Skip to main content

Advertisement

Log in

Action mechanisms of Onabotulinum toxin-A: hints for selection of eligible patients

  • SYMPOSIUM - TREATMENT PERSPECTIVES FOR Onabotulinum toxin-A
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

In the past few decades, the so-feared botulinum toxin has conversely acquired the role of a ever more versatile therapeutic substance, used in an increasing number of pathological situations, including chronic headache and more precisely in the prophylaxis of chronic migraine. The medical use of botulinum toxin allowed to better understand its multiple mechanisms of action. Investigations about the pathophysiology of primary and secondary headaches has shown a series of common biological elements that frequently are also targets of the action of botulinum toxin. These increasing evidences allowed to identify some biochemical, neurophysiological and radiological markers that may be useful in the individuation of patients which probably will respond to the treatment with Onabotulinum toxin-A among chronic migraineurs. These predictors include CGRP plasmatic levels, specific laser-evoked potential responses, peculiar brain MRI and fMRI and characteristic clinical manifestations. Unfortunately, at now, these predictors are still not available for the clinical practice. Furthermore, the better knowledge about biology of headaches and regarding botulinum toxin activities may also help in directing investigations on the possible use of Onabotulinum toxin-A in other headaches different from migraine. This review tries to show in detail these biological mechanisms and their implication in selecting patients eligible for the treatment with Onabotulinum toxin-A.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Welch MJ, Purkiss JR, Foster KA (2000) Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon 38(2):245–258 (PMID: 10665805)

    Article  CAS  PubMed  Google Scholar 

  2. Waseem Z, Boulias C, Gordon A, Ismail F, Sheean G, Furlan AD (2011) Botulinum toxin injections for low-back pain and sciatica. Cochrane Database Syst Rev CD1:008257. doi:10.1002/14651858.CD008257.pub2 (Review, PMID: 21249702)

    Google Scholar 

  3. Silberstein SD. (2016) The use of botulinum toxin in the management of headache disorders. Semin Neurol. Thieme Medical Publishers, 333 Seventh Avenue, New York, NY 10001, USA (PMID 26866501)

  4. Aurora SK, Dodick DW et al (2010) PREEMPT 1 Chronic Migraine Study Group. Onabotulinum toxin A for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia 30(7):793–803. doi:10.1177/0333102410364676 (Epub 2010 Mar 17)

    Article  CAS  PubMed  Google Scholar 

  5. Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE, Lipton RB, Silberstein SD, Brin MF (2010) PREEMPT 2 Chronic Migraine Study Group. Onabotulinum toxin A for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia 30(7):804–814. doi:10.1177/0333102410364677 (Epub 2010 Mar 17)

    Article  CAS  PubMed  Google Scholar 

  6. McCoy ES, Taylor-Blake B, Zylka MJ (2012) CGRPα-expressing sensory neurons respond to stimuli that evoke sensations of pain and itch. PLoS One 7(5):e36355. doi:10.1371/journal.pone.0036355 (PMID: 22563493)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hou Q et al (2011) Keratinocyte expression of calcitonin gene-related peptide β: implications for neuropathic and inflammatory pain mechanisms. Pain 152(9):2036–2051. doi:10.1016/j.pain.2011.04.033 (PMID: 21641113)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Malon JT, Cao L (2016) Calcitonin gene-related peptide contributes to peripheral nerve injury-induced mechanical hypersensitivity through CCL5 and p38 pathways. J Neuroimmunol 15(297):68–75. doi:10.1016/j.jneuroim.2016.05.003 (PMID: 27397078)

    Article  Google Scholar 

  9. Vega AV, et al. (2010) CGRP, a vasodilator neuropeptide that stimulates neuromuscular transmission and EC coupling. Curr Vasc Pharmacol 8(3):394–403

    Article  CAS  PubMed  Google Scholar 

  10. Goadsby PJ (2005) Calcitonin gene-related peptide antagonists as treatments of migraine and other primary headaches. Drugs 65(18):2557–2567

    Article  CAS  PubMed  Google Scholar 

  11. Tfelt-Hansen P et al (2009) Calcitonin gene-related peptide in blood: is it increased in the external jugular vein during migraine and cluster headache? A review. J Headache Pain 10(3):137–143. doi:10.1007/s10194-009-0112-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Arulmani U et al (2004) Calcitonin gene-related peptide and its role in migraine pathophysiology. Eur J Pharmacol 500(1–3):315–330

    Article  CAS  PubMed  Google Scholar 

  13. Durham P (2006) Calcitonin gene-related peptide (CGRP) and migraine. Headache 48(Suppl 1):S3–S8. doi:10.1111/j.1526-4610.2006.00483.x (PMC 3134175, freely accessible, PMID 16927957)

    Article  Google Scholar 

  14. Cernuda-Morollón E (2013) Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology 81(14):1191–1196. doi:10.1212/WNL.0b013e3182a6cb72

    Article  PubMed  Google Scholar 

  15. Wang Y et al. (2016) Induction of calcitonin gene-related peptide expression in rats by cortical spreading depression. Cephalalgia. doi:10.1177/0333102416678388

