Targeting Reinforcement Mechanisms for Smoking Cessation Using Very Low Nicotine Content Cigarettes in Individuals with Opioid Use Disorder and Chronic Pain

Tobacco smoking, opioid use disorder, and chronic pain are highly comorbid conditions, and smoking cessation in this population is extremely difficult to achieve. Co-administration of nicotine and opioids results in mutual enhancement of positive reinforcement, which is likely to contribute to persistent smoking in the context of opioid agonist therapy, such as office-based

buprenorphine treatment (OBBT). Moreover, nicotine has been shown to provide mild, short- term anti-nociceptive effects, which may contribute to powerful negative reinforcement in individuals with chronic pain. The goal of the proposed research is to examine whether switching to very low nicotine content (VLNC) cigarettes can directly weaken these positive and

negative reinforcement cycles to improve cessation outcomes among people who smoke (PWS) receiving OBBT with non-cancer chronic pain. The research will employ a randomized between- subjects design to evaluate the effects of smoking VLNCs versus normal nicotine content (NNC) cigarettes on smoking behavior, pain, craving and withdrawal symptoms, and motivation to quit

smoking. Ecological momentary assessment (EMA) will be used to examine changes in bidirectional associations between pain, timing of buprenorphine dose, and smoking urge and behavior as a function of cigarette condition. Participants will complete 1-week of baseline EMA while smoking their usual brand of cigarettes; they will then be randomized to 4-weeks of NNCs

or VLNCs. EMA will continue during weeks 1 and 4 of study cigarette use. Participants will attend weekly in-person visits to obtain biomarker verification of cigarette compliance and complete self-report measures. At baseline and at the end of 4-weeks of study cigarette use, a 24-hr smoking abstinence test will be used to assess withdrawal symptoms, pain intensity and

sensitivity, and demand for usual brand cigarettes. At the conclusion of study cigarette use, participants will engage in qualitative interviews about their experiences to guide treatment development, and they will be provided with nicotine lozenges to support cessation. In general, we hypothesize that switching to VLNCs will attenuate the bidirectional associations between

smoking, pain, and timing of buprenorphine administration as assessed via EMA, and will lead to decreased symptoms of withdrawal and pain during the 24-hour abstinence test. We also hypothesize that VLNCs will be associated with increased willingness to make a quit attempt, and greater duration of achieved abstinence. These results will provide critical insights into the

role of nicotine in maintaining smoking/pain/opioid associations and the potential for VLNCs to extinguish learned associations to promote smoking cessation in this vulnerable population.