Dear Editor,
We read with interest the recently published meta-analysis by Makkar et al.[1] The authors have systematically reviewed the literature on perioperative ketamine or esketamine use to prevent rebound pain after regional nerve block. There are two methodological remarks that might be considered with regard to this meta-analysis.
First, the relationship between ketamine or esketamine and hallucinations [odds ratio (OR) 12.73, 95% confidence interval 2.98–54.41] seems to be based on zero events in all control groups.[1] Imprecision of standard Mantel–Haenszel methods may occur when data are sparse and the cells contain no events. Under suitable circumstances, a Peto OR sensitivity analysis might be appropriate to check the consistency of this association in the setting of rare events.[2]
Second, the reported I² of 39% for rebound pain does not necessarily represent clinically relevant heterogeneity.[1] There were variations among the studies regarding the definition of rebound pain, including transition to severe pain, threshold of severe pain, and the difference in pain measured over a 12-hour period.[1] Regional anaesthetic techniques and surgical procedures also differed. Low statistical heterogeneity does not necessarily imply low clinical heterogeneity, particularly because there is no universal definition of rebound pain.[3] These differences may have affected the pooled estimate.
Another source of clinical heterogeneity could be the absence of dose adjustment between racemic ketamine and esketamine. At nominal doses, the analgesic and anaesthetic properties of esketamine are about twice as potent as those of racemic ketamine.[4]
These observations are not intended to detract from the value of this review but may be relevant to understanding the findings and planning future comparative studies.
Disclosure of use of artificial intelligence (AI)-assistive or generative tools
An AI-assisted tool was used minimally for grammar and language editing. No AI tool was used to generate the scientific content, analysis, or conclusions.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
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REFERENCES
- 1.Makkar JK, Khurana BJ, Singh PM, Singh NP. Role of perioperative ketamine on the incidence of rebound pain after regional nerve block in the adult surgical population: A systematic review and meta-analysis of randomised controlled trials. Indian J Anaesth. 2026;70:797–805. doi: 10.4103/ija.ija_100_26. [DOI] [PMC free article] [PubMed] [Google Scholar]
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