PURPOSE: This pooled analysis of data from three Phase 3 studies investigated the effects of incobotulinumtoxinA on spasticity-related pain (SRP) in children/adolescents with uni-/bilateral cerebral palsy (CP). METHODS: Children/adolescents (ambulant and non-ambulant) were evaluated for SRP on increasingly difficult activities/tasks 4 weeks after each of four incobotulinumtoxinA injection cycles (ICs) using the Questionnaire on Pain caused by Spasticity (QPS; six modules specific to lower limb [LL] or upper limb [UL] spasticity and respondent type [child/adolescent, interviewer, or parent/caregiver]). IncobotulinumtoxinA doses were personalized, with all doses pooled for analysis. RESULTS: QPS key item responses were available from 331 and 155 children/adolescents with LL- and UL-spasticity, respectively, and 841/444 (LL/UL) of their parents/caregivers. IncobotulinumtoxinA efficacy was evident with the first IC. Efficacy was sustained and became more robust with further subsequent ICs. By Week 4 of the last (i.e. fourth) IC, 33.8-53.3% of children/adolescents reported complete SRP relief from their baseline pain for respective QPS items. Children/adolescents reported reductions in mean LL SRP intensity at levels that surpassed clinically meaningful thresholds. Similarly, parents/caregivers observed complete SRP relief and less frequent SRP with incobotulinumtoxinA. Similar results were found for UL SRP. CONCLUSION: These findings indicate that incobotulinumtoxinA could bring considerable benefit to children/adolescents with spasticity by reducing SRP, even during strenuous activities.

Beaumont Pediatric Physical Medicine and Rehabilitation Royal Oak Royal Oak MI USA

Department of Neurology Jagiellonian University Medical College Krakow Poland

Division of Paediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity Dr von Hauner Children's Hospital Ludwig Maximilian University of Munich Munich Germany

Faculty of Medicine and Dentistry and University Hospital Palacký University Olomouc Olomouc Czech Republic

Merz Therapeutics GmbH Frankfurt am Main Germany

Rady Children's Hospital San Diego CA USA

Shirley Ryan Ability Lab Northwestern Feinberg School of Medicine Chicago IL USA

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Westbom L, Rimstedt A, Nordmark E, Assessments of pain in children and adolescents with cerebral palsy: a retrospective population-based registry study, Dev Med Child Neurol 2017;59(8):858–63. doi: 10.1111/dmcn.13459. PubMed DOI

Parkinson KN, Dickinson HO, Arnaud C, Lyons A, Colver A, Pain in young people aged 13 to 17 years with cerebral palsy: cross-sectional, multicentre European study, Arch Dis Child 2013;98(6):434–40. doi: 10.1136/archdischild-2012-303482. PubMed DOI PMC

Parkinson KN, Gibson L, Dickinson HO, Colver AF, Pain in children with cerebral palsy: a cross-sectional multicentre European study, Acta Paediatr 2010;99(3):446–51. doi: 10.1111/j.1651-2227.2009.01626.x. PubMed DOI

Ostojic K, Paget S, Kyriagis M, Morrow A, Acute and chronic pain in children and adolescents with cerebral palsy: prevalence, interference, and management, Arch Phys Med Rehabil 2020;101(2):213–19. doi: 10.1016/j.apmr.2019.08.475. PubMed DOI

Michelsen JS, Normann G, Wong C, Analgesic effects of botulinum toxin in children with CP, Toxins (Basel) 2018;10(4):162. doi: 10.3390/toxins10040162. PubMed DOI PMC

Eriksson E, Hägglund G, Alriksson-Schmidt AI. Pain in children and adolescents with cerebral palsy - a cross-sectional register study of individuals, BMC Neurol 2020;20(1):15. doi: 10.1186/s12883-019-1597-7. PubMed DOI PMC

Hägglund G, Burman-Rimstedt A, Czuba T, Alriksson-Schmidt AI. Self-versus proxy-reported pain in children with cerebral palsy: a population-based registry study of children, J Prim Care Community Health 2020;11:1523. doi: 10.1177/2150132720911523. PubMed DOI PMC

Horwood L, Li P, Mok E, Shevell M, Constantin E. A systematic review and meta-analysis of the prevalence of sleep problems in children with cerebral palsy: how do children with cerebral palsy differ from each other and from typically developing children? Sleep Health 2019;5(6):555–71. doi: 10.1016/j.sleh.2019.08.006. PubMed DOI

