{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:13:11Z","timestamp":1787029991306,"version":"build-2736575974"},"reference-count":54,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,6,22]],"date-time":"2025-06-22T00:00:00Z","timestamp":1750550400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Background: The aim of this systematic review is to investigate effectiveness and safety of sedation\u2013analgesia techniques in controlling pain during botulinum injections in patients with cerebral palsy (CP). Methods: The Pubmed, Cinahl, and Scopus databases were searched. Inclusion criteria were as follows: cerebral palsy; any type of outcome measure regarding pain and side effects assessment; any type of studies; and English language. RoB2 and Robins-I were applied to assess the risk of bias. Tables and forest plots synthetized the findings. Results: Seventeen reports were included; most regarded pain control, and ten investigated side effects. Three were RCTs, three were controlled, and twelve were observational studies. Several techniques were used, often in combination, such as non-pharmacological approaches (clown care or virtual reality); topical anesthesia with Emla\u00ae\u00ae, vapocoolant spray, or ice; and light-to-deep sedation with inhaled nitrous oxide, intranasal fentanyl, rectal, enteral, or intravenous midazolam, or intravenous ketamine or propofol. Vomiting and oxygen desaturation were uncommon complications. Conversely, the pooled incidence of other minor side effects was 6.39% (95% CI: 1.47\u201314.42%) under the random-effects model, with considerable heterogeneity. Conclusions: All the techniques are safe, if administered in an appropriate setting. Deep sedation is more effective in pain control but requires an anesthetist. A combined individualized approach is preferrable. PROSPERO CRD42025639999.<\/jats:p>","DOI":"10.3390\/toxins17070317","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T04:50:05Z","timestamp":1750654205000},"page":"317","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Procedural Pain Management in Patients with Cerebral Palsy Undergoing Botulinum Toxin Injection: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0170-3766","authenticated-orcid":false,"given":"Silvia","family":"Faccioli","sequence":"first","affiliation":[{"name":"Pediatric Rehabilitation Unit, Azienda Unit\u00e0 Sanitaria Locale IRCCS of Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Ehsani","sequence":"additional","affiliation":[{"name":"Physical Medicine and Rehabilitation Unit, Sant\u2019Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1166-2961","authenticated-orcid":false,"given":"Shaniko","family":"Kaleci","sequence":"additional","affiliation":[{"name":"Surgical Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Tonini","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Tagliani","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Vetrano","sequence":"additional","affiliation":[{"name":"Physical Medicine and Rehabilitation Unit, Sant\u2019Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Sassi","sequence":"additional","affiliation":[{"name":"Pediatric Rehabilitation Unit, Azienda Unit\u00e0 Sanitaria Locale IRCCS of Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1067\/mem.2003.138","article-title":"Underuse of analgesia in very young pediatric patients with isolated painful injuries","volume":"41","author":"Alexander","year":"2003","journal-title":"Ann. Emerg. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1197\/j.aem.2004.07.014","article-title":"Factors affecting emergency department opioid administration to severely injured patients","volume":"11","author":"Neighbor","year":"2004","journal-title":"Acad. Emerg. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1067\/mem.2003.275","article-title":"Emergency department analgesia for fracture pain","volume":"42","author":"Brown","year":"2003","journal-title":"Ann. Emerg. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1542\/peds.99.5.711","article-title":"Pain management in the emergency department: Patterns of analgesic utilization","volume":"99","author":"Petrack","year":"1997","journal-title":"Pediatrics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1097\/PEC.0b013e31822877f7","article-title":"Pain assessment for children: Overcoming challenges and optimizing care","volume":"27","author":"Drendel","year":"2011","journal-title":"Pediatr. Emerg. Care."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1111\/j.1742-6723.2008.01150.x","article-title":"Procedural sedation in children in the emergency department: A PREDICT study","volume":"21","author":"Borland","year":"2009","journal-title":"Emerg. Med. Australas."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1111\/1467-8624.00200","article-title":"Children\u2019s memories for painful cancer treatment procedures: Implications for distress","volume":"71","author":"Chen","year":"2000","journal-title":"Child. Dev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1001\/archpedi.152.2.147","article-title":"Consequences of inadequate analgesia during painful procedures in children","volume":"152","author":"Weisman","year":"1998","journal-title":"Arch. Pediatr. Adolesc. