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Drugs

, Volume 77, Issue 13, pp 1413–1422 | Cite as

Benefits and Risks of Non-Approved Injection Regimens for Botulinum Toxins in Spasticity

  • Andrea Santamato
  • Francesco Panza
Review Article

Abstract

Spasticity with muscle paresis and loss of dexterity is a common feature of upper motor neuron syndrome due to injuries or the pyramidal tract in several neurological conditions. Botulinum toxin type A has been considered the gold standard treatment for spasticity and movement disorders, with efficacy, reversibility, and low prevalence of complications. During the last 30 years, thousands of studies of its use have been performed, but few guidelines are available. Therefore, there is great variability in both the doses and intervals of administration and the approaches taken by clinicians with considerable experience in spasticity and movement disorder treatment. In the present review article, we provide a short overview of the benefits and risks of non-approved injection regimens and doses for botulinum toxins, focusing on the treatment of post-stroke spasticity, where there is great interest in the potential for increasing the number of treatment/years and the dose of botulinum toxin treatment for subjects with upper and lower limb spasticity. However, many doubts exist regarding antibody development and possible adverse effects.

Notes

Acknowledgements

We wish to thank Professor Anthony B. Ward for translation and preparation of the English text.

Compliance with Ethical Standards

Funding

Dr. Santamato and Dr. Panza reported no funding for the present paper.

Conflicts of interest

Dr. Santamato and Dr. Panza reported no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References

