Summary: A new prospective cohort study finds that smokers who are temporarily abstinent show greater pain sensitivity during nicotine withdrawal and require more postoperative pain medication—particularly opioids—than nonsmokers. The study links these changes in pain perception to altered activity and connectivity in specific brain regions and shows the effect is strongest within a limited abstinence window, with evidence that pain responses may return to baseline after roughly three months.
Researchers say understanding these neural changes could improve preoperative planning and help reduce reliance on opioids for patients who quit smoking shortly before surgery. The findings point toward targeted strategies—such as tailored pain control or nicotine replacement—to manage withdrawal-related hyperalgesia in surgical settings.
Key Findings
- Increased pain sensitivity: Abstinent smokers had lower pain thresholds and needed more postoperative analgesics compared with nonsmokers.
- Altered brain activity and connectivity: Distinct changes in resting-state brain function were associated with withdrawal-related hyperalgesia and with postoperative analgesic requirements.
- Time-limited effect: Pain sensitivity rose with shorter abstinence duration but showed signs of normalizing after about three months without nicotine.
The study, published in the Journal of Neuroscience, was led by Zhijie Lu (Fudan University Minhang Hospital) and Kai Wei (Shanghai Eastern Hepatobiliary Surgery Hospital). The research team enrolled 60 male patients scheduled for partial hepatectomy: 30 were recent abstinent smokers and 30 were lifelong nonsmokers. Investigators collected clinical measures, smoking histories, perioperative pain assessments and resting-state functional MRI (rs-fMRI) data to examine neural correlates of nicotine withdrawal and pain sensitivity.
Compared with nonsmokers, the abstinent smokers demonstrated a lower pain threshold before surgery and required higher doses of postoperative analgesics, with opioids used more frequently. Neuroimaging results showed multiple functional differences in the abstinent group: reduced fractional amplitude of low-frequency fluctuations (fALFF) in the ventromedial prefrontal cortex (vmPFC), increased regional homogeneity (ReHo) in the left middle occipital gyrus, and reduced functional connectivity between the vmPFC and both the bilateral middle temporal gyrus and the precuneus.
The team also found that preoperative pain threshold correlated positively with the length of abstinence and with specific regional brain activity and connectivity measures. Mediation analyses suggested that activity in the calcarine cortex and posterior cingulate cortex helped explain the link between abstinence duration and pain threshold. Similarly, dysfunction in the vmPFC and left anterior cingulate cortex appeared to mediate the relationship between withdrawal symptoms and higher postoperative analgesic needs.
Importantly, the study indicates this heightened pain sensitivity is not permanent. The observed effects were most evident within a defined abstinence window and are consistent with prior data suggesting pain sensitivity tends to normalize after approximately three months without nicotine.
Dr. Kai Wei emphasized that these results should not discourage patients from quitting smoking prior to surgery. Instead, the goal is to deepen scientific understanding of short-term withdrawal-related hyperalgesia so clinicians can develop strategies—such as optimized analgesic regimens, alternatives to opioids, or preoperative nicotine replacement—to reduce postoperative pain and unnecessary opioid exposure in patients who have recently stopped smoking.
Key Questions Answered
A: The study links nicotine withdrawal to altered activity and connectivity in brain regions involved in pain processing, which increases pain sensitivity during short-term abstinence.
A: No. The results underscore the need to identify and manage withdrawal-related pain but do not argue against smoking cessation. They support developing perioperative plans to mitigate short-term hyperalgesia.
A: The effect appears time-limited; evidence suggests pain sensitivity may return to baseline after roughly three months of abstinence.
Editorial Notes
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by the editorial team.
- Additional context and clarifications were added by staff for readability and clinical relevance.
About this research
Author: SfN Media
Source: SfN
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Image credit: Neuroscience News
Original Research: Closed access. Title: “Altered Regional Brain Activity Underlying the Higher Postoperative Analgesic Requirements in Abstinent Smokers: A Prospective Cohort Study” by Zhijie Lu et al., Journal of Neuroscience. DOI: 10.1523/JNEUROSCI.0109-25.2025
Abstract (rephrased)
Perioperative smokers who are temporarily abstinent experience increased pain sensitivity and higher postoperative analgesic requirements, likely driven by nicotine withdrawal–induced hyperalgesia. To investigate neural mechanisms in humans, researchers enrolled 60 male patients undergoing partial hepatectomy (30 recent abstinent smokers and 30 nonsmokers) and collected clinical pain measures alongside resting-state fMRI data. Abstinent smokers showed lower pain thresholds and greater postoperative analgesic use. Neuroimaging revealed reduced spontaneous low-frequency activity in the ventromedial prefrontal cortex, increased regional synchrony in the left middle occipital gyrus, and weakened connectivity between the vmPFC and regions such as the middle temporal gyrus and precuneus. Preoperative pain thresholds correlated with abstinence duration and with activity in visual and default-mode regions; some of these relationships were mediated by calcarine and posterior cingulate activity. Dysfunction in vmPFC and left anterior cingulate cortex mediated the link between withdrawal symptoms and higher analgesic needs. These findings provide new insights into supraspinal mechanisms of nicotine withdrawal–related hyperalgesia and suggest potential targets for improving postoperative pain management in recently abstinent smokers.