LAUSR

In Reply O’Hagan and Gustin (2022) suggest that our conclusion that perioperative sleep promotion may beneficially impact postoperative pain perception is ‘based on imprecise conclusions of causality, which may lead to unnecessary efforts for implementation’. On the contrary, substantial evidence from preclinical research, experimental studies and largescale longitudinal studies consistently demonstrates dysregulation of sleep causally increases pain sensitivity and contributes to pain chronification (Smith et al., 2019). Moreover, clinical trials, for example, multicomponent cognitive behavioural therapy for insomnia in patients with persistent pain, show significant beneficial effects on pain intensity (Selvanathan et al., 2021). Congruent with results from the referenced systematic review by O’Hagan et al., we have also found that perioperative pharmacologic sleep promotion may improve postoperative pain control (Bjurstrom & Irwin, 2019). Our results demonstrated a connection between poor preoperative sleep quality and adverse postoperative pain outcomes, which strengthens prior evidence of a causal relationship between sleep and pain (Bjurstrom et al., 2021). We acknowledge, however, as stated in ‘Limitations and recommendations for future studies’, that longitudinal objective sleep data (actigraphy and/or polysomnography) would add specificity to these findings. In the final paragraph, O’Hagan and Gustin further suggest ‘a key shared mechanism of pain intensity and sleep quality has not been identified’. Whereas our observational study design limits conclusions regarding causation, previous research has shown that regulation of wake, sleep and nociception share multiple overlapping neuroanatomic circuits and molecular mechanisms. Briefly, sleep disturbance alters central nervous system (CNS) pain processing through increases in proinflammatory and adenosinergic signalling, dysregulation of monoaminergic systems and possibly enhanced NmethylDaspartate (NMDA) receptor function (Bjurstrom & Irwin, 2019; Smith et al., 2019). These changes amplify nociception in the CNS (central sensitization) and decrease endogenous descending pain inhibitory capacity, which together aggravate pain. Additionally, sleep fragmentation may heighten pain intensity through decreased distraction analgesia and attenuated opioid analgesic effects. Hence, multiple identified mechanisms underlie the negative cycle of dysregulation of sleep and increased pain sensitivity. We agree that there are limitations in generating causal inference from observational data. In the setting of sleeppromoting interventions for pain conditions, the issue of reverse inference seems mute, given strong evidence underlying bidirectional sleeppain interactions, with a direct causal influence of sleep on pain. Furthermore, O’Hagan and Gustin express concerns related to selection bias and unmeasured confounders, and recommend calculation of Evalue. Although we controlled for variables known to influence postoperative pain severity (e.g. age, sex, body mass index, depression, anxiety, pain catastrophizing and preoperative pain intensity) it is not possible to control for all confounders, some of which are not identified or measured. In this case the Evalue is 1.28 (lower 95% CI: 1.03), suggesting modest unmeasured confounding could potentially impact causal interpretations. Hence, future research should seek to identify such confounders, and include them within the model. This would then strengthen the conclusion that treatment of disordered sleep will likely improve painrelated outcomes. In the final sentence, O’Hagan and Gustin conclude that ‘sleep management strategies should be further investigated before being endorsed to support pain management’. While we agree that clearly more research is needed to fully understand the relationship between sleep structure and pain neurophysiology, evidence suggests that sleeptargeting interventions should be prioritized for inclusion as an important component of multimodal pain management that has typically been neglected. Despite the serious effects of longterm pain, treatments remain