Pregabalin and duloxetine combination for painful diabetic neuropathy: a systematic review and meta-analysis

Background 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. Methods 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. Results 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, P 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, P 0.00001), brief pain inventory-modified short form (BPI-MSF, MD=-1.46, 95%CI=-2.35, -0.57, P = 0.001), and neuropathic pain symptoms on the pain detect questionnaire (PDQ, MD=-3.00, 95%CI=-5.55, -0.45, P = 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, P = 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, P = 0.48) or in key individual adverse effects, including somnolence (RR = 0.79, 95%CI=0.30, 2.08, P = 0.63) and nausea/vomiting (RR = 2.02, 95%CI=0.77, 5.27, P = 0.15). The certainty of evidence ranged from very low to low for most outcomes (GRADE). Conclusion 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. Systematic review registration https://www.crd.york.ac.uk/prospero/ , identifier CRD420251179997.