Kitamura Y, Matsuka Y, Spigelman I, et al. Botulinum toxin type a (150 kDa) decreases exaggerated neurotransmitter release from trigeminal ganglion neurons and relieves neuropathy behaviors induced by infraorbital nerve constriction. Neuroscience. 2009;159:1422–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Oshinsky ML. Botulinum toxins and migraine: how does it work. Pract Neurol. 2004;(Suppl):10–3.Google Scholar
  31. 31.
    Matak I, Bach-Rojecky L, Filipovi B, Lackovic Z. Behavioral and immunohistochemical evidence for central antinociceptive activity of botulinum toxin A. Neuroscience. 2011;186:201–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Mark MA, Colvin LA, Duggan AW. Spontaneous release of immunoreactive neuropeptide Y from the central terminals of large diameter primary afferents of rats with peripheral nerve injury. Neuroscience. 1998;83:581–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Gardell LR, Vanderah TW, Gardell SE, et al. Enhanced evoked excitatory transmitter release in experimental neuropathy requires descending facilitation. J Neurosci. 2003;23:8370–9.PubMedGoogle Scholar
  34. 34.
    Oshinsky ML, Luo J. Neurochemistry of trigeminal activation in an animal model of migraine. Headache. 2006;46:S39–44.PubMedCrossRefGoogle Scholar
  35. 35.
    Oshinsky M, Gomonchareonsiri S. Dural stimulation in awake rats: a model for recurrent headache. Headache. 2011;47:1026–36.CrossRefGoogle Scholar
  36. 36.
    Ma W, Quirion R. Increased calcitonin gene-related peptide in neuroma and invading macrophages is involved in the upregulation of interleukin-6 and thermal hyperalgesia in a rat model of neuropathy. J Neurochem. 2006;98:180–92.PubMedCrossRefGoogle Scholar
  37. 37.
    Mika J, Rojeswka E, Makuch W, et al. The effect of botulinum neurotoxin A on sciatic nerve injury-induced neuroimmunological changes in rat dorsal root ganglia and spinal cord. Neuroscience. 1998;2011:358–66.Google Scholar
  38. 38.
    Humm AM, Pabst C, Lauterburg T, Burgunder JM. Enkephalin and aFGF are differentially regulated in rat spinal motoneurons after chemodenervation with botulinum toxin. Exp Neurol. 2000;161:361–72.PubMedCrossRefGoogle Scholar
  39. 39.
    Malick A, Burstein R. Peripheral and central sensitization during migraine. Funct Neurol. 2000;15 Suppl 3:28–35.PubMedGoogle Scholar
  40. 40.
    Guyuron B, Tucker T, Davis J. Surgical treatment of migraine headaches. Plast Reconstr Surg. 2002;109:2183–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Ishikawa H, Mitsui Y, Yoshitomi T, et al. Presynaptic effects of botulinum toxin type A on the neuronally evoked response of albino and pigmented rabbit iris sphincter and dilator muscles. Jpn J Ophthalmol. 2000;44:106–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Welch MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon. 2000;38:245–58.PubMedCrossRefGoogle Scholar
  43. 43.
    Morris JL, Jobling P, Gibbins IL. Differential inhibition by botulinum neurotoxin A of cotransmitters released from autonomic vasodilator neurons. Am J Physiol Heart Circ Physiol. 2001;281:H2124–32.PubMedGoogle Scholar
  44. 44.
    Gazerani P, Staahl C, Drewes AM, Arendt-Nielsen L. The effects of botulinum toxin type A on capsaicin-evoked pain, flare, and secondary hyperalgesia in an experimental model of trigeminal sensitization. Pain. 2006;122:315–25.PubMedCrossRefGoogle Scholar
  45. 45.
    Schmitt WJ, Slowey E, Fravi N, Weber S, Burgunder JM. Effect of Botulinum toxin A injections in the treatment of chronic tension-type headache: a double-blind, placebo-controlled trial. Headache. 2001;41:658–64.PubMedCrossRefGoogle Scholar
  46. 46.
    Silberstein SD, Gobel H, Jensen R, et al. Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study. Cephalalgia. 2006;26:790–800.PubMedCrossRefGoogle Scholar
  47. 47.