  1. 1.
    Das TK, Park DM. Effect of treatment with botulinum toxin on spasticity. Postgrad Med J. 1989;65:208–10.CrossRefGoogle Scholar
  2. 2.
    Kassicieh VD, Marciniak C, Do M, Lee CH, Jenkins S, Turkel C, Botox Post-Stroke Spasticity Study Group. Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med. 2002;347:395–400.CrossRefGoogle Scholar
  3. 3.
    Simpson DM, Gracies JM, Graham HK, Miyasaki JM, Naumann M, Russman B, Simpson LL, So Y, Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70:1691–8.CrossRefGoogle Scholar
  4. 4.
    Esquenazi A, Albanese A, Chancellor MB, Elovic E, Segal KR, Simpson DM, Smith CP, Ward AB. Evidence-based review and assessment of botulinum neurotoxin for the treatment of adult spasticity in the upper motor neuron syndrome. Toxicon. 2013;67:115–28.CrossRefGoogle Scholar
  5. 5.
    Wissel J, Ward AB, Erztgaard P, Bensmail D, Hecht MJ, Lejeune TM, Schnider P, Altavista MC, Cavazza S, Deltombe T, Duarte E, Geurts AC, Gracies JM, Haboubi NH, Juan FJ, Kasch H, Kätterer C, Kirazli Y, Manganotti P, Parman Y, Paternostro-Sluga T, Petropoulou K, Prempeh R, Rousseaux M, Slawek J. European consensus table on the use of botulinum toxin type A in adult spasticity. J Rehabil Med. 2009;41:13–25.CrossRefGoogle Scholar
  6. 6.
    Jost WH, Kohl A, Brinkmann S, Comes G. Efficacy and tolerability of a botulinum toxin type A free of complexing proteins (NT 201) compared with commercially available botulinum toxin type A (BOTOX) in healthy volunteers. J Neural Transm (Vienna). 2005;112:905–13.CrossRefGoogle Scholar
  7. 7.
    Dressler D, Mander G, Fink K. Measuring the potency labelling of onabotulinumtoxinA (Botox(®)) and incobotulinumtoxinA (Xeomin (®)) in an LD50 assay. J Neural Transm (Vienna). 2012;119:13–5.CrossRefGoogle Scholar
  8. 8.
    Sheean G, Lannin NA, Turner-Stokes L, Rawicki B, Snow BJ. Botulinum toxin assessment, intervention and after-care for upper limb hypertonicity in adults: international consensus statement. Eur J Neurol. 2010;17(Suppl 2):74–93.CrossRefGoogle Scholar
  9. 9.
    Sheean GL. Botulinum treatment of spasticity: why is it so difficult to show a functional benefit? Curr Opin Neurol. 2001;14:771–6.CrossRefGoogle Scholar
  10. 10.
    Benecke R. Clinical relevance of botulinum toxin immunogenicity. BioDrugs. 2012;26:e1–9.CrossRefGoogle Scholar
  11. 11.
    Bakheit AM, Thilmann AF, Ward AB, Poewe W, Wissel J, Muller J, Benecke R, Collin C, Muller F, Ward CD, Neumann C. A randomized, doubleblind, placebo-controlled, dose-ranging study to compare the efficacy and safety of three doses of botulinum toxin type A (Dysport) with placebo in upper limb spasticity after stroke. Stroke. 2000;31:2402–6.CrossRefGoogle Scholar
  12. 12.
    Kanovský P, Slawek J, Denes Z, Platz T, Sassin I, Comes G, Grafe S. Efficacy and safety of botulinum neurotoxin NT 201 in poststroke upper limb spasticity. Clin Neuropharmacol. 2009;32:259–65.CrossRefGoogle Scholar
  13. 13.
    Varghese-Kroll E, Elovic EP. Contralateral weakness and fatigue after high-dose botulinum toxin injection for management of poststroke spasticity. Am J Phys Med Rehabil. 2009;88:495–9.CrossRefGoogle Scholar
  14. 14.
    Crowner BE, Torres-Russotto D, Carter AR, Racette BA. Systemic weakness after therapeutic injections of botulinum toxin a: a case series and review of the literature. Clin Neuropharmacol. 2010;33:243–7.CrossRefGoogle Scholar
  15. 15.
    Thomas AM, Simpson DM. Contralateral weakness following botulinum toxin for poststroke spasticity. Muscle Nerve. 2012;46:443–8.CrossRefGoogle Scholar
  16. 16.
    Baricich A, Grana E, Carda S, Santamato A, Cisari C, Invernizzi M. High doses of onabotulinumtoxinA in post-stroke spasticity: a retrospective analysis. J Neural Transm (Vienna). 2015;122:1283–7.CrossRefGoogle Scholar
  17. 17.
    Hesse S, Jahnke MT, Luecke D, Mauritz KH. Short-term electrical stimulation enhances the effectiveness of Botulinum toxin in the treatment of lower limb spasticity in hemiparetic patients. Neurosci Lett. 1995;201:37–40.CrossRefGoogle Scholar
  18. 18.
    Dressler D. Routine use of Xeomin® in patients previously treated with Botox®: long term results. Eur J Neurol. 2009;16(Suppl 2):2–5.CrossRefGoogle Scholar
  19. 19.
    Santamato A, Panza F, Ranieri M, Frisardi V, Micello MF, Filoni S, Fortunato F, Intiso D, Basciani M, Logroscino G, Fiore P. Efficacy and safety of higher doses of botulinum toxin type A NT 201 free from complexing proteins in the upper and lower limb spasticity after stroke. J Neural Transm. 2013;120:469–76.CrossRefGoogle Scholar
  20. 20.
    Intiso D, Simone V, Di Rienzo F, Iarossi A, Pazienza L, Santamato A, Maruzzi G, Basciani M. High doses of a new botulinum toxin type A (NT-201) in adult patients with severe spasticity following brain injury and cerebral palsy. NeuroRehabilitation. 2014;34:515–22.PubMedGoogle Scholar
