  Citation: Datta Gupta, A.; Edwards, S.; Smith, J.; Snow, J.; Visvanathan, R.; Tucker, G.; Wilson, D. A Systematic Review and Meta-Analysis of Efficacy of Botulinum Toxin A for Neuropathic Pain. Toxins 2022, 14, 36. https://doi.org/10.3390/ toxins14010036 Received: 14 December 2021 Accepted: 29 December 2021 Published: 3 January 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). toxins Review A Systematic Review and Meta-Analysis of Efficacy of Botulinum Toxin A for Neuropathic Pain Anupam Datta Gupta 1, * , Suzanne Edwards 2 , Jessica Smith 1 , John Snow 3 , Renuka Visvanathan 4 , Graeme Tucker 4 and David Wilson 4 1 Central Adelaide Rehabilitation Services, Queen Elizabeth Hospital, University of Adelaide, Adelaide, SA 5005, Australia; Jessica.Smith6@sa.gov.au 2 Adelaide Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia; Suzanne.Edwards@adelaide.edu.au 3 Lyell McEwin Hospital, Northern Adelaide Local Health Network, Adelaide, SA 5112, Australia; John.Snow@sa.gov.au 4 National Health and Medical Research Council Centre of Research Excellence in Frailty and Healthy Aging, Basil Hetzel Institute, 28 Woodville Road, Adelaide, SA 5011, Australia; Renuka.Visvanathan@adelaide.edu.au (R.V.); grtucker@adam.com.au (G.T.); David.Wilson@adelaide.edu.au (D.W.) * Correspondence: Anupam.Dattagupta@adelaide.edu.au Abstract: We performed a systematic review and meta-analysis of randomised controlled trials (RCTs) conducted from January 2005 to June 2021 to update the evidence of Botulinum toxin A (BoNT-A) in neuropathic pain (NP) in addition to quality of life (QOL), mental health, and sleep outcomes. We conducted a Cochrane Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria analysis of RCTs from the following data sources: EMBASE, CINAHL, WHO International Clinical Trial Registry Platform, ClinicalTrials.gov, Cochrane database, Cochrane Clinical Trial Register, Australia New Zealand Clinical Trials Registry, and EU Clinical Trials Register. Meta-analysis of 17 studies showed a mean final VAS reduction in pain in the intervention group of 2.59 units (95% confidence interval: 1.79, 3.38) greater than the mean for the placebo group. The overall mean difference for sleep, Hospital Anxiety and Depression Scale (HADS) anxiety, HADS depression, and QOL mental and physical sub-scales were, respectively, 1.10 (95% CI: -1.71, 3.90), 1.41 (95% CI: -0.61, 3.43), -0.16 (95% CI: -1.95, 1.63), 0.85 (95% CI: -1.85, 3.56), and -0.71 (95% CI: -3.39, 1.97), indicating no significance. BoNT-A is effective for NP; however, small-scale RCTs to date have been limited in evidence. The reasons for this are discussed, and methods for future RCTs are developed to establish BoNT-A as the first-line agent. Keywords: neuropathic pain; botulinum toxin; systematic review; meta-analysis Key Contribution: Neuropathic pain (NP) is a prevalent condition with inadequate response to currently available treatment. RCT evidence supports the role of Botulinum toxin A for NP but failed to provide the evidence for its use as the first line treatment. This systematic review with meta-analysis has called for the design of an RCT investigating botulinum toxin for its use as a first line agent. 1. Introduction Neuropathic pain (NP) resulting from damage or dysfunction of the peripheral or central nervous systems is one of the most common forms of pain, affecting up to 10% of the general population [1,2]. The current evidence of treatment outcomes puts success rates at best between 30% and 50%, and existing treatments come with significant side effects [3]. The effect of NP pervades patient sensation, thoughts, feelings, and behaviours. Treatment outcomes of these patients’ experiences have been described as “woefully inadequate” [1,3]. Toxins 2022, 14, 36. https://doi.org/10.3390/toxins14010036 https://www.mdpi.com/journal/toxins