Subanesthetic Ketamine for Chronic Non-Cancer Pain: A Systematic Review of Evidence from Randomized Trials over the Past Two Decades

Introduction: Chronic non-cancer pain represents a major global health challenge because of its high prevalence, functional impact, and limited response to conventional therapies, highlighting the need for alternative approaches. In this context, subanesthetic-dose ketamine has emerged as a promising therapeutic option because of its ability to modulate central sensitization and enhance analgesia through NMDA receptor antagonism. However, current evidence regarding its long-term efficacy and safety remains limited and heterogeneous. Objective: To evaluate the efficacy and safety of subanesthetic ketamine for the management of chronic non-cancer pain in adults, based on randomized controlled trials published between 2005 and 2025. Methods: A systematic review was conducted in accordance with the PRISMA 2020 guidelines. Randomized controlled trials involving adults with chronic non-cancer pain were included, comparing ketamine with placebo or other active agents. The databases searched were PubMed, ScienceDirect, and the Cochrane Library. Risk of bias was assessed using the Cochrane RoB-2 tool, and the certainty of evidence was evaluated using GRADE. Results: Five trials met the inclusion criteria. All included studies evaluated intravenous ketamine at doses ranging from 0.3 to 0.5 mg/kg. Overall, ketamine demonstrated significant short-term pain relief (p < 0.05), particularly in neuropathic conditions; however, the magnitude of this effect decreased progressively after the infusion ended. Reported adverse effects were mild and transient, with no evidence of severe toxicity. Heterogeneity in dosing protocols, pain phenotypes, comparator strategies, and follow-up duration limited cross-study comparability. Conclusions: Current evidence supports the short-term efficacy and safety of subanesthetic-dose ketamine as an analgesic option for chronic non-cancer pain, especially in neuropathic syndromes. However, the transient nature of its effects and the heterogeneity among studies underscore the need for standardized protocols and longer follow-up periods. Despite its generally favorable short-term safety profile, subanesthetic ketamine should be used with caution under strict clinical supervision, as the potential for long-term neurocognitive, urological, and hepatic adverse effects remains insufficiently defined.