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The aim of this study was to determine the structural and functional brain alterations associated with prescription opioid use in a large cohort of people with painful DPN.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A total of 82 patients with diabetes were enrolled: 57 with painful DPN (18 with long-term opioid prescription [O+ individuals] and 39 who were not prescribed opioids [O\u2212 individuals]) and a control group of 25 patients with diabetes but without DPN (no DPN) matched for age (\u00b1 2 years), sex and type of diabetes. All participants underwent detailed clinical\/neurophysiological assessment and brain MRI at 3\u00a0T, and a subset (14 in each group,\n                      <jats:italic>n<\/jats:italic>\n                      =42) also underwent resting-state functional MRI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      O+ individuals had greater caudate volume (ANOVA,\n                      <jats:italic>p<\/jats:italic>\n                      =0.03) compared with O\u2212 individuals (\n                      <jats:italic>p<\/jats:italic>\n                      =0.03) and those with no DPN (\n                      <jats:italic>p<\/jats:italic>\n                      =0.01). Functional connectivity was lower between the caudate and thalamus (\n                      <jats:italic>r<\/jats:italic>\n                      \u03b2 = \u22120.24, seed-level correction \u22123.9,\n                      <jats:italic>p<\/jats:italic>\n                      <jats:sub>FDR<\/jats:sub>\n                      \u22640.05) in O+ individuals compared to those with no DPN. Moreover, seed-to-voxel analysis using caudate as the seed showed a significantly lower functional connectivity in O+ individuals compared with O\u2212 individuals in a cluster encompassing the superior frontal gyri bilaterally.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>We demonstrate that disruption of dopaminergic pathways occurs within the brain when opioids are used for analgesic purposes for painful DPN, which may reflect alterations in reward systems. This study has important clinical implications, as the measures of dopaminergic pathways found in this study may represent neuroimaging biomarkers that could be used to diagnose and monitor the negative consequences of prescription opioid use.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-025-06529-w","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T14:06:10Z","timestamp":1759759570000},"page":"2867-2878","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Beyond pain relief: the effects of chronic opioid use on brain structure and function in diabetic neuropathy\u2014a multimodal neuroimaging study"],"prefix":"10.1007","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6164-2662","authenticated-orcid":false,"given":"Gordon","family":"Sloan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Teh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marni","family":"Greig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pallai","family":"Shillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Caunt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain D.","family":"Wilkinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solomon","family":"Tesfaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh","family":"Selvarajah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"issue":"7","key":"6529_CR1","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1038\/s41574-021-00496-z","volume":"17","author":"G Sloan","year":"2021","unstructured":"Sloan G, Selvarajah D, Tesfaye S (2021) Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. 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The authors also greatly appreciate the cooperation of the study participants who spent considerable time participating in this study. Dr Iain D. Wilkinson, who substantially contributed to this research, died on 22 October 2020 before publication of this work. Dr Wilkinson will be fondly remembered and is sadly missed.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The datasets generated and\/or analysed during the current study are available from the corresponding author upon reasonable request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This study was supported by the European Foundation for the Study of Diabetes European Research Programme in Microvascular Complications of Diabetes supported by Novartis; the Knowledge Exchange Support Fund, University of Sheffield (X\/162218); the Efficacy and Mechanism Evaluation Programme (NIHR129921), a Medical Research Council and National Institute for Health and Care Research partnership; and Sheffield Teaching Hospitals Diabetes Charitable Trust. The views expressed in this publication are those of the authors and not those of the Medical Research Council, National Institute for Health and Care Research, the Department of Health and Social Care, nor the Sheffield Teaching Hospitals Charities. The study sponsor\/funder was not involved in the design of the study; collection, analysis, and interpretation of data or writing of the report and did not impose any restrictions regarding publication of the report.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"ST has received lecture honoraria from W\u00f6rwag Pharma, Pfizer, Novo Nordisk, Merck, EVA Pharma, Hikma Pharmaceuticals, Gr\u00fcnenthal, Abbott Laboratories, AstraZeneca, Trigocare International, and Procter & Gamble and is on the medical advisory board of Bayer. GS has received honoraria from Procter & Gamble and Eli Lilly. DS is a member of the editorial board of\n                      Diabetologia\n                      . The remaining authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"GS and DS recruited participants, undertook clinical and neurophysiological assessments and research, and analysed clinical and magnetic resonance data and wrote the manuscript. MG and PS undertook clinical and neurophysiological assessments. KT and IDW contributed to the design of the study, acquisition, analysis and interpretation of data. SC contributed to the design of the study, recruitment of patients and oversight of study procedures. ST contributed to the design of the study. GS, DS, KT, MG, PS, SC and ST all contributed to drafting of the manuscript and approved the final draft of the manuscript. DS is the guarantor of the work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}