Østergaard CS, Pedersen NSA, Thomasen A, Mechlenburg I, Nordbye-Nielsen K, Pain is frequent in children with cerebral palsy and negatively affects physical activity and participation, Acta Paediatr 2021;110(1):301–6. doi: 10.1111/apa.15341. PubMed DOI

Riquelme I, do Rosário RS, Vehmaskoski K, Natunen P, Montoya P. Influence of chronic pain in physical activity of children with cerebral palsy, NeuroRehabilitation 2018;43(2):113–23. doi: 10.3233/NRE-172409. PubMed DOI

Delgado MR, Hirtz D, Aisen M, Ashwal S, Fehlings DL, McLaughlin J, et al.., Practice parameter: pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 2010;74(4):336–43. doi: 10.1212/WNL.0b013e3181cbcd2f. PubMed DOI PMC

Spasticity in under 19s: management. Clinical guideline [CG145]. National Institute for Health and Care Excellence (NICE); 25 Jul 2012 [updated 29 Nov 2016; cited 11 Mar 2021]. Available from: http://www.nice.org.uk/guidance/cg145.

Hareb F, Bertoncelli CM, Rosello O, Rampal V, Solla F, Botulinum toxin in children with cerebral palsy: An update, Neuropediatrics 2020;51(1):1–5. doi: 10.1055/s-0039-1694988. PubMed DOI

Sadowska M, Sarecka-Hujar B, Kopyta I, Cerebral palsy: current opinions on definition, epidemiology, risk factors, classification and treatment options, Neuropsychiatr Dis Treat 2020;16:1505–18. doi: 10.2147/NDT.S235165. PubMed DOI PMC

Fehlings D, Novak I, Berweck S, Hoare B, Stott NS, Russo RN, et al.., Botulinum toxin assessment, intervention and follow-up for paediatric upper limb hypertonicity: international consensus statement, Eur J Neurol 2010;17(Suppl 2):38–56. doi: 10.1111/j.1468-1331.2010.03127.x. PubMed DOI

Love SC, Novak I, Kentish M, Desloovere K, Heinen F, Molenaers G, et al.., Botulinum toxin assessment, intervention and after-care for lower limb spasticity in children with cerebral palsy: international consensus statement, Eur J Neurol 2010;17(Suppl 2):9–37. doi: 10.1111/j.1468-1331.2010.03126.x. PubMed DOI

Almina S, Karile Y, Audrone P, Indre B, Analgesic effect of botulinum toxin in children with cerebral palsy: A systematic review, Toxicon 2021;199:60–7. doi: 10.1016/j.toxicon.2021.05.012. PubMed DOI

Roscigno CI, Addressing spasticity-related pain in children with spastic cerebral palsy, J Neurosci Nurs 2002;34(3):123–33. doi: 10.1097/01376517-200206000-00005. PubMed DOI

Li S, Francisco GE, The use of botulinum toxin for treatment of spasticity, Handb Exp Pharmacol 2021;263:127–46. doi: 10.1007/164_2019_315. PubMed DOI

Heinen F, Kanovský P, Schroeder AS, Chambers HG, Dabrowski E, Geister TL, et al.., IncobotulinumtoxinA for the treatment of lower-limb spasticity in children and adolescents with cerebral palsy: a phase 3 study, J Pediatr Rehabil Med 2021;14(2):183–97. doi: 10.3233/PRM-210040. PubMed DOI PMC

Kanovský P, Heinen F, Schroeder AS, Chambers HG, Dabrowski E, Geister TL, et al.. Safety and efficacy of repeat long-term incobotulinumtoxinA treatment for lower limb or combined upper/lower limb spasticity in children with cerebral palsy, J Pediatr Rehabil Med 2022;15(1):113–27. doi: 10.3233/PRM-210041. PubMed DOI PMC

Dabrowski E, Chambers HG, Gaebler-Spira D, Banach M, Kanovský P, Dersch H, et al.., IncobotulinumtoxinA efficacy/safety in upper-limb spasticity in pediatric cerebral palsy: Randomized controlled trial, Pediatr Neurol 2021;123:10–20. doi: 10.1016/j.pediatrneurol.2021.05.014. PubMed DOI

Heinen F, Kanovsky P, Schroeder AS, Chambers HG, Dabrowski E, Geister T, et al.., Pooled efficacy analysis of incobotulinumtoxinA in the multipattern treatment of upper- and lower-limb spasticity in children and adolescents with cerebral palsy. Poster presented at TOXINS 2021 Virtual Conference, January 16-17, 2021.