    Google Scholar 

  16. Ashina H et al. (2016) CGRP in human models of primary headaches. Cephalalgia. doi:10.1177/0333102416684344

    Google Scholar 

  17. Edvinsson L et al. (2005) Neurobiology in primary headaches. Brain Res Brain Res Rev 48(3):438–456

    Article  PubMed  Google Scholar 

  18. Leone M et al. (2017) Advances in the understanding of cluster headache. Expert Rev Neurother 17(2):165–172. doi:10.1080/14737175.2016.1216796

    Article  CAS  PubMed  Google Scholar 

  19. Neeb L et al. (2016) Methylprednisolone blocks interleukin 1 beta induced calcitonin gene related peptide release in trigeminal ganglia cells. J Headache Pain 17:19. doi:10.1186/s10194-016-0609-x

    Article  PubMed  PubMed Central  Google Scholar 

  20. Frese A et al. (2005) Calcitonin gene-related peptide in cervicogenic headache. Cephalalgia 25(9):700–703

    Article  CAS  PubMed  Google Scholar 

  21. Cernuda-Morollón E et al. (2015) Onabotulinum toxin A decreases interictal CGRP plasma levels in patients with chronic migraine. Pain 156(5):820–824. doi:10.1097/j.pain.0000000000000119

    Article  PubMed  Google Scholar 

  22. Lacković Z et al. (2016) Activity of botulinum toxin type A in cranial dura: implications for treatment of migraine and other headaches. Br J Pharmacol 173(2):279–291. doi:10.1111/bph.13366

    Article  PubMed  Google Scholar 

  23. Antonucci F et al (2016) SNAP-25, a known presynaptic protein with emerging postsynaptic functions. Front Synaptic Neurosci 24(8):7. doi:10.3389/fnsyn.2016.00007 (review, PMID: 27047369)

    Google Scholar 

  24. Garrity P (2010) Analysis of Drosophila TRPA1 reveals an ancient origin for human chemical nociception. Nature 464:25. doi:10.1038/nature08848597 (Macmillan Publishers Limited, all rights reserved © 2010)

    Google Scholar 

  25. Clapham DE (2003) TRP channels as cellular sensors. Nature 426(6966):517–524 (review, PMID: 14654832)

    Article  CAS  PubMed  Google Scholar 

  26. Starowicz K, Nigam S, Di Marzo V (2007) Biochemistry and pharmacology of endovanilloids. Pharmacol Ther 114(1):13–33

    Article  CAS  PubMed  Google Scholar 

  27. Blair NT et al (2015) Transient receptor potential channels. Last modified on 21 May 2015. IUPHAR/BPS guide to pharmacology

  28. Story GM et al (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112(6):819–829 (PMID: 12654248)

    Article  CAS  PubMed  Google Scholar 

  29. Geppetti P, Holzer P (1996) Neurogenic inflammation. CRC Press, Boca Raton

    Google Scholar 

  30. Caterina MJ, Schumacher MA et al (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824

    Article  CAS  PubMed  Google Scholar 

  31. Gibson HE, Edwards JG et al (2008) TRPV1 channels mediate long-term depression at synapses on hippocampal interneurons. Neuron 57(5):746–759. doi:10.1016/j.neuron.2007.12.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huang D, Li S, Dhaka A et al (2012) Expression of the transient receptor potential channels TRPV1, TRPA1 and TRPM8 in mouse trigeminal primary afferent neurons innervating the dura. Mol Pain 8:66. doi:10.1186/1744-8069-8-66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Diamond S, Freitag F, Phillips SB et al (2000) Intranasal civamide for the acute treatment of migraine headache. Cephalalgia 20(6):597–602

    Article  CAS  PubMed  Google Scholar 

  34. Fusco BM, Barzoi G, Agro F (2003) Repeated intranasal capsaicin applications to treat chronic migraine. Br J Anaesth 90(6):812

    Article  CAS  PubMed  Google Scholar 

  35. Nassini R, Materazzi S, Vriens J et al (2012) The ‘headache tree’ via umbellulone and TRPA1 activates the trigeminovascular system. Brain 135:376–390

    Article  PubMed  Google Scholar 

  36. Edelmayer RM, Le LN, Yan J et al (2012) Activation of TRPA1 on dural afferents: a potential mechanism of headache pain. Pain 153:1949–1958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Materazzi S, Benemei S, Fusi C et al (2013) Parthenolide inhibits nociception and neurogenic vasodilatation in the trigeminovascular system by targeting the TRPA1 channel. Pain 154:2750–2758

    Article  CAS  PubMed  Google Scholar 

  38. Zhong J, Minassi A, Prenen J et al (2011) Umbellulone modulates TRP channels. Pflugers Arch 2011(462):861–870

    Article  Google Scholar 

  39. O’Neill J, Brock C, Olesen AE et al (2012) Unravelling the mystery of capsaicin: a tool to understand and treat pain. Pharmacol Rev 64:939–971