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.ejpn.2006.08.006","article-title":"European consensus Table 2006 on botulinum toxin for children with cerebral palsy","volume":"10","author":"Heinen","year":"2006","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1212\/01.wnl.0000311389.26145.95","article-title":"Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology","volume":"70","author":"Simpson","year":"2008","journal-title":"Neurology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.ejpn.2008.07.008","article-title":"Long-term use of botulinum toxin type A in children with cerebral palsy: Treatment consistency","volume":"13","author":"Molenaers","year":"2009","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1111\/dmcn.13135","article-title":"Should botulinum toxin A injections be repeated in children with cerebral palsy? A systematic review","volume":"58","author":"Kahraman","year":"2016","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1016\/j.apmr.2006.08.343","article-title":"Parent evaluation of spasticity treatment in cerebral palsy using botulinum toxin type A","volume":"87","author":"Symons","year":"2006","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1017\/S0012162206000697","article-title":"\u2018Why do children with cerebral palsy discontinue therapy with botulinum toxin A?","volume":"48","author":"Kirschner","year":"2006","journal-title":"\u2019 Dev. Med. Child Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S59","DOI":"10.1097\/01.PHM.0000141131.66648.E9","article-title":"Botulinum toxin A injections in children: Technique and dosing issues","volume":"83","author":"Kinnett","year":"2004","journal-title":"Am. J. Phys. Med. Rehabil."},{"key":"ref_16","unstructured":"(2025, May 11). Statement on ASA Physical Status Classification System. Available online: https:\/\/www.asahq.org\/standards-and-practice-parameters\/statement-on-asa-physical-status-classification-system."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"160","DOI":"10.4103\/0970-9185.182085","article-title":"Intravenous sub-anesthetic ketamine for perioperative analgesia","volume":"32","author":"Gorlin","year":"2016","journal-title":"J. Anaesthesiol. Clin. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1097\/00000539-200107000-00022","article-title":"The management of preoperative anxiety in children: An update","volume":"93","author":"McCann","year":"2001","journal-title":"Anesth. Analg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e97","DOI":"10.1183\/20734735.017416","article-title":"Respiratory illness in children with disability: A serious problem?","volume":"12","author":"Proesmans","year":"2016","journal-title":"Breathe"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1136\/adc.88.1.75","article-title":"Respiratory problems in children with neurological impairment","volume":"88","author":"Seddon","year":"2003","journal-title":"Arch. Dis. Child."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.bjae.2021.08.003","article-title":"Anaesthesia and cerebral palsy","volume":"22","author":"Hayakawa","year":"2022","journal-title":"BJA Educ."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1111\/pan.14359","article-title":"Respiratory prehabilitation in pediatric anesthesia in children with muscular and neurologic disease","volume":"32","author":"Zielinski","year":"2022","journal-title":"Paediatr. Anaesth."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ejpn.2009.09.005","article-title":"The updated European Consensus 2009 on the use of Botulinum toxin for children with cerebral palsy","volume":"14","author":"Heinen","year":"2010","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1002\/pmrj.12713","article-title":"A consensus statement on the use of botulinum toxin in pediatric patients","volume":"14","author":"Vova","year":"2022","journal-title":"PM&R"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1177\/08830738241288431","article-title":"Efficacy and Safety of OnabotulinumtoxinA for the Treatment of Pediatric Upper and Lower Limb Spasticity: Results From 2 Open-Label, Long-term Extension Trials","volume":"40","author":"Gormley","year":"2024","journal-title":"J. Child. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/S0140-6736(06)68230-5","article-title":"Procedural sedation and analgesia in children","volume":"367","author":"Krauss","year":"2006","journal-title":"Lancet"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e804","DOI":"10.1097\/PR9.0000000000000804","article-title":"Pediatric pain treatment and prevention for hospitalized children","volume":"5","author":"Friedrichsdorf","year":"2019","journal-title":"Pain. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.jpain.2004.05.001","article-title":"Children\u2019s memory for pain: Overview and implications for practice","volume":"5","author":"Marche","year":"2004","journal-title":"J. Pain."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1111\/j.1469-8749.2008.03069.x","article-title":"Effectiveness of sedation using nitrous oxide compared with enteral midazolam for botulinum toxin A injections in children","volume":"50","author":"Zier","year":"2008","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1111\/j.1469-8749.2009.03355.x","article-title":"Effectiveness of sedation using nitrous oxide compared with enteral midazolam for botulinum toxin A injections in children","volume":"51","author":"Kumar","year":"2009","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1016\/j.apmr.2012.03.012","article-title":"Effect of topical anesthetics on needle insertion pain during botulinum toxin type A injections for limb spasticity","volume":"93","author":"Fung","year":"2012","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.anpedi.2018.12.018","article-title":"Protocolo sedoanalg\u00e9sico para la infiltraci\u00f3n de toxina botul\u00ednica A en par\u00e1lisis cerebral [Sedation-analgesia protocol for the injection of botulinum toxin A in cerebral palsy]","volume":"91","year":"2019","journal-title":"An. Pediatr."