{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T07:35:12Z","timestamp":1774596912991,"version":"3.50.1"},"reference-count":28,"publisher":"Frontiers Media SA","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":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pain Res."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Current pharmacotherapy options for neuropathic pain (NPP) are limited. RM191A is a novel copper-amino acid complex that mimics superoxide dismutase and has anecdotal evidence for fast-onset analgesia. The aim of this pilot randomized clinical trial (RCT) was to evaluate the safety and efficacy of a topical gel containing RM191A compared with placebo in adults with moderate-to-severe chronic peripheral NPP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>This single-site study was conducted at an Australian pain clinic. Eligible patients were randomized to receive either active or placebo gel, applied four times daily to the painful site for 3 days, followed by a 4-day washout and crossover to the other gel. Co-primary outcomes were changes in the Numerical Pain Rating Scale (NPRS) scores for average pain from baseline to Days 1 and 3. Secondary outcomes included safety\/tolerability and neuropathic pain characteristics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Twenty-seven participants (14 males, 13 females, mean age 67\u2009\u00b1\u200915 years) were screened, with 25 proceeding to randomization and 24 completing both treatment periods. No first-order (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.816) or second-order carryover effects (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.322) were detected. The Day 1 coprimary outcome was not significant (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.323), but there was a trend toward one-sided statistical significance for the Day 3 coprimary outcome (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.073). The mean reduction in NPRS Average Pain by Day 3 was significant for the active gel (\u20130.9\u2009\u00b1\u20091.6,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.012) but not the placebo (\u20130.2\u2009\u00b1\u20091.7,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.485).\n                      <jats:italic>Post hoc<\/jats:italic>\n                      analysis revealed the superiority of the active gel in participants with Douleur Neuropathique 4 (DN4) scores \u22654 (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200915,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.047). The number needed to treat (NNT) for 50% pain reduction by Day 3 was 8 (95% CI: greater than 3.9). The active gel was more effective against burning pain, paroxysmal pain, and paraesthesia\/dysesthesia than other types of NPP. There were no serious adverse events, while four (16%) participants reported mild skin irritation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This small pilot RCT found that 3 days of RM191A gel modestly reduced chronic peripheral neuropathic pain. The NNT of 8 compares favorably with topical lidocaine (14.5) and is similar to duloxetine (7.4) and gabapentinoids (8.9). Larger, longer studies in well-defined neuropathic pain populations are warranted.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>\n                      ANZCTRN 12617000206325.\n                      <jats:ext-link>https:\/\/www.anzctr.org.au\/<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpain.2026.1772899","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T06:37:48Z","timestamp":1774593468000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Topical RM191A gel for chronic peripheral neuropathic pain: randomized, double-blind, placebo-controlled, crossover pilot study"],"prefix":"10.3389","volume":"7","author":[{"given":"Paul A.","family":"Glare","sequence":"first","affiliation":[{"name":"Northern Clinical School, Sydney Medical School, University of Sydney","place":["Sydney, NSW, Australia"]},{"name":"Pain Management Research Institute, Kolling Institute","place":["St Leonards, NSW, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Brooker","sequence":"additional","affiliation":[{"name":"Pain Management Research Institute, Kolling Institute","place":["St Leonards, NSW, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew D.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Pain Management Research Institute, Kolling Institute","place":["St Leonards, NSW, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J.","family":"Costa","sequence":"additional","affiliation":[{"name":"Pain Management Research Institute, Kolling Institute","place":["St Leonards, NSW, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofia","family":"Casbolt","sequence":"additional","affiliation":[{"name":"RR MedSciences Pty Ltd.","place":["Sydney, NSW, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Llewellyn","family":"Casbolt","sequence":"additional","affiliation":[{"name":"RR MedSciences Pty Ltd.","place":["Sydney, NSW, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e1066","DOI":"10.1097\/PR9.0000000000001066","article-title":"Epidemiology of neuropathic pain: an analysis of prevalence and associated factors in UK biobank","volume":"8","author":"Baskozos","year":"2023","journal-title":"Pain Rep"},{"key":"B2","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1097\/j.pain.0000000000001365","article-title":"The IASP classification of chronic pain for ICD-11: chronic neuropathic pain","volume":"160","author":"Scholz","year":"2019","journal-title":"Pain"},{"key":"B3","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/S1474-4422(25)00068-7","article-title":"Pharmacotherapy and non-invasive neuromodulation for neuropathic pain: a systematic review and meta-analysis","volume":"24","author":"Soliman","year":"2025","journal-title":"Lancet Neurol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1097\/j.pain.0000000000001136","article-title":"Emerging therapies for neuropathic pain: new molecules or new indications for old treatments?","volume":"159","author":"Bouhassira","year":"2018","journal-title":"Pain"},{"key":"B5","doi-asserted-by":"publisher","first-page":"101790","DOI":"10.1016\/j.redox.2020.101790","article-title":"Skin protective and regenerative effects of RM191A, a novel superoxide dismutase mimetic","volume":"38","author":"Shariev","year":"2021","journal-title":"Redox Biol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/j.pain.2007.01.011","article-title":"Reactive