    Article  PubMed  PubMed Central  Google Scholar 

  40. Burstein R, Zhang X et al (2014) Selective inhibition of meningeal nociceptors by botulinum neurotoxin type A: therapeutic implications for migraine and other pains. Cephalalgia 34(11):853–869. doi:10.1177/0333102414527648 (Epub 2014 Apr 2)

    Article  PubMed  PubMed Central  Google Scholar 

  41. Amaya F, Oh-hashi K et al (2003) Local inflammation increases vanilloid receptor 1 expression within distinct subgroups of DRG neurons. Brain Res 963:190–196

    Article  CAS  PubMed  Google Scholar 

  42. Schueler M, Messlinger K et al (2013) Extracranial projections of meningeal afferents and their impact on meningeal nociception and headache. Pain 154:1622–1631

    Article  PubMed  Google Scholar 

  43. Zhang X, Strassman AM, Novack V (2016) Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors’ responses to stimulation of TRPV1 and TRPA1 channels: are we getting closer to solving this puzzle? Cephalalgia 36(9):875–886. doi:10.1177/0333102416636843 (Epub 2016 Mar 16 PMID: 26984967)

    Article  PubMed  PubMed Central  Google Scholar 

  44. Denner AC et al. (2016) Role of transient receptor potential ankyrin 1 receptors in rodent models of meningeal nociception—experiments in vitro. Eur J Pain. doi:10.1002/ejp.986

    PubMed  Google Scholar 

  45. Devesa I, Ferrándiz-Huertas C et al (2014) αCGRP is essential for algesic exocytotic mobilization of TRPV1 channels in peptidergic nociceptors. Proc Natl Acad Sci USA 111(51):18345–18350. doi:10.1073/pnas.1420252111 (Epub 2014 Dec 8)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Valeriani M et al. (2003) Reduced habituation to experimental pain in migraine patients: a CO(2) laser evoked potential study. Pain 105(1–2):57–64

    Article  CAS  PubMed  Google Scholar 

  47. de Tommaso M et al. (2016) Effects of OnabotulintoxinA on Habituation of Laser Evoked Responses in Chronic Migraine. Toxins (Basel) 8(6). doi:10.3390/toxins8060163

  48. Hubbard CS, Becerra L, Smith JH et al (2016) Brain changes in responders vs. non-responders in chronic migraine: markers of disease reversal. Front Hum Neurosci 10:497 (eCollection 2016, PMID: 27766076)

    Article  PubMed  PubMed Central  Google Scholar 

  49. Finkel AG (2015) Botulinum toxin and the treatment of headache: a clinical review. Toxicon 107(Pt A):114–119. doi:10.1016/j.toxicon.2015.09.008

    Article  CAS  PubMed  Google Scholar 

  50. Miller S, Correia F, Lagrata S, Matharu MS (2015) Onabotulinum toxin A for Hemicrania continua: open label experience in 9 patients. J Headache Pain 16:19. doi:10.1186/s10194-015-0502-z

    Article  PubMed  PubMed Central  Google Scholar 

  51. Khalil M et al. (2013) Hemicrania continua responsive to botulinum toxin type a: a case report. Headache 53(5):831–833, doi:10.1111/head.12086

    Article  PubMed  Google Scholar 

  52. Rozen D et al. (2006) Treatment of tension-type headache with botox: a review of the literature. Mt Sinai J Med 73(1):493–498

    PubMed  Google Scholar 

  53. Mathew NT et al. (2008) Predictors of response to botulinum toxin type A (BoNTA) in chronic daily headache. Headache 48(2):194–200

    PubMed  Google Scholar 

  54. Bratbak DF et al (2016) Pilot study of sphenopalatine injection of onabotulinum toxin A for the treatment of intractable chronic cluster headache. Cephalalgia 36(6):503–509. doi:10.1177/0333102415597891 (PMID: 26232105)

    Article  PubMed  Google Scholar 

  55. Cernuda-Morollón E et al (2014) CGRP and VIP levels as predictors of efficacy of onabotulinum toxin type A in chronic migraine. Headache 54(6):987–995. doi:10.1111/head.12372 (Epub 2014 May 6)

    Article  PubMed  Google Scholar 

  56. Kim CC et al (2010) Predicting migraine responsiveness to botulinum toxin type A injections. Arch Dermatol 146(2):159–163. doi:10.1001/archdermatol.2009.356

    Article  CAS  PubMed  Google Scholar 

  57. Pagola I et al. (2014) Predictive factors of the response to treatment with onabotulinum toxin A in refractory migraine. Rev Neurol 58(6):241–246

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Carlo Lovati.

Ethics declarations

Conflict of interest

I certify that there is no actual or potential conflict of interest in relation to this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lovati, C., Giani, L. Action mechanisms of Onabotulinum toxin-A: hints for selection of eligible patients. Neurol Sci 38 (Suppl 1), 131–140 (2017). https://doi.org/10.1007/s10072-017-2884-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-017-2884-y

Keywords

Navigation