Efficacy of ketamine in relieving neuropathic pain: a systematic review and meta-analysis of animal studies

Abstract

In humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking. To improve our understanding of ketamine behavior under various administration conditions, we performed a systematic review and meta-analyses of controlled studies on the efficacy of ketamine in mice and rats with a disease model of nerve injury on relief of allodynia. Searches in PubMed and EMBASE identified 31 unique studies. Four meta-analyses were conducted. The first analysis included 19 comparisons on a single ketamine dose and measurement of effect within 3 hours of dosing and showed an appreciable effect (standardized mean difference 1.6, 95% confidence interval 1.1-2.1). Subgroup analyses showed no effect of species, administration route, or dose. A single administration was insufficient to sustain relief of allodynia at 24 or 72 hours after dosing, as observed in our second analysis (7 comparisons) with similar effects in ketamine-treated and control animals. Chronic ketamine administration (9 comparisons) caused profound relief of allodynia when tested during ketamine exposure (effect size 5.1, 3.7-6.5). The final analysis (6 comparisons) showed that chronic administration caused a slow loss of relief of allodynia with 70% loss of effect 24 days after end of treatment. No subgroups analyses were possible in the last 3 meta-analyses due to small group sizes. These results indicate long-term ketamine anti-allodynic effects after chronic exposure (>3 days) but not after a single administration. Given several limitations, extrapolation of the animal data to the human condition is tenuous.

Figure 1.

Flowchart of study search and selection process.

Figure 2.

(A) Main characteristics of studies selected in the meta-analysis. Pain models: SCI, spinal cord injury; SNL, spinal nerve ligation; SNI, spared nerve injury; CCI, chronic nerve constriction injury; and “other” pain models were constriction of infraorbital nerve (n = 1), brachial plexus ablation (n = 1), postherpetic neuralgia (n = 1), and streptozotocin-induced neuropathy (n = 1). Administration route: i.t., intrathecal; i.p., intraperitoneal; and “other” routes were subcutaneous (n = 2), intranasal (n = 1), and intravenous (n = 2). Measurement techniques: “other” includes measuring withdrawal latency to cold and heat stimuli. (B) Summary of the 4 meta-analyses. No delay indicates that the measurement of neuropathic pain was performed during the period of ketamine administration. The data point of the single administration 24-72 h is without Fang et al. (Ref. 11).

Figure 3.

(A) Risk of bias assessment of the included studies. (B) Reporting questions on randomization, blinding, and power calculation.

Figure 4.

(A) Forest plot of the effect of a single ketamine injection on neuropathic pain measured within 3 hours of injection. (B) Forest plot of the effect of a single ketamine injection on neuropathic pain measured at 24 or 72 hours after injection. (C) Forest plot of the effect of repetitive ketamine injections or a continuous infusion on neuropathic pain, measured during ketamine administration. (D) Forest plot of the effect of repetitive ketamine injections or a continuous infusion on neuropathic pain, measured in the days after ketamine administration. The green diamonds are the group effect sizes ± 95% confidence intervals.

Figure 5.

Subgroups of comparisons on the effect of a single administration of ketamine on relief of allodynia measured within 3 hours of administration. The data are pooled effect size (Hedges g) ± 95% confidence interval. The dotted line and gray area are the effect size of all the complete data set ± 95% confidence interval. CCI, chronic nerve constriction injury; i.t., intrathecal; SNL spinal nerve ligation injury.

Figure 6.

Funnel plot of meta-analysis 1 examining the ketamine effect within 3 hours of a single administration. Each symbol represents an independent comparison.