  21. 21.
    Dressler D, Adib Saberi F, Kollewe K, Schrader C. Safety aspects of incobotulinumtoxinA high-dose therapy. J Neural Transm (Vienna). 2015;122:327–33.CrossRefGoogle Scholar
  22. 22.
    Invernizzi M, Carda S, Molinari C, Stagno D, Cisari C, Baricich A. Heart Rate Variability (HRV) modifications in adult hemiplegic patients after botulinum toxin type A (nt-201) injection. Eur J Phys Rehabil Med. 2015;51:353–9.PubMedGoogle Scholar
  23. 23.
    Wissel J, Bensmail D, Ferreira JJ, Molteni F, Satkunam L, Moraleda S, Rekand T, McGuire J, Scheschonka A, Flatau-Baqué B, Simon O, Rochford ET, Dressler D, Simpson DM, TOWER study investigators. Safety and efficacy of incobotulinumtoxinA doses up to 800 U in limb spasticity: the TOWER study. Neurology. 2017;88:1321–8.CrossRefGoogle Scholar
  24. 24.
    Santamato A, Panza F, Intiso D, Baricich A, Picelli A, Smania N, Fortunato F, Seripa D, Fiore P, Ranieri M. Long-term safety of repeated high doses of incobotulinumtoxinA injections for the treatment of upper and lower limb spasticity after stroke. J Neurol Sci. 2017. doi: 10.1016/j.jns.2017.04.052 (Epub ahead of print).CrossRefPubMedGoogle Scholar
  25. 25.
    Lance JW. Symposium synopsis. In: Feldman RG, Young RR, Koella WP, editors. Spasticity: disordered motor control. Chicago: Year Book Medical Publishers; 1980. p. 485–94.Google Scholar
  26. 26.
    Franceschini M, Iocco M, Molteni F, Santamato A, Smania N, Italian Spasticity Study Group. Management of stroke patients submitted to botulinum toxin type A therapy: a Delphi survey of an Italian expert panel of specialist injectors. Eur J Phys Rehabil Med. 2014;50:525–33.PubMedGoogle Scholar
  27. 27.
    Santamato A, Micello MF, Panza F, Fortunato F, Picelli A, Smania N, Logroscino G, Fiore P, Ranieri M. Adhesive taping vs. daily manual muscle stretching and splinting after botulinum toxin type A injection for wrist and fingers spastic overactivity in stroke patients: a randomized controlled trial. Clin Rehabil. 2015;29:50–8.CrossRefGoogle Scholar
  28. 28.
    Hafer-Macko CE, Ryan AS, Ivey FM, Macko RF. Skeletal muscle changes after hemiparetic stroke and potential beneficial effects of exercise intervention strategies. J Rehabil Res Dev. 2008;45:261–72.CrossRefGoogle Scholar
  29. 29.
    Vattanasilp W, Ada L, Crosbie J. Contribution of thixotropy, spasticity, and contracture to ankle stiffness after stroke. J Neurol Neurosurg Psychiatry. 2000;69:34–9.CrossRefGoogle Scholar
  30. 30.
    de Paiva A, Meunier FA, Molgó 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 USA. 1999;96:3200–5.CrossRefGoogle Scholar
  31. 31.
    Fortuna R, Horisberger M, Vaz MA, Herzog W. Do skeletal muscle properties recover following repeat onabotulinum toxin A injections? J Biomech. 2013;46:2426–33.CrossRefGoogle Scholar
  32. 32.
    Fortuna R, Vaz MA, Sawatsky A, Hart DA, Herzog W. A clinically relevant BTX-A injection protocol leads to persistent weakness, contractile material loss, and an altered mRNA expression phenotype in rabbit quadriceps muscles. J Biomech. 2015;48:1700–6.CrossRefGoogle Scholar
  33. 33.
    Childers MK. The importance of electromyographic guidance and electrical stimulation for injection of botulinum toxin. Phys Med Rehabil Clin N Am. 2003;14:781–92.CrossRefGoogle Scholar
  34. 34.
    Walter U, Dressler D. Ultrasound-guided botulinum toxin injections in neurology: technique, indications and future perspectives. Expert Rev Neurother. 2014;14:923–36.CrossRefGoogle Scholar
  35. 35.
    Picelli A, Roncari L, Baldessarelli S, Berto G, Lobba D, Santamato A, Fiore P, Smania N. Accuracy of botulinum toxin type A injection into the forearm muscles of chronic stroke patients with spastic flexed wrist and clenched fist: manual needle placement evaluated using ultrasonography. J Rehabil Med. 2014;46:1042–5.CrossRefGoogle Scholar
  36. 36.
    Santamato A, Micello MF, Panza F, Fortunato F, Baricich A, Cisari C, Pilotto A, Logroscino G, Fiore P, Ranieri M. Can botulinum toxin type A injection technique influence the clinical outcome of patients with post-stroke upper limb spasticity? A randomized controlled trial comparing manual needle placement and ultrasound-guided injection techniques. J Neurol Sci. 2014;347:39–43.CrossRefGoogle Scholar
  37. 37.
    Picelli A, Tamburin S, Bonetti P, Fontana C, Barausse M, Dambruoso F, Gajofatto F, Santilli V, Smania N. Botulinum toxin type A injection into the gastrocnemius muscle for spastic equinus in adults with stroke: a randomized controlled trial comparing manual needle placement, electrical stimulation and ultrasonography-guided injection techniques. Am J Phys Med Rehabil. 2012;91:957–64.CrossRefGoogle Scholar
  38. 38.
