{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T03:06:54Z","timestamp":1785208014535,"version":"3.55.0"},"reference-count":35,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"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>Complex regional pain syndrome (CRPS) is a heterogeneous and disabling chronic pain condition characterized by maladaptive neuroplasticity involving persistent peripheral nociceptive input, autonomic dysregulation, and central sensitization. Despite increasing clinical use, the role of botulinum toxin in CRPS remains controversial, with inconsistent outcomes reported across studies. This review synthesizes mechanistic, translational, and clinical evidence suggesting that these apparent inconsistencies may be partly explained by heterogeneity in anatomical targeting and route of administration rather than absence of biological efficacy. Available evidence suggests that botulinum toxin may exhibit its most consistent therapeutic signal when delivered to neural structures directly implicated in dominant CRPS pathophysiology, particularly the sympathetic nervous system and proximal somatic afferents, whereas superficial or non-specific delivery strategies appear to yield more variable responses. Importantly, differences across anatomical targets should not be interpreted as evidence of comparative effectiveness, as observed variation may reflect phenotype selection, procedural heterogeneity, confounding, and differences in outcome reporting. By integrating experimental data, randomized trials, and case-based clinical evidence, an anatomy-informed, route-specific neuromodulation framework is proposed to reconcile existing findings and inform future research. This mechanism-informed perspective is intended to guide rational trial design and phenotype-aligned clinical application of botulinum toxin in CRPS, rather than to provide a definitive evidence-closing synthesis.<\/jats:p>","DOI":"10.3390\/toxins18040160","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T11:32:47Z","timestamp":1774611167000},"page":"160","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Botulinum Toxin as Targeted Neuromodulation in Complex Regional Pain Syndrome: An Anatomy-Informed Mechanistic Review"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9920-7188","authenticated-orcid":false,"given":"Areerat","family":"Suputtitada","sequence":"first","affiliation":[{"name":"Department of Rehabilitation Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Principles and Practice of Clinical Research (PPCR) Program, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.pain.2010.04.030","article-title":"Validation of proposed diagnostic criteria (the \u201cBudapest Criteria\u201d) for Complex Regional Pain Syndrome","volume":"150","author":"Harden","year":"2010","journal-title":"Pain"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1093\/pm\/pnad144","article-title":"Impact of different CRPS phenotypes and diagnostic criteria on quantitative sensory testing outcomes: Systematic review and meta-analysis","volume":"25","author":"Sobeeh","year":"2024","journal-title":"Pain Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.pain.2006.09.008","article-title":"The incidence of complex regional pain syndrome: A population-based study","volume":"129","author":"Huygen","year":"2007","journal-title":"Pain"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1097\/AJP.0000000000000234","article-title":"Factors Associated with Disability and Sick Leave in Early Complex Regional Pain Syndrome Type-1","volume":"32","author":"Bean","year":"2016","journal-title":"Clin. J. Pain"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"h2730","DOI":"10.1136\/bmj.h2730","article-title":"Complex regional pain syndrome","volume":"351","author":"Bruehl","year":"2015","journal-title":"BMJ"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S94","DOI":"10.1097\/01.j.pain.0000460344.54470.20","article-title":"Complex regional pain syndrome-significant progress in understanding","volume":"156","author":"Birklein","year":"2015","journal-title":"Pain"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/S1474-4422(10)70143-5","article-title":"Neuropathic pain: Diagnosis, pathophysiological mechanisms, and treatment","volume":"9","author":"Baron","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1111\/j.1468-1331.2010.02947.x","article-title":"Complex regional pain syndromes: New pathophysiological concepts and therapies","volume":"17","author":"Seifert","year":"2010","journal-title":"Eur. J. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1097\/ALN.0b013e3181e3db38","article-title":"An update on the pathophysiology of complex regional pain syndrome","volume":"113","author":"Bruehl","year":"2010","journal-title":"Anesthesiology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/msc.1107","article-title":"\u2018What I Really Needed Was the Truth\u2019. Exploring the Information Needs of People with Complex Regional Pain Syndrome","volume":"14","author":"Grieve","year":"2016","journal-title":"Musculoskelet. Care"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1097\/j.pain.0000000000000814","article-title":"Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: A randomized comparative trial","volume":"158","author":"Deer","year":"2017","journal-title":"Pain"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ejpain.2005.02.004","article-title":"Spinal cord stimulation for complex regional pain syndrome: A systematic review of the clinical and cost-effectiveness literature and assessment of prognostic factors","volume":"10","author":"Taylor","year":"2006","journal-title":"Eur. J. Pain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1097\/PHM.0b013e31825a134b","article-title":"Do botulinum toxins have a role in the management of neuropathic pain? A focused review","volume":"91","author":"Francisco","year":"2012","journal-title":"Am. J. Phys. Med. Rehabil."