{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T19:34:50Z","timestamp":1788377690663,"version":"build-2803163510"},"reference-count":55,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Pharmacological combinations are commonly used for treating refractory neuropathic pain, although supporting evidence is lacking. Gabapentinoid\u2010opioid combination is one of the most studied; however, their efficacy is inconsistent across clinical trials. This trial investigated the feasibility, effectiveness and safety of adding pregabalin to buprenorphine for managing this condition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This single\u2010center, phase IV, double\u2010blind, placebo\u2010controlled trial enrolled adults with peripheral chronic neuropathic pain, refractory to tricyclic antidepressants and\/or serotonin\u2010norepinephrine reuptake inhibitors. Participants were randomized to receive transdermal buprenorphine up to 20 mcg\/day, plus pregabalin up to 300\u2009mg\/day (group C) or placebo (group M). Participants underwent a 3\u2010week tolerability\u2010based dose titration and a 6\u2010week maintenance phase. Primary outcome was \u2265\u200930% average pain reduction at week 9.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Sixty individuals (66.7% female, 53 [45\u201358.5] years old) were enrolled. After titration, pregabalin dose was 100\u2009mg\/day for most group C participants (87%), and transdermal buprenorphine doses were similar between groups (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.787). At week 9, \u2265\u200930% pain reduction was achieved by 38% in group C and 32% in group M (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.942). Pain interference, mood, anxiety and quality\u2010of\u2010life scores did not significantly differ between groups. Baseline pain phenotype was not associated with primary outcome results. Side\u2010effect frequencies were similar between groups, and no serious adverse events occurred.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Adding pregabalin to transdermal buprenorphine was not found to be effective for treating neuropathic pain. However, low\u2010to\u2010moderate analgesic effects cannot be excluded. Although no major side effects occurred, opioid use may have led to lower pregabalin tolerability, hindering the feasibility of this combination in clinical practice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>Although pharmacological combinations are widely prescribed for neuropathic pain (NP), consistent evidence of their benefit is lacking. This phase IV, pragmatic trial does not support the effectiveness of pregabalin\u2010buprenorphine combination for refractory NP, even across distinct pain phenotypes. Besides suggesting the poor feasibility of this combination due to poor tolerability, it adds to the mounting evidence challenging earlier reports of an opioid\u2010sparing effect for gabapentinoids.<\/jats:p>\n                    <jats:p>Clinical Study Registration Number: 52145215.0.0000.0068.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejp.70359","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T09:35:12Z","timestamp":1786959312000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Combination of Buprenorphine and Pregabalin in the Management of Peripheral Neuropathic Pain: A Phase\n                    <scp>IV<\/scp>\n                    , Randomized, Double\u2010Blind and Placebo\u2010Controlled Clinical Trial"],"prefix":"10.1002","volume":"30","author":[{"given":"Larissa I.","family":"Moreira","sequence":"first","affiliation":[{"name":"Pain Center, Department of Neurology University of S\u00e3o Paulo  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro N.","family":"Martins","sequence":"additional","affiliation":[{"name":"Federal University of Juiz de Fora  Juiz de Fora Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoel J.","family":"Teixeira","sequence":"additional","affiliation":[{"name":"Pain Center, Department of Neurology University of S\u00e3o Paulo  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C.","family":"de Andrade","sequence":"additional","affiliation":[{"name":"Pain Center, Department of Neurology University of S\u00e3o Paulo  S\u00e3o Paulo Brazil"},{"name":"Center for Neuroplasticity and Pain, Department of Health Sciences and Technology, Faculty of Medicine Aalborg University  Aalborg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7790-8111","authenticated-orcid":false,"given":"Gabriel T.","family":"Kubota","sequence":"additional","affiliation":[{"name":"Pain Center, Department of Neurology University of S\u00e3o Paulo  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000002688"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-014-0262-2"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/papr.12200"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2377-12-8"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejp.1496"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0034-89101995000500004"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2004.12.010"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2003.12.024"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000002130"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.09.021"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.08.141"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0280593"},{"key":"e_1_2_11_14_1","first-page":"129","article-title":"Pain Assessment: Global Use of the Brief Pain Inventory","volume":"23","author":"Cleeland C. 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