{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:32:28Z","timestamp":1787236348019,"version":"build-2736575974"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012151","name":"Sanming Project of Medicine in Shenzen Municipality","doi-asserted-by":"publisher","award":["SZZYSM202411016"],"award-info":[{"award-number":["SZZYSM202411016"]}],"id":[{"id":"10.13039\/501100012151","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Diabetic neuropathy is one of the most common complications of diabetes, affecting about half of all people with the disease. Among these, 30%-50% experience nerve-related pain, characterized by abnormal sensations, burning, or stabbing pain, a condition known as painful diabetic neuropathy (PDN). PDN not only severely impairs quality of life but is also closely associated with sleep disturbances, depression or anxiety, and foot complications. Together, these problems substantially increase healthcare costs and place a considerable economic burden on both families and society.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We systematically searched multiple databases from their inception to 1 November 2025 to identify randomized controlled trials evaluating pregabalin combined with duloxetine for the treatment of painful diabetic neuropathy. The methodological quality and risk of bias of the included trials were assessed using the Cochrane risk-of-bias tool (version 2.0). Statistical analyses were performed with RevMan 5.4.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Three randomized trials involving a total of 471 patients were included. In two studies that could be pooled, combination therapy produced significantly greater pain relief than monotherapy (MD=-1.82, 95%CI=-2.10, -1.54,\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt;0.00001). For secondary continuous outcomes reported in single studies, all results favored the combination, pain intensity on the visual analogue scale (VAS, MD=-1.42, 95%CI=-1.83, -1.01,\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt;0.00001), brief pain inventory-modified short form (BPI-MSF, MD=-1.46, 95%CI=-2.35, -0.57,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.001), and neuropathic pain symptoms on the pain detect questionnaire (PDQ, MD=-3.00, 95%CI=-5.55, -0.45,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.02). The proportion of patients achieving at least 50% pain reduction was also higher with the combination than with duloxetine 120 mg alone (RR = 1.81, 95%CI=1.17, 2.81,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.008). In contrast, there were no significant differences between combination therapy and monotherapy in the overall risk of adverse events (RR = 1.10, 95%CI=0.84, 1.46,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.48) or in key individual adverse effects, including somnolence (RR = 0.79, 95%CI=0.30, 2.08,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.63) and nausea\/vomiting (RR = 2.02, 95%CI=0.77, 5.27,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.15). The certainty of evidence ranged from very low to low for most outcomes (GRADE).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Low-certainty evidence suggests that pregabalin plus duloxetine may improve short-term pain scores compared with monotherapy in painful diabetic neuropathy. Safety outcomes remain uncertain due to few trials and imprecision.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/prospero\/<\/jats:ext-link>\n                      , identifier CRD420251179997.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1750441","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T05:35:43Z","timestamp":1773207343000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Pregabalin and duloxetine combination for painful diabetic neuropathy: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Yifan","family":"Shi","sequence":"first","affiliation":[{"name":"The Fourth Clinical Medical School of Guangzhou University of Chinese Medicine","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyang","family":"Chen","sequence":"additional","affiliation":[{"name":"The Fourth Clinical Medical School of Guangzhou University of Chinese Medicine","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengxia","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Shenzhen Traditional Chinese Medicine Hospital","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"B1","article-title":"Facts & figures","volume-title":"IDF diabetes atlas","year":"2025"},{"key":"B2","article-title":"Total diabetes-related health expenditure, USD million","volume-title":"IDF Diabetes Atlas - Data by indicator","year":"2025"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab079","article-title":"Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management","volume":"144","author":"Jensen","year":"2021","journal-title":"Brain"},{"key":"B4","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41572-019-0092-1","article-title":"Diabetic neuropathy","volume":"5","author":"Feldman","year":"2019","journal-title":"Nat Rev Dis Primers"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-021-00496-z","article-title":"Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy","volume":"17","author":"Sloan","year":"2021","journal-title":"Nat Rev Endocrinol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.2337\/dc16-2042","article-title":"Diabetic neuropathy: A position statement by the american diabetes association","volume":"40","author":"Pop-Busui","year":"2017","journal-title":"Diabetes