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.neuro.2005.01.017","article-title":"Review of a proposed mechanism for the antinociceptive action of botulinum toxin type A","volume":"26","author":"Aoki","year":"2005","journal-title":"Neurotoxicology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1016\/j.pain.2014.04.027","article-title":"Botulinum toxin type A selectivity for certain types of pain is associated with capsaicin-sensitive neurons","volume":"155","author":"Matak","year":"2014","journal-title":"Pain"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1002\/ana.21601","article-title":"Sympathetic block with botulinum toxin to treat complex regional pain syndrome","volume":"65","author":"Carroll","year":"2009","journal-title":"Ann. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1097\/ALN.0000000000004084","article-title":"Botulinum Toxin Type A for Lumbar Sympathetic Ganglion Block in Complex Regional Pain Syndrome: A Randomized Trial","volume":"136","author":"Yoo","year":"2022","journal-title":"Anesthesiology"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lee, Y., Lee, C.J., Choi, E., Lee, P.B., Lee, H.J., and Nahm, F.S. (2018). Lumbar Sympathetic Block with Botulinum Toxin Type A and Type B for the Complex Regional Pain Syndrome. Toxins, 10.","DOI":"10.3390\/toxins10040164"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Moon, Y.E., Choi, J.H., Park, H.J., Park, J.H., and Kim, J.H. (2016). Ultrasound-Guided Nerve Block with Botulinum Toxin Type A for Intractable Neuropathic Pain. Toxins, 8.","DOI":"10.3390\/toxins8010018"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1080\/03007995.2019.1626228","article-title":"Perineural injection of botulinum toxin-A in painful peripheral nerve injury\u2014A case series: Pain relief, safety, sensory profile and sample size recommendation","volume":"35","author":"Eitner","year":"2019","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"559","DOI":"10.4103\/1658-354X.140903","article-title":"Successful management of complex regional pain syndrome type 1 using single injection interscalene brachial plexus block","volume":"8","author":"Fallatah","year":"2014","journal-title":"Saudi J. Anaesth."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1002\/mds.1186","article-title":"Treatment of dystonic clenched fist with botulinum toxin","volume":"16","author":"Cordivari","year":"2001","journal-title":"Mov. Disord."},{"key":"ref_23","first-page":"419","article-title":"Intramuscular botulinum toxin in complex regional pain syndrome: Case series and literature review","volume":"14","author":"Kharkar","year":"2011","journal-title":"Pain Physician"},{"key":"ref_24","first-page":"761","article-title":"Responsiveness to botulinum toxin type A in muscles of complex regional pain patients with tonic dystonia","volume":"121","author":"Schilder","year":"2014","journal-title":"J. Neural Transm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e1847","DOI":"10.1097\/GOX.0000000000001847","article-title":"Botulinum Toxin A: A Novel Therapeutic Modality for Upper Extremity Chronic Regional Pain Syndrome","volume":"6","author":"Lessard","year":"2018","journal-title":"Plast. Reconstr. Surg. Glob. Open"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1111\/j.1526-4637.2010.00897.x","article-title":"Botulinum toxin A for treatment of allodynia of complex regional pain syndrome: A pilot study","volume":"11","author":"Safarpour","year":"2010","journal-title":"Pain Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Tereshko, Y., Dalla Torre, C., Lettieri, C., Belgrado, E., Gigli, G.L., and Valente, M. (2022). Subcutaneous BoNT\/A Injection for Intractable Pain and Disability in Complex Regional Pain Syndrome: A Case Report. Toxins, 14.","DOI":"10.3390\/toxins14060411"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.toxicon.2019.01.002","article-title":"Intra-articular botulinum toxin injection in complex regional pain syndrome: Case report and review of the literature","volume":"159","author":"Bellon","year":"2019","journal-title":"Toxicon"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"75","DOI":"10.2147\/JPR.S276095","article-title":"The Lateral Decubitus Body Position Might Improve the Safety of Ultrasound-Guided Supraclavicular Brachial Plexus Nerve Block","volume":"14","author":"Chen","year":"2021","journal-title":"J. Pain Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/sj.sc.3101404","article-title":"Complex regional pain syndrome\u2013diagnostic, mechanisms, CNS involvement and therapy","volume":"41","author":"Wasner","year":"2003","journal-title":"Spinal Cord"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e60","DOI":"10.1097\/PHM.0000000000001527","article-title":"The Change in Body Positioning to Improve Safety in Performing Ultrasound-Guided Supraclavicular Brachial Plexus Nerve Block","volume":"100","author":"Chen","year":"2021","journal-title":"Am. J. Phys. Med. Rehabil."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1111\/papr.12610","article-title":"Risk Factors for Post-treatment Complex Regional Pain Syndrome (CRPS): An Analysis of 647 Cases of CRPS from the Danish Patient Compensation Association","volume":"18","author":"Petersen","year":"2018","journal-title":"Pain Pract."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Klee, M., Karottki, N.C., and Biering-S\u00f8rensen, B. (2025). Intramuscular Botulinum Toxin for Complex Regional Pain Syndrome: A Narrative Review of Published Cases. Toxins, 17.","DOI":"10.3390\/toxins17070350"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1093\/pm\/pnac046","article-title":"Complex Regional Pain Syndrome: Practical Diagnostic and Treatment Guidelines, 5th Edition","volume":"23","author":"Harden","year":"2022","journal-title":"Pain Med."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Su, Y.C., Hsieh, P.C., Guo, Y.H., and Lin, Y.C. (2022). Meta-Analysis of Effectiveness and Safety of Botulinum Toxin in the Treatment of Complex Regional Pain Syndrome. Life, 12.","DOI":"10.3390\/life12122037"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/18\/4\/160\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T11:53:20Z","timestamp":1774612400000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/18\/4\/160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":35,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["toxins18040160"],"URL":"https:\/\/doi.org\/10.3390\/toxins18040160","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]}}}