oxygen species (ROS) are involved in enhancement of NMDA-receptor phosphorylation in animal models of pain","volume":"131","author":"Gao","year":"2007","journal-title":"Pain"},{"key":"B7","doi-asserted-by":"publisher","first-page":"102109","DOI":"10.1016\/j.cbpa.2021.102109","article-title":"SOD Mimics: from the tool box of the chemists to cellular studies","volume":"67","author":"Policar","year":"2022","journal-title":"Curr Opin Chem Biol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1186\/s12889-018-6135-9","article-title":"Pilot field testing of the chronic pain classification for ICD-11: the results of ecological coding","volume":"18","author":"Barke","year":"2018","journal-title":"BMC Public Health"},{"key":"B9","doi-asserted-by":"publisher","first-page":"l4378","DOI":"10.1136\/bmj.l4378","article-title":"CONSORT 2010 Statement: extension to randomised crossover trials","volume":"366","author":"Dwan","year":"2022","journal-title":"Br Med J"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.1097\/j.pain.0000000000000492","article-title":"Neuropathic pain: an updated grading system for research and clinical practice","volume":"157","author":"Finnerup","year":"2016","journal-title":"Pain"},{"key":"B11","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/S0304-3959(01)00349-9","article-title":"Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale","volume":"94","author":"Farrar","year":"2001","journal-title":"Pain"},{"key":"B12","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.pain.2010.07.031","article-title":"NeuPSIG guidelines on neuropathic pain assessment","volume":"152","author":"Haanpaa","year":"2011","journal-title":"Pain"},{"key":"B13","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/S1474-4422(14)70251-0","article-title":"Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis","volume":"14","author":"Finnerup","year":"2015","journal-title":"Lancet Neurol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.pain.2003.12.024","article-title":"Development and validation of the neuropathic pain symptom inventory","volume":"108","author":"Bouhassira","year":"2004","journal-title":"Pain"},{"key":"B15","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1111\/j.1464-5491.2011.03500.x","article-title":"Validation of DN4 as a screening tool for neuropathic pain in painful diabetic polyneuropathy","volume":"29","author":"Spallone","year":"2012","journal-title":"Diabet Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"109","DOI":"10.3109\/15569528209051516","article-title":"A reappraisal of the 21-day cumulative irritation test in man","volume":"1","author":"Berger","year":"1982","journal-title":"J Toxicol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.jclinepi.2018.05.007","article-title":"Minimum clinically important differences in chronic pain vary considerably by baseline pain and methodological factors: systematic review of empirical studies","volume":"101","author":"Olsen","year":"2018","journal-title":"J Clin Epidemiol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.jpain.2009.06.007","article-title":"The clinical importance of changes in the 0\u201310 numeric rating scale for worst, least, and average pain intensity: analyses of data from clinical trials of duloxetine in pain disorders","volume":"11","author":"Farrar","year":"2010","journal-title":"J Pain"},{"key":"B19","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1201\/b17537","volume-title":"The 2 x 2 Cross-Over Trial. Design and Analysis of Cross-Over Trials","author":"Jones","year":"2014"},{"key":"B20","first-page":"1637741","year":"2026"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2177","DOI":"10.1111\/ene.15831","article-title":"Joint European Academy of Neurology-European Pain Federation-Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment","volume":"30","author":"Truini","year":"2023","journal-title":"Eur J Neurol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1002\/j.1532-2149.2013.00350.x","article-title":"Diagnostic accuracy of two questionnaires for the detection of neuropathic pain in the Spanish population","volume":"18","author":"Hamdan","year":"2014","journal-title":"Eur J Pain"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1006908","DOI":"10.3389\/fnmol.2022.1006908","article-title":"The distinctive role of menthol in pain and analgesia: mechanisms, practices, and advances","volume":"15","author":"Li","year":"2022","journal-title":"Front Mol Neurosci"},{"key":"B24","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1124\/jpet.103.064154","article-title":"A newly identified role for superoxide in inflammatory pain","volume":"309","author":"Wang","year":"2004","journal-title":"J Pharmacol Exp Ther"},{"key":"B25","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1038\/s41583-022-00611-7","article-title":"TRP Channels: a journey towards a molecular understanding of pain","volume":"23","author":"Rosenbaum","year":"2022","journal-title":"Nat Rev Neurosci"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1080\/10715762.2021.2010731","article-title":"FeTMPyP a peroxynitrite decomposition catalyst ameliorated functional and behavioral deficits in chronic constriction injury induced neuropathic pain in rats","volume":"55","author":"Komirishetty","year":"2021","journal-title":"Free Radic Res"},{"key":"B27","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1016\/j.tins.2016.10.003","article-title":"Nitroxidative signaling mechanisms in pathological pain","volume":"39","author":"Grace","year":"2016","journal-title":"Trends Neurosci"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2687","DOI":"10.1016\/j.pain.2014.09.036","article-title":"Expectations and positive emotional feelings accompany reductions in ongoing and evoked neuropathic pain following placebo interventions","volume":"155","author":"Petersen","year":"2014","journal-title":"Pain"}],"container-title":["Frontiers in Pain Research"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpain.2026.1772899\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T06:37:49Z","timestamp":1774593469000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpain.2026.1772899\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":28,"alternative-id":["10.3389\/fpain.2026.1772899"],"URL":"https:\/\/doi.org\/10.3389\/fpain.2026.1772899","relation":{},"ISSN":["2673-561X"],"issn-type":[{"value":"2673-561X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]},"article-number":"1772899"}}