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ben-Pazi, H., Cohen, A., Kroyzer, N., Lotem-Ophir, R., Shvili, Y., Winter, G., Deutsch, L., and Pollak, Y. (2017). Clown-care reduces pain in children with cerebral palsy undergoing recurrent botulinum toxin injections- A quasi-randomized controlled crossover study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0175028"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1111\/dmcn.15303","article-title":"Biofeedback assisted relaxation training and distraction therapy for pain in children undergoing botulinum neurotoxin A injections: A crossover randomized controlled trial","volume":"64","author":"Ostojic","year":"2022","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/j.rehab.2009.09.001","article-title":"Effectiveness of nitrous oxide and analgesic cream (lidocaine and prilocaine) for prevention of pain during intramuscular botulinum toxin injections in children","volume":"52","author":"Brochard","year":"2009","journal-title":"Ann. Phys. Rehabil. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/j.1469-8749.2009.03297_1.x","article-title":"Effectiveness of sedation using nitrous oxide compared with enteral midazolam for botulinum toxin A injections in children","volume":"51","author":"Gubbay","year":"2009","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.ejpn.2010.12.006","article-title":"Determining the technical and clinical factors associated with pain for children undergoing botulinum toxin injections under nitrous oxide and anesthetic cream","volume":"15","author":"Brochard","year":"2011","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.ejpn.2011.07.006","article-title":"Conscious sedation or general anaesthetic for intramuscular botulinum toxin injections in children\u2014A two centre cross-sectional prospective audit","volume":"16","author":"Forrester","year":"2012","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1111\/apa.13710","article-title":"A rectally administered combination of midazolam and ketamine was easy, effective and feasible for procedural pain in children with cerebral palsy","volume":"106","author":"Nilsson","year":"2017","journal-title":"Acta Paediatr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.ejpn.2015.11.009","article-title":"Ketamine-based procedural sedation and analgesia for botulinum toxin A injections in children with cerebral palsy","volume":"20","author":"Chow","year":"2016","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_41","first-page":"e61","article-title":"Pain management during botulinum toxin A injections in cerebral palsy children Pediatric PMR","volume":"60","year":"2017","journal-title":"Ann. Phys. Rehabil. Med."},{"key":"ref_42","first-page":"193","article-title":"Factors affecting procedural pain in children during and immediately after intramuscular botulinum toxin injections for spasticity","volume":"11","author":"Fisher","year":"2018","journal-title":"J. Pediatr. Rehabil. Med."},{"key":"ref_43","first-page":"199","article-title":"Decreasing pediatric pain and agitation during botulinum toxin injections for spasticity with virtual reality: Lessons learned from clinical use","volume":"11","author":"Chau","year":"2018","journal-title":"J. Pediatr. Rehabil. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1002\/pmrj.12146","article-title":"Safety and Efficacy of a Propofol and Ketamine Based Procedural Sedation Protocol in Children with Cerebral Palsy Undergoing Botulinum Toxin A Injections","volume":"11","author":"Louer","year":"2019","journal-title":"PM&R"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.rehab.2018.12.004","article-title":"Do clowns attenuate pain and anxiety undergoing botulinum toxin injections in children?","volume":"63","author":"Houx","year":"2020","journal-title":"Ann. Phys. Rehabil. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: A revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"i4919","DOI":"10.1136\/bmj.i4919","article-title":"ROBINS-I: A tool for assessing risk of bias in non-randomized studies of interventions","volume":"355","author":"Sterne","year":"2016","journal-title":"BMJ"},{"key":"ref_48","first-page":"2127","article-title":"Methodological quality of case series studies: An introduction to the JBI critical appraisal tool","volume":"18","author":"Munn","year":"2020","journal-title":"JBI Evid. Synth."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1136\/bmj.2.5920.656","article-title":"Controlled sedation with alphaxalone-alphadolone","volume":"22","author":"Ramsay","year":"1974","journal-title":"Br. Med. J."},{"key":"ref_50","unstructured":"(2025, May 11). Standard Clinico-Organizzativi SIAARTI-SARNePI per l\u2019anestesia in et\u00e0 pediatrica. Available online: https:\/\/www.siaarti.it\/news\/371363."},{"key":"ref_51","unstructured":"(2025, May 11). Analgesia e sedazione procedurale in radiologia diagnostica ed operativa pediatrica. Available online: https:\/\/www.siaarti.it\/news\/1788257. SIAARTI."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"n160","DOI":"10.1136\/bmj.n160","article-title":"PRISMA 2020 explanation and elaboration: Updated guidance and exemplars for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Higgins, J.P.T., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M.J., and Welch, V.A. (2019). Cochrane Handbook for Systematic Reviews of Interventions, John Wiley & Sons. [2nd ed.].","DOI":"10.1002\/9781119536604"},{"key":"ref_54","unstructured":"(2025, May 18). MedCalc Statistical Software version 14.8.1. Available online: http:\/\/www.medcalc.org."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/17\/7\/317\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:56:44Z","timestamp":1760032604000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/17\/7\/317"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,22]]},"references-count":54,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["toxins17070317"],"URL":"https:\/\/doi.org\/10.3390\/toxins17070317","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,22]]}}}