Schroeder AS, Kanovsky P, Chambers HG, Dabrowski E, Geister TL, Dersch H, et al.., Sustained efficacy of incobotulinumtoxinA over six injection cycles for the treatment of lower-limb spasticity in children and adolescents with cerebral palsy. Poster presented at TOXINS 2021 Virtual Conference, January 16-17, 2021.

Banach M, Kanovsky P, Schraeder AS, Chambers HG, Dabrowski E, Geister T, et al.., Safety of incobotulinumtoxinA in multipattern treatment of upper- and lower-limb spasticity in children/adolescents with cerebral palsy: a pooled analysis of three large phase 3 studies. Poster pre- sented at TOXINS 2021 Virtual Conference, January 16-17, 2021.

Geister TL, Quintanar-Solares M, Martin M, Aufhammer S, Asmus F, Qualitative development of the ‘Questionnaire on Pain caused by Spasticity (QPS),’ a pediatric patient-reported outcome for spasticity-related pain in cerebral palsy, Qual Life Res 2014;23(3):887–96. doi: 10.1007/s11136-013-0526-2. PubMed DOI PMC

Geister TL, Bushnell DM, Yang J, Zhang Y, Martin ML, Heilbronn A, et al.. Initial psychometric validation of the questionnaire on pain caused by spasticity (QPS), Health Qual Life Outcomes. 2017;15(1):229. doi: 10.1186/s12955-017-0804-8. PubMed DOI PMC

Heinen F, Bonfert M, Kanovský P, Schroeder AS, Chambers HG, Dabrowski E, et al.., Spasticity-related pain in children/adolescents with cerebral palsy, Part prevalence and clinical characteristics from a pooled analysis. J Pediatr Rehabil Med. 2022;15(1):129–43. doi: 10.3233/PRM-220011. PubMed DOI PMC

Bhardwaj P, Yadav RK Measuring pain in clinical trials: Pain scales, endpoints, and challenges, Int J Clin Exp Physiol 2015;2(3):43151–6.

Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al.., Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations, J Pain 2008;9(2):105–21. doi: 10.1016/j.jpain.2007.09.005. PubMed DOI

Hirschfeld G, Wager J, Schmidt P, Zernikow B, Minimally clinically significant differences for adolescents with chronic pain –Variability of ROC-based cut points, J Pain 2014;15(1):32–9. doi: 10.1016/j.jpain.2013.09.006. PubMed DOI

Ostojic K, Paget SP, Morrow AM, Management of pain in children and adolescents with cerebral palsy: a systematic review, Dev Med Child Neurol 2019;61(3):315–21. doi: 10.1111/dmcn.14088. PubMed DOI

McKinnon C, White J, Morgan P, Harvey A, Clancy C, Fahey M, et al.., Clinician perspectives of chronic pain management in children and adolescents with cerebral palsy and dyskinesia, Phys Occup Ther Pediatr 2021;41(3):244–58. doi: 10.1080/01942638.2020.1847236. PubMed DOI

Gooch JL, Sandell TV. Botulinum toxin for spasticity and athetosis in children with cerebral palsy, Arch Phys Med Rehabil 1996;77(5):508–11. doi: 10.1016/s0003-9993(96)90042-8. PubMed DOI

Rivard PF, Nugent AC, Symons FJ. Parent-proxy ratings of pain before and after botulinum toxin type A treatment for children with spasticity and cerebral palsy, Clin J Pain 2009;25(5):413–7. doi: 10.1097/AJP.0b013e31819a6d07. PubMed DOI

Lundy CT, Doherty GM, Fairhurst CB. Botulinum toxin type A injections can be an effective treatment for pain in children with hip spasms and cerebral palsy, Dev Med Child Neurol 2009;51(9):705–10. doi: 10.1111/j.1469-8749.2009.03315.x. PubMed DOI

Misra AK, Kumar S, Biswas A, Das SK, Botulinum toxin type A in subjects with spastic cerebral palsy from Eastern India, J Pediatr Neurol 2010;8(4):349–57. doi: 10.3233/PN-2010-0410. DOI

Chaléat-Valayer E, Parratte B, Colin C, Denis A, Oudin S, Bérard C, et al.., A French observational study of botulinum toxin use in the management of children with cerebral palsy: BOTULOSCOPE, Eur J Paediatr Neurol 2011;15(5):439–48. doi: 10.1016/j.ejpn.2010.04.006. PubMed DOI

Jabbari B Chapter 11. Botulinum neurotoxins for relief of pain associated with spasticity. In: Jabbari B. Botulinum toxin treatment of pain disorders. New York: Springer Science++ Business Media; 2015. pp. 153-66.

