Mode of anaesthesia and persistent postoperative opioid use: A reply

We appreciate the thoughtful comments from Yuan [1] on our study investigating the association between mode of anaesthesia and persistent postoperative opioid use [2]. We agree that regional anaesthesia encompasses a spectrum of procedures with differing mechanisms and clinical effects. Therefore, categorising diverse regional anaesthesia techniques into a single variable may introduce heterogeneity and warrants careful interpretation. There are some reasons for this approach. First, granular clinical details for individual regional anaesthesia techniques are not available in administrative claim data from the Korean National Health Insurance Service, precluding detailed stratification. Second, despite variability in anatomical targets and medications used, regional anaesthesia techniques share a fundamental mechanism, which is interruption of nociceptive transmission from the surgical site, thereby attenuating peripheral and central sensitisation [3] and preventing the development of chronic postoperative pain [4]. Finally, our procedure-specific analyses, which partially account for differences in pain profiles and anaesthetic selection across surgeries, may have mitigated, albeit incompletely, the limitations of this categorisation. The relationships between persistent postoperative pain and opioid use are complex, circular and bidirectional [3]. While persistent postoperative pain may lead to opioid use, the prolonged use of opioids can cause opioid-induced hyperalgesia. This involves activation of the N-methyl-D-aspartate receptors and increased spinal dynorphin release, resulting in reduced pain thresholds and heightened pain sensitivity. Such central sensitisation may increase overall opioid consumption further. Moreover, these two conditions share common psychosocial, biophysical and socio-economic risk factors [3]. Accordingly, by interrupting nociceptive input, regional anaesthesia may theoretically reduce central sensitisation, thereby lowering the risk of chronic pain and subsequent opioid reliance. Nevertheless, we acknowledge that the retrospective design of our study, based on the administrative claim data, precludes causal inference regarding the effect of regional anaesthesia on persistent postoperative opioid use. The significant differences in opioid consumption observed in the overall cohort were not retained consistently in postoperative periods following propensity-score matching. However, inconsistencies between matched and unmatched populations are well recognised in observational research [5]. Matching discards unmatched individuals, thereby shifting the target estimate from the average treatment effect of the entire population to the average treatment effect of those treated, while simultaneously reducing statistical power. Thus, attenuation of statistical significance after matching may reflect a more conservative and internally valid estimate rather than the absence of an underlying association. In addition, in procedures with low incidence, matching may yield groups with few or no outcome events, resulting in unstable or non-estimable effect sizes. Finally, the lack of detailed clinical information in claims data limits our ability to determine the rationale for the selection of anaesthesia technique. Although our findings suggest that regional anaesthesia is associated with a lower incidence of persistent postoperative opioid use, the cause-and-effect relationship between anaesthetic techniques cannot be established from this retrospective claims-based analysis. As suggested by Yuan, we hope that our study will encourage future prospective trials incorporating detailed characterisation of regional anaesthesia techniques alongside peri-operative and community analgesic strategies.