Benefits and harms of Ketamine for management of chronic non-cancer pain

Abstract

Background: Chronic non-cancer pain (CNCP) is a prevalent condition, imposing significant burden on healthcare systems. Ketamine is suggested as a potential intervention for CNCP management. We conducted a systematic review and network meta-analysis to assess ketamine's effects in adults with CNCP. Methods: We searched Medline, Embase, CINAHL, and Cochrane CENTRAL up to January-2024 for randomized trials involving adults with CNCP, comparing ketamine with placebo, usual care, or other interventions. Reviewers independently assessed trial eligibility, extracted data, and evaluated risk-of-bias using the Cochrane tool. A random-effects network meta-analysis was performed. We assessed evidence certainty using GRADE. Results: We included 38 trials, with the following comparisons made between ketamine and placebo, using 0-10 VAS: At <30 minutes, ketamine may slightly reduce pain intensity (-1.32, 95% CI: [-1.73 to -0.90], low-certainty). At 1-3 hours follow-up, ketamine may slightly reduce pain intensity (MD: -1.25, (95% CI: [-1.76 to -0.74], low-certainty). At 3-to-7 days follow-up, ketamine may have little to no effect on pain intensity (MD: -1.34, 95% CI: [-2.29 to -0.39], low-certainty). At 3-to-5 weeks follow-up, ketamine likely results in no pain reduction (MD: -0.99, 95% CI: [-2.00 to 0.03], moderate-certainty). At beyond 5 weeks the evidence about ketamine pain reduction is very uncertain (MD: -1.09, 95% CI: [-1.86 to -0.32], very-low-certainty). Ketamine had no effect on physical functioning. Compared to placebo, ketamine may result in a slight increase in the risk of gastrointestinal adverse events (RR: 3.97, 95% CI: [2.18 to 7.22], RD: 12%, 95% CI: [5% to 25%], very-low-certainty), an increase in risk of dizziness (RR: 3.66, 95% CI: [1.25 to 10.74], RD: 11%, 95% CI: [1% to 40%], low-certainty), may increase the risk of fatigue, somnolence, and sedation (RR: 2.89, 95% CI: [1.84 to 4.53], RD: 27%, 95% CI: [12% to 50%], low-certainty), may increase of the incidence of dissociative symptoms (RR: 4.22, 95% CI: [2.20 to 8.10], RD: 17%, 95% CI: [6% to 37%], low- M.Sc. Thesis – Sara Moradi; McMaster University – Health Research Methodology iv certainty), and it may result in a slight increase in the risk of visual impairment (RR: 10.21, 95% CI: [2.86 to 36.42], RD: not evaluable, very-low-certainty). We did not have enough data to pool effect estimates for other outcomes. Conclusion: Ketamine may provide small but important benefit in CNCP patients at immediate-to-short follow-up, but it probably has little to no benefit at beyond 3-weeks. Ketamine is likely to provide similar benefits compared to alternative active interventions; however, these benefits may be associated with important side-effects.