Altered Regional Brain Activity Underlying the Higher Postoperative Analgesic Requirements in Abstinent Smokers: A Prospective Cohort Study

Perioperative abstinent smokers experience heightened pain sensitivity and increased postoperative analgesic requirements, likely due to nicotine withdrawal-induced hyperalgesia. However, the underlying neural mechanisms in humans remain unclear. To address this issue, this study enrolled 60 male patients (30 abstinent smokers and 30 nonsmokers) undergoing partial hepatectomy, collecting clinical data, smoking history, pain-related measures, and resting-state functional magnetic resonance imaging. Compared with nonsmokers, abstinent smokers showed lower pain threshold and higher postoperative analgesic requirements. Neuroimaging revealed altered brain function in abstinent smokers, including reduced fractional amplitude of low-frequency fluctuations (0.01-0.1 Hz) in the ventromedial prefrontal cortex (vmPFC), increased regional homogeneity in the left middle occipital gyrus, and decreased functional connectivity between the vmPFC to both the bilateral middle temporal gyrus and precuneus. Preoperative pain threshold was positively correlated with abstinence duration and specific regional brain activities and connectivity. Furthermore, the observed association between abstinent time and pain threshold was mediated by the calcarine and posterior cingulate cortex activity. The dysfunction in vmPFC and the left anterior cingulate cortex was totally mediated by the association between withdrawal symptoms and postoperative analgesic requirements. These findings suggest that nicotine withdrawal might alter brain functional activity and contribute to hyperalgesia for the abstinent smokers. This study provided novel insights into the supraspinal neurobiological mechanisms underlying nicotine withdrawal-induced hyperalgesia and potential therapeutic targets for postoperative pain in abstinent smokers.