Care"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.05.003","article-title":"New perspectives in diabetic neuropathy","volume":"111","author":"Eid","year":"2023","journal-title":"Neuron"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0212574","article-title":"The risk factors for diabetic peripheral neuropathy: A meta-analysis","volume":"14","author":"Liu","year":"2019","journal-title":"PloS One"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-1108","article-title":"Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K","volume":"34","author":"Abbott","year":"2011","journal-title":"Diabetes Care"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000000785","article-title":"Risk factors for neuropathic pain in diabetes mellitus","volume":"158","author":"H\u00e9bert","year":"2017","journal-title":"Pain"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001034","article-title":"Sensory phenotype and risk factors for painful diabetic neuropathy: a cross-sectional observational study","volume":"158","author":"Raputova","year":"2017","journal-title":"Pain"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000000491","article-title":"The Pain in Neuropathy Study (PiNS): a cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy","volume":"157","author":"Themistocleous","year":"2016","journal-title":"Pain"},{"key":"B13","doi-asserted-by":"publisher","first-page":"109928","DOI":"10.1016\/j.diabres.2022.109928","article-title":"An overview of painful diabetic peripheral neuropathy: Diagnosis and treatment advancements","volume":"188","author":"Hagedorn","year":"2022","journal-title":"Diabetes Res Clin Pract"},{"key":"B14","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1111\/jdi.13388","article-title":"Prevalence and risk factors for diabetic neuropathy and painful diabetic neuropathy in primary and secondary healthcare in Qatar","volume":"12","author":"Ponirakis","year":"2021","journal-title":"J Diabetes Investig"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.2337\/dc25-S012","article-title":"Retinopathy, neuropathy, and foot care: standards of care in diabetes-2025","volume":"48","year":"2025","journal-title":"Diabetes Care"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2025.1564867","article-title":"Prevalence and risk factors for painful diabetic peripheral neuropathy: a systematic review and meta-analysis","volume":"16","author":"Zhou","year":"2025","journal-title":"Front Neurol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/s41582-024-01041-y","article-title":"The global and regional burden of diabetic peripheral neuropathy","volume":"21","author":"Savelieff","year":"2025","journal-title":"Nat Rev Neurol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1212\/WNL.0000000000013038","article-title":"Oral and topical treatment of painful diabetic polyneuropathy: practice guideline update summary: report of the AAN guideline subcommittee","volume":"98","author":"Price","year":"2022","journal-title":"Neurology"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S442595","article-title":"Update on treating painful diabetic peripheral neuropathy: A review of current US guidelines with a focus on the most recently approved management options","volume":"17","author":"Mallick-Searle","year":"2024","journal-title":"J Pain Res"},{"key":"B20","doi-asserted-by":"publisher","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":"B21","doi-asserted-by":"publisher","DOI":"10.1177\/19322968211060075","article-title":"Neuromodulation in the treatment of painful diabetic neuropathy: A review of evidence for spinal cord stimulation","volume":"16","author":"Strand","year":"2022","journal-title":"J Diabetes Sci Technol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.v65n0501","article-title":"Anticonvulsants and the relief of chronic pain: pregabalin and gabapentin as alpha(2)delta ligands at voltage-gated calcium channels","volume":"65","author":"Stahl","year":"2004","journal-title":"J Clin Psychiatry"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S185995","article-title":"A comparative double-blind randomized study on the effectiveness of Duloxetine and Gabapentin on painful diabetic peripheral polyneuropathy","volume":"13","author":"Majdinasab","year":"2019","journal-title":"Drug Des Devel Ther"},{"key":"B24","volume-title":"CYMBALTA (duloxetine) US prescribing information","author":"Food","year":"2023"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD007115.pub3","article-title":"Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia","volume":"2014","author":"Lunn","year":"2014","journal-title":"Cochrane Database Syst Rev"},{"key":"B26","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s13643-023-02185-6","article-title":"Efficacy and safety of duloxetine in painful diabetic peripheral neuropathy: a systematic review and meta-analysis of randomized controlled trials","volume":"12","author":"Wu","year":"2023","journal-title":"Syst Rev"},{"key":"B27","volume-title":"LYRICA (pregabalin) US prescribing information","year":"2025"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD007076.pub3","article-title":"Pregabalin for neuropathic pain in adults","volume":"1","author":"Derry","year":"2019","journal-title":"Cochrane Database Syst Rev"},{"key":"B29","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1111\/j.1526-4637.2007.00305.x","article-title":"Duloxetine for the management of diabetic peripheral neuropathic pain: response