    Freitag FG. Botulinum toxin type A (BnTxA) in the treatment of chronic migraine. Headache. 2006;46:849 (Abstract).Google Scholar
  48. 48.
    Mathew NT, Kaup AO. The use of botulinum toxin type A in headache treatment. Curr Treat Options Neurol. 2002;4:365–73.PubMedCrossRefGoogle Scholar
  49. 49.
    Silberstein SD, Lipton RB, Solomon S, Mathew NT. Classification of daily and near daily headaches: proposed revisions to the IHS classification. Headache. 1994;34:1–7.CrossRefGoogle Scholar
  50. 50.
    Aurora SK, Nagesh V, Norris LL, Welch KM. Functional imaging of subcortical nociceptive structures in response to treatment of chronic daily headache. Neurology. 2002;58(7):A91 (Abstract).Google Scholar
  51. 51.
    Blumenfeld AM, Binder W, Silbrestein SD, Blizter A. Procedures for administering botulinum toxin type A for migraine and tension-type headache. Headache. 2003;43:884–91.PubMedCrossRefGoogle Scholar
  52. 52.
    Aurora SK, Gawel M, Brandes J, Pokta S, VanDenburgh AM. Botulinum toxin type A prophylactic treatment for episodic migraine using a modified follow-the-pain treatment paradigm: a randomized, double-blind, placebo-controlled Phase II study. Headache. 2005;45:766–840.CrossRefGoogle Scholar
  53. 53.
    Silberstein SD, Winner PK, Chmiel JJ. Migraine preventive medication reduces resource utilization. Headache. 2003;43:171–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Smith T, Stoneman J. Medication overuse headache from antimigraine therapy: clinical features, pathogenesis and management. Drugs. 2004;64:2503–14.PubMedCrossRefGoogle Scholar
  55. 55.
    Freitag FG, McAllister P, Freund B, et al. Botulinum toxin type A for the prophylaxis of chronic daily headache in migraineurs: effect on acute headache pain medication use. J Neurol. 2005;252:62 (Abstract).CrossRefGoogle Scholar
  56. 56.
    Silberstein SD, Olesen J, Bousser MG, et al. The International Classification of Headache Disorders, 2nd edition (ICHD-II)–revision of criteria for 8.2 Medication-overuse headache. Cephalalgia. 2005;25:460–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Saper JR, Brandes J, Wrubel B, Dodick DW, DeGryse R, VanDenburgh AM. Efficacy of prophylactic treatment with Botulinum Toxin Type A in migraineurs with chronic daily headache overusing acute headache pain medications. Headache. 2005;45:825 (Abstract).Google Scholar
  58. 58.
    Silberstein SD, Stark SR, Lucas SM, Christie SN, DeGryse RE, Turkel CC. Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. 2005;80:1126–37.PubMedCrossRefGoogle Scholar
  59. 59.
    Porter JA, Hill JEG, McKenzie B, Porter K, Williams Guynn N. A randomized, double-blind comparison of botulinum toxin Type A (BOTOX) and divalproex sodium (DEPAKOTE) for the prophylactic treatment of episodic migraine: a pilot study. Headache. 2006;46:847 (Abstract).CrossRefGoogle Scholar
  60. 60.
    Blumenfeld A, Schim J. Botulinum toxin type A compared with divalproex sodium for the prophylactic treatment of migraine: a 9 month randomized, double-blind trial. Headache. 2006;46:847 (Abstract).Google Scholar
  61. 61.
    Cady RK, Schreiber CP, Porter JA, Blumenfeld AM, Farmer KU. A multi-center double-blind pilot comparison of onabotulinumtoxinA and topiramate for the prophylactic treatment of chronic migraine. Headache. 2011;51(1):21–32.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Andrew Blumenfeld
    • 1
    Email author
  • Stephen D. Silberstein
    • 2
  • Michael L. Oshinsky
    • 2
  1. 1.The Headache Center of Southern CaliforniaSan DiegoUSA
  2. 2.Department of NeurologyJefferson Headache Center, Thomas Jefferson UniversityPhiladelphiaUSA

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