    Kwon JY, Hwang JH, Kim JS. Botulinum toxin A injection into calf muscles for treatment of spastic equinus in cerebral palsy: a controlled trial comparing sonography and electric stimulation-guided injection techniques: a preliminary report. Am J Phys Med Rehabil. 2010;89:279–86.CrossRefGoogle Scholar
  39. 39.
    US Food and Drug Administration.FDA gives update on botulinum toxin safety warnings; established names of drugs changed. https://wayback.archive-it.org/7993/20170112032330/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm175013.htm. Accessed 24 May 2017.
  40. 40.
    Allergan Pharmaceuticals. BOTOX® (OnabotulinumtoxinA). Package insert. ©2009. Allergan Pharmaceuticals, Inc., Irvine.Google Scholar
  41. 41.
    Merz Pharmaceuticals GmbH. Xeomin® US Prescribing Information [updated July 2011]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125360s045lbl.pdf. Accessed 24 May 2017.
  42. 42.
    Royal College of Physicians. Guidance to good practice. Guidelines for the use of botulinum toxin (BTX) in the management of spasticity in adults. London: Royal College of Physicians; 2002.Google Scholar
  43. 43.
    Santamato A, Micello MF, Ranieri M, et al. Employment of higher doses of botulinum toxin type A to reduce spasticity after stroke. J Neurol Sci. 2015;350:1–6.CrossRefGoogle Scholar
  44. 44.
    Dressler D, Saberi FA. Safety of botulinum toxin short interval therapy using incobotulinumtoxin A. J Neural Transm (Vienna). 2017;124:437–40.CrossRefGoogle Scholar
  45. 45.
    Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and meta-analysis. Curr Med Res Opin. 2004;20:981–90.CrossRefGoogle Scholar
  46. 46.
    Bakheit AM, Ward CD, McLellan DL. Generalised botulism-like syndrome after intramuscular injections of botulinum toxin type A: a report of two cases. J Neurol Neurosurg Psychiatry. 1997;62:198.CrossRefGoogle Scholar
  47. 47.
    Dressler D, Dirnberger G. Botulinum toxin therapy: risk factors for therapy failure. Mov Disord. 2000;15(suppl 2):51.Google Scholar
  48. 48.
    Greene P, Fahn S, Diamond B. Development of resistance to botulinum toxin type A in patients with torticollis. Mov Disord. 1994;9:213–7.CrossRefGoogle Scholar
  49. 49.
    Frevert J, Dressler D. Complexing proteins in botulinum toxin type A drugs: a help or a hindrance? Biologics. 2010;4:325–32.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Dressler D, Hallett M. Immunological aspects of Botox, Dysport and Myobloc/NeuroBloc. Eur J Neurol. 2006;13(Suppl 1):11–5.CrossRefGoogle Scholar
  51. 51.
    Fabbri M, Leodori G, Fernandes RM, Bhidayasiri R, Marti MJ, Colosimo C, Ferreira JJ. Neutralizing antibody and botulinum toxin therapy: a systematic review and meta-analysis. Neurotox Res. 2016;29:105–17.CrossRefGoogle Scholar
  52. 52.
    Yablon SA, Brashear A, Gordon MF, Elovic EP, Turkel CC, Daggett S, Liu J, Brin MF. Formation of neutralizing antibodies in patients receiving botulinum toxin type A for treatment of poststroke spasticity: a pooled-data analysis of three clinical trials. Clin Ther. 2007;29:683–90.CrossRefGoogle Scholar
  53. 53.
    Dressler D, Bigalke H, Benecke R. Botulinum toxin type B in antibody-induced botulinum toxin type A therapy failure. J Neurol. 2003;250:1263–5.CrossRefGoogle Scholar
  54. 54.
    Trompetto C, Marinelli L, Mori L, Puce L, Pelosin E, Serrati C, Fattapposta F, Rinalduzzi S, Abbruzzese G, Currà A. Do flexible inter-injection intervals improve the effects of botulinum toxin A treatment in reducing impairment and disability in patients with spasticity? Med Hypotheses. 2017;102:28–32.CrossRefGoogle Scholar
  55. 55.
    Gracies JM, Brashear A, Jech R, McAllister P, Banach M, Valkovic P, Walker H, Marciniak C, Deltombe T, Skoromets A, Khatkova S, Edgley S, Gul F, Catus F, De Fer BB, Vilain C, Picaut P, International AbobotulinumtoxinA Adult Upper Limb Spasticity Study Group. Safety and efficacy of abobotulinumtoxinA for hemiparesis in adults with upper limb spasticity after stroke or traumatic brain injury: a double-blind randomised controlled trial. Lancet Neurol. 2015;14:992–1001.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Physical Medicine and Rehabilitation Section, “OORR Hospital”University of FoggiaFoggiaItaly
  2. 2.“Fondazione Turati” Rehabilitation CentreViesteItaly
  3. 3.Complex Structure of Geriatrics, Department of Medical SciencesIRCCS “Casa Sollievo della Sofferenza”FoggiaItaly
  4. 4.Unit of Neurodegenerative Disease, Department of Basic Medicine Sciences, Neuroscience, and Sense OrgansUniversity of Bari “Aldo Moro”BariItaly
  5. 5.Unit of Neurodegenerative Disease, Department of Clinical Research in NeurologyUniversity of Bari “Aldo Moro” at “Pia Fondazione Card. G. Panico”TricaseItaly

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