Copeland L, Edwards P, Thorley M, Donaghey S, Gascoigne-Pees L, Kentish M, et al.., Botulinum toxin A for nonambulatory children with cerebral palsy: a double blind randomized controlled trial, J Pediatr 2014;165(1):140–146.e4. doi: 10.1016/j.jpeds.2014.01.050. PubMed DOI

Russo RN, Crotty M, Miller MD, Murchland S, Flett P, Haan E. Upper-limb botulinum toxin A injection and occupational therapy in children with hemiplegic cerebral palsy identified from a population register: a single-blind, randomized, controlled trial, Pediatrics 2007;119(5):e1149–58. doi: 10.1542/peds.2006-2425. PubMed DOI

Dickinson HO, Parkinson KN, Ravens-Sieberer U, Schirripa G, Thyen U, Arnaud C, et al... Self-reported quality of life of 8-12-year-old children with cerebral palsy: a cross-sectional European study, Lancet. 2007;369(9580):2171–8. doi: 10.1016/S0140-6736(07)61013-7. PubMed DOI

Swiggum M, Hamilton ML, Gleeson P, Roddey T. Pain in children with cerebral palsy: implications for pediatric physical therapy, Pediatr Phys Ther 2010;22(1):86–92. doi: 10.1097/PEP.0b013e3181cd18a7. PubMed DOI

Houx L, Pons C, Saudreau H, Dubois A, Creusat M, Le Moine P, et al.. No pain, no gain? Children with cerebral palsy and their experience with physiotherapy, Ann Phys Rehabil Med 2021;64(3):101448.. doi: 10.1016/j.rehab.2020.10.002. PubMed DOI

Penner M, Xie WY, Binepal N, Switzer L, Fehlings D. Characteristics of pain in children and youth with cerebral palsy, Pediatrics 2013;132(2):e407–13. doi: 10.1542/peds.2013-0224. PubMed DOI

Ryan JM, Hensey O, McLoughlin B, Lyons A, Gormley J. Associations of sedentary behaviour, physical activity, blood pressure and anthropometric measures with cardiorespiratory fitness in children with cerebral palsy, PLoS One. 2015;10(4):e0123267. doi: 10.1371/journal.pone.0123267. PubMed DOI PMC

Badia M, Riquelme I, Orgaz B, Acevedo R, Longo E, Montoya P. Pain, motor function and health-related quality of life in children with cerebral palsy as reported by their physiotherapists, BMC Pediatr. 2014;14:192. doi: 10.1186/1471-2431-14-192. PubMed DOI PMC

Colver A, Rapp M, Eisemann N, Ehlinger V, Thyen U, Dickinson HO, et al... Self-reported quality of life of adolescents with cerebral palsy: a cross-sectional and longitudinal analysis, Lancet 2015;385(9969):705–16. doi: 10.1016/S0140-6736(14)61229-0. PubMed DOI PMC

Michelsen SI, Flachs EM, Damsgaard MT, Parkes J, Parkinson K, Rapp M, et al.., European study of frequency of participation of adolescents with and without cerebral palsy, Eur J Paediatr Neurol 2014;18(3):282–94. doi: 10.1016/j.ejpn.2013.12.003. PubMed DOI PMC

De Icco R, Perrotta A, Berra E, Allena M, Alfonsi E, Tamburin S, et al.., OnabotulinumtoxinA Reduces Temporal Pain Processing at Spinal Level in Patients with Lower Limb Spasticity, Toxins (Basel) 2019;11(6):359. doi: 10.3390/toxins11060359. PubMed DOI PMC

Matak I, Bölcskei K, Bach-Rojecky L, Helyes Z, Mechanisms of Botulinum toxin type A action on pain, Toxins (Basel) 2019;11(8):459. doi: 10.3390/toxins11080459. PubMed DOI PMC

Chambers HG, Kanovsky P, Schroeder AS, Dabrowski E, Geister TL, Dersch H, et al.. Absence of neutralizing antibody formation during incobotulinumtoxinA treatment of spasticity in botulinum toxin-naïve children with cerebral palsy: pooled analysis of three phase 3 studies. TOXINS 2021 Virtual Conference, January 16-17, 2021.