Intravenous (IV) ketamine may provide clinically meaningful short-term analgesia in complex regional pain syndrome (CRPS), but predictors of success are only suggestive, according to study results published in the Journal of Pain.
IV ketamine is well-cited for its analgesic effects in the setting of pain; however, variable responses and uncertainty around durability limit patient selection for treatment. Researchers therefore conducted a systematic review and meta-analysis of medical databases (inception through March 2026) to evaluate predictors of response to IV ketamine in CRPS, estimate the treatment effects, time course of pain relief after infusion, and determine predictors associated with clinical improvement.
Randomized trials and observational studies were eligible for inclusion if the study population included adults or children diagnosed with CRPS who received IV ketamine (any formulation or infusion regimen); acceptable outcomes included pain scores, functional outcomes, and/or predictive measures.
Overall, 21 studies including 605 patients (mean age 45.7 years; 69.2% women; 95.2% with CRPS type 1) were included in the analysis. 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). Treatment responder definitions varied among the studies and showed a median responder rate of 65%.
High-quality research is needed to define optimal treatment protocols, identify reliable predictors of response, and clarify ketamine’s role in the long-term management of CRPS.
The analysis revealed that the presence of sympathetically maintained pain (adjusted odds ratio [aOR]: 6.54), obesity (aOR: 8.75), bone-to-vascular phase uptake ratio on 3-phase bone scintigraphy, and circulating microRNAs were the only predictors formally evaluated among the studies, albeit supported by very low certainty evidence.
Results also demonstrated that IV ketamine provided meaningful immediate to short-term analgesia, particularly on the day of infusion — but that functional outcomes only showed modest improvement. Adverse events associated with ketamine were predominantly transient, and early termination of treatment was uncommon.
Limitations include the design of most studies (uncontrolled observational cohorts) and considerably between-study heterogeneity, suggesting that treatment benefits may vary substantially across comparable study settings. Further, there was little evidence of pain relief beyond 14 day follow up which limits assessment of long-term effects. Finally, the authors highlighted concern about publication bias and potential overestimation of treatment effects.
“Individual responses vary widely, and only a few exploratory predictors have been investigated, none of which have been sufficiently validated to inform clinical decision-making,” the authors concluded. “High-quality research is needed to define optimal treatment protocols, identify reliable predictors of response, and clarify ketamine’s role in the long-term management of CRPS.”
References:
van den Brink J, van der Spek DPC, Baart, SJ, et al. Intravenous ketamine for complex regional pain syndrome: pain outcomes and predictors of response. A systematic review and meta-analysis. J. Pain. Published online: August 4, 2026. doi:10.1016/j.jpain.2026.106397