Smoking Abstinence Elicits Hyperalgesia: Neural Mechanism, Clinical Implications, and Pharmacological Managements

<jats:title>ABSTRACT</jats:title> <jats:sec> <jats:title>Purpose</jats:title> <jats:p>Nicotine exerts acute analgesic effects and serves as the major addictive component of tobacco. Nicotine withdrawal contributes to altered pain perception and hyperalgesia, further exacerbating postoperative pain and increasing opioid consumption in abstinent smokers during the perioperative period. This review aimed to systematically summarize the alterations in pain sensitivity induced by nicotine abstinence, elaborate the underlying neurochemical mechanisms, and clarify clinical intervention strategies as well as existing research limitations, so as to provide theoretical evidence for perioperative pain management in smoking cessation populations.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>This was a narrative review based on published animal and human studies. We comprehensively summarized changes in somatic sensitivity to cold, heat, and mechanical pain stimuli following nicotine abstinence. The clinical relevance of perioperative nicotine/tobacco abstinence for postoperative pain control was outlined. Moreover, we analyzed the regulatory roles of central neurotransmitters (serotonin, norepinephrine, endogenous opioids, and dopamine) and receptor activation remodeling in abstinence‐related pain sensitization. Additionally, the application value of nicotine replacement therapy in improving withdrawal‐induced hyperalgesia was summarized.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Nicotine abstinence significantly reduces pain threshold and enhances nociceptive sensitivity, leading to aggravated postoperative pain and elevated demand for opioid analgesics in perioperative smokers. Neurotransmitter dysfunction and abnormal receptor activation in the brain are core neural mechanisms mediating nicotine withdrawal‐induced hyperalgesia. Nicotine replacement therapy can effectively alleviate withdrawal‐evoked pain hypersensitivity and relieve its adverse impacts on postoperative pain outcomes. Current studies are limited by insufficient clinical data, especially studies focusing on chronic pain patients, while neuroimaging techniques exhibit great potential for exploring the neural mechanisms of abstinence‐related pain perception changes.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Nicotine abstinence induces prominent pain sensitization via central neurochemical maladjustment. Nicotine replacement therapy is an effective pharmacological intervention for withdrawal‐induced hyperalgesia. This review deepens the systematic understanding of the mechanism underlying nicotine withdrawal‐altered pain sensitivity and provides feasible clinical strategies for perioperative pain management and smoking cessation intervention, supporting translational research and clinical practice in related fields.</jats:p> </jats:sec>