Pain remains a common and disabling condition with large personal and societal impact. Existing analgesics, including opioids, have limited long-term benefit for many chronic pain states and carry risks such as tolerance, dependence and addiction. This protocol describes a systematic review to evaluate the potential role of metformin—a widely used oral antihyperglycaemic agent—as a repurposed analgesic therapy for adults with acute or chronic pain.
Preclinical and early clinical evidence suggests metformin may have analgesic effects. Proposed mechanisms involve indirect activation of AMP-activated protein kinase (AMPK) with downstream inhibition of mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase signalling pathways implicated in nociceptive sensitisation, neuroinflammation and maladaptive plasticity associated with chronic pain states. Emerging trials have examined metformin in diverse pain conditions, including osteoarthritis, neuropathic pain, postoperative pain and other musculoskeletal disorders. This review aims to comprehensively synthesise randomized controlled trial evidence across these conditions to clarify metformin’s efficacy and safety for pain management.
The primary objective is to evaluate the efficacy and safety of metformin for the treatment or prevention of acute and chronic pain in adults. Using PICOTS: Population comprises adult human participants (≥18 years) with acute or chronic pain of any aetiology; Intervention includes orally administered metformin at any dose, formulation, frequency and duration; Comparators include placebo, usual care, standard analgesic therapy or other active comparators; Outcomes focus on participant-reported pain intensity and pain relief as primary outcomes, with multiple secondary outcomes; Time frames are short-term (<1 week), medium-term (1 week to 3 months) and long-term (>3 months); Study design is randomized controlled trials, double-blind.
A comprehensive search will be run in the Cochrane Central Register of Controlled Trials, MEDLINE (Ovid MEDLINE ALL) and EMBASE from inception to the date of final searches. Trial registries (ClinicalTrials.gov and WHO ICTRP) will be searched to identify ongoing or unpublished trials. Reference lists of included trials and relevant reviews will be screened. Search strategies include terms for metformin and biguanides alongside pain-related conditions and outcomes; full strategies are provided in the supplemental appendix.
Eligible studies are randomized, double-blind, placebo-controlled or active-controlled clinical trials evaluating metformin for pain-related outcomes. Non-randomized designs, observational studies, case reports, conference abstracts without sufficient data, study protocols without results and preclinical studies will be excluded. Adults (≥18 years) with acute or chronic pain of any aetiology are eligible. Trials where metformin was administered for non-pain indications will be included only if prespecified pain-related outcomes are reported. Interventions include any oral metformin formulation, dose, frequency and duration; trials with combination therapies are eligible if cointerventions are balanced across arms. Comparators include placebo, usual care, standard pain management or other active comparators allowing attribution of effects to metformin.
Primary outcomes are participant-reported pain intensity and pain relief, measured with validated instruments such as the Numeric Rating Scale (NRS) or Visual Analogue Scale (VAS). Responder outcomes (≥30% or ≥50% pain reduction) will be included where reported. Outcomes will be categorised as short-term (up to 1 week), medium-term (greater than 1 week to 3 months) and long-term (greater than 3 months).
Secondary outcomes include physical function and interference with activities, emotional function and comorbidities (eg, anxiety, depression), analgesic consumption including opioid-sparing effects, withdrawals for any cause or lack of efficacy, and specific adverse events of interest (eg, gastrointestinal side effects, hypoglycaemia, lactic acidosis, weight change). Neuropathy and sensory outcomes (eg, nerve conduction, altered sensation) will also be collected when reported.
Two reviewers will independently screen titles, abstracts and full texts and extract data using a standardised form. Extracted items include study design, pain condition, participant characteristics, sample size, intervention and comparator details (metformin dose, formulation, frequency, duration), cointerventions, outcome measures, follow-up durations and adverse events. Discrepancies will be resolved by discussion and, if needed, consultation with a third reviewer. Study selection will be summarised using a PRISMA flow diagram.
Risk of bias will be assessed at the outcome level by two independent reviewers using the Cochrane Risk of Bias 2.0 tool. Domains include bias arising from randomisation, deviations from intended interventions, missing outcome data, measurement of the outcome and selection of reported results. Each domain and overall judgement will be classified as low risk, some concerns or high risk, with disagreements resolved by consensus or third-party adjudication.
Dichotomous outcomes (eg, responder rates, adverse events) will be expressed as risk ratios with 95% confidence intervals; absolute risk differences will be calculated where appropriate. Continuous outcomes (eg, pain intensity scores) will use mean differences when the same scale is used and standardised mean differences when different validated scales are reported. Analyses will follow intention-to-treat principles where possible; the handling of missing data in individual trials will be documented and considered when interpreting results.
When at least three trials are sufficiently similar in population, intervention, comparator and outcomes, random-effects meta-analysis will be performed. Heterogeneity will be assessed with the I2 statistic and χ2 test; interpretations of I2 will follow predefined thresholds. If substantial heterogeneity (I2 ≥50%) or clinical/methodological differences preclude pooling, predefined subgroup analyses will be explored and a structured narrative synthesis will be used to summarise findings, grouping studies by pain condition, metformin regimen and comparator type.
Planned subgroup analyses include pain type (neuropathic, musculoskeletal, postoperative), pain duration (acute vs chronic), metformin dose and treatment duration, comparator type and presence of diabetes or obesity. Sensitivity analyses will exclude studies judged at high risk of bias or explore alternative analytic choices when data permit.
Strengths include prospective protocol registration (PROSPERO CRD420261296816), adherence to PRISMA-P and PRISMA 2020 reporting guidance, comprehensive multi-database searches without language restriction, and planned use of rigorous tools for risk of bias and certainty assessment (Cochrane RoB 2.0, GRADE). Anticipated limitations include heterogeneity in pain conditions, metformin dosing and outcome measures that may limit quantitative pooling; small trial sizes and imprecision may affect certainty of evidence.
Ethics approval is not required because only published data will be synthesised. The protocol is registered with PROSPERO (CRD420261296816). Findings will be disseminated via peer-reviewed publication and presentations at scientific conferences.