profile","volume":"8","author":"Pritchett","year":"2007","journal-title":"Pain Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.2337\/dc07-2105","article-title":"Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses","volume":"31","author":"Freeman","year":"2008","journal-title":"Diabetes Care"},{"key":"B31","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.tips.2006.12.006","article-title":"Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission","volume":"28","author":"Dooley","year":"2007","journal-title":"Trends Pharmacol Sci"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.104.070656","article-title":"Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats","volume":"311","author":"Iyengar","year":"2004","journal-title":"J Pharmacol Exp Ther"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"B34","doi-asserted-by":"publisher","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: a revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2012.08.001","article-title":"GRADE guidelines: 13. Preparing summary of findings tables and evidence profiles-continuous outcomes","volume":"66","author":"Guyatt","year":"2013","journal-title":"J Clin Epidemiol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1080\/17581869.2024.2370758","article-title":"PPAR\u03b3 and AKt gene modulation following pregabalin and duloxetine combination for painful diabetic polyneuropathy","volume":"14","author":"Saxena","year":"2024","journal-title":"Pain Manag"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2013.05.043","article-title":"Duloxetine and pregabalin: high-dose monotherapy or their combination? The \u201cCOMBO-DN study\u201d--a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain","volume":"154","author":"Tesfaye","year":"2013","journal-title":"Pain"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3969\/j.issn.1672-0369.2022.08.005","article-title":"Effects of Pregabalin combined with Duloxetine in treatment of elderly patients with painful diabetic peripheral neuropathy","volume":"34","author":"JI","year":"2022","journal-title":"Med J Chin People\u2019s Health"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.10.5768","article-title":"The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel","volume":"271","author":"Gee","year":"1996","journal-title":"J Biol Chem"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2005.11.003","article-title":"The mechanisms of action of gabapentin and pregabalin","volume":"6","author":"Sills","year":"2006","journal-title":"Curr Opin Pharmacol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"10432","DOI":"10.3390\/ijms262110432","article-title":"Duloxetine, an SNRI, targets pSTAT3 signaling: in-silico, RNA-seq and in-vitro evidence for a pleiotropic mechanism of pain relief","volume":"26","author":"Abdi","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B42","doi-asserted-by":"publisher","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":"B43","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1152\/physrev.00045.2019","article-title":"Neuropathic pain: from mechanisms to treatment","volume":"101","author":"Finnerup","year":"2021","journal-title":"Physiol Rev"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182166ebe","article-title":"Evidence-based guideline: Treatment of painful diabetic neuropathy [RETIRED]: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation","volume":"76","author":"Bril","year":"2011","journal-title":"Neurology"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2004.05.001","article-title":"Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial","volume":"110","author":"Rosenstock","year":"2004","journal-title":"Pain"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000145767.36287.A1","article-title":"Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial","volume":"63","author":"Lesser","year":"2004","journal-title":"Neurology"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4637.2005.00061.x","article-title":"A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain","volume":"6","author":"Raskin","year":"2005","journal-title":"Pain Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2005.03.029","article-title":"Duloxetine vs. placebo in patients with painful diabetic neuropathy","volume":"116","author":"Goldstein","year":"2005","journal-title":"Pain"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2008.07.004","article-title":"Safety and tolerability of duloxetine treatment of diabetic peripheral neuropathic pain between patients with and without cardiovascular conditions","volume":"23","author":"Wernicke","year":"2009","journal-title":"J Diabetes Comp"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD008943.pub2","article-title":"Combination pharmacotherapy for the treatment of neuropathic pain in adults","volume":"2012","author":"Chaparro","year":"2012","journal-title":"Cochrane Database Syst Rev"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)61081-3","article-title":"Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial","volume":"374","author":"Gilron","year":"2009","journal-title":"Lancet"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1750441\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T05:35:46Z","timestamp":1773207346000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1750441\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,11]]},"references-count":51,"alternative-id":["10.3389\/fendo.2026.1750441"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1750441","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,11]]},"article-number":"1750441"}}