PAIN+ CPN

Intravenous ketamine is used for complex regional pain syndrome (CRPS), but variable response and uncertain durability limit patient selection. This systematic review evaluated reported predictors of response to intravenous ketamine in CRPS and quantified the extent and duration of pain relief. The protocol is registered in PROSPERO (CRD420250655066). Databases were searched from inception through March 26, 2026. Randomized trials and observational studies reporting intravenous ketamine in CRPS were included. Pain scores were rescaled to a 0-10 scale, and the mean difference in change from baseline was pooled for the earliest post-infusion assessment within 14 days using inverse-variance random-effects meta-analysis. Random-effects meta-regression modeled outcomes at 14 days or later. Predictors of response were synthesized narratively. Twenty-one studies (3 randomized trials) included 605 ketamine-treated patients, with most studies having a moderate to high risk of bias. The pooled mean baseline pain score was 7.4. At the earliest post-infusion assessment within 14 days, the mean change in pain was -3.6 (95%CI -4.7 to -2.5). Limited longer-term data up to 90 days suggested attenuation of effect, with a gradual return toward baseline. Responder definitions varied widely, with a median responder rate of 65% (range 0-100%). Only 3 studies formally evaluated predictors, and quantitative synthesis was not feasible. Reported associations included sympathetically maintained pain (aOR 6.54, 95%CI 1.83-23.44) and obesity (aOR 8.75, 95%CI 1.45-52.73). Other exploratory predictors included bone scintigraphy phase ratios and baseline microRNAs. Intravenous ketamine may reduce pain, but limited predictor evidence precludes firm conclusions for individualized treatment selection. PERSPECTIVE: This systematic review supports intravenous ketamine as a potential interventional option for complex regional pain syndrome, while emphasizing that standardized outcome reporting and validated predictors are needed before treatment can be reliably individualized.

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