Neural correlates and behavioral impact of withdrawal-induced hyperalgesia among people who smoke with and without chronic pain

Tobacco smoking is extremely addictive and remains a leading cause of preventable death. Individuals with chronic pain are approximately twice as likely to smoke cigarettes as those without pain, and smoking cessation among people with comorbid pain is more difficult to achieve. Smoking and pain have been proposed to influence each other through a maladaptive reciprocal positive feedback loop, in which pain increases motivation to smoke and smoking worsens pain over time. Moreover, smoking withdrawal exacerbates pain, thus presenting an additional barrier to smoking cessation. However, the mechanisms underlying withdrawal- induced exacerbation of pain (hyperalgesia) and the real-world impact of withdrawal-induced hyperalgesia among people attempting to stop smoking, remain unclear. To fill this important scientific gap, we will evaluate among people who smoke (PWS) with and without chronic pain: 1) the impact of smoking withdrawal on brain fMRI-based response to noxious heat stimuli (Aim 1); and 2) the influences of withdrawal-induced hyperalgesia on the ability to abstain from smoking (Aim 2). Adults who smoke daily with (n=48) and without (n=48) chronic pain will each complete 2 fMRI scans with counterbalanced conditions: after smoking ad libitum, and after 24- hrs biochemically verified abstinence. During the fMRI scans, participants will experience and provide pain ratings to a pseudorandom series of neutral and noxious heat stimuli. Participants will complete a 1-week abstinence test with a descending reinforcement schedule previously used by our group, accompanied by ecological momentary assessment (EMA) of pain, affect, and smoking urge. We hypothesize based on our preliminary data that: 1) increased pain during smoking withdrawal will correlate with decreased activation of the bilateral inferior frontal gyrus (IFG) indicating reduced cognitive-affective regulation of pain; 2) PWS with chronic pain will exhibit greater withdrawal-induced deficits in IFG activation; and 3) Chronic pain status and withdrawal-induced changes in pain ratings and pain-related brain activation will predict shorter time to lapse. By addressing a critical gap in scientific knowledge regarding the neural basis and behavioral impact of smoking withdrawal-induced hyperalgesia, the project will provide a foundation for development of targeted behavioral, pharmacological, and neurostimulation interventions to aid smoking cessation.