B. BACKGROUND/SIGNIFICANCE B.1. Tobacco Smoking. Smoking is responsible for over 40% of premature deaths and disability in the US1, and has been estimated to cost $96 billion in direct medical expenses and $97 billion in lost productivity each year12. Although over 40% of the 48 million Americans that still smoke make a serious quit attempt each year, either on their own (i.e., self-guided quit) or with assistance from formal treatment, less than 5% are able to abstain from smoking for greater than 3 months9. The selection hypothesis of smoking prevalence posits that smokers who are not able to quit successfully are "burdened" by specific characteristics that make it more challenging to quit13. For example, those less successful in quitting smoking may be more nicotine dependent or more likely to suffer from substance use, psychiatric, or medical conditions. According to this perspective, smoking prevalence should begin to stabilize as the remaining population becomes increasingly representative of those "at-risk smokers" who are unable to quit1. There is consensus that significant populations of at-risk adult smokers are present in the general population2. Yet, there remains little understanding of the subgroups of "at-risk smokers" and the processes governing relapse among them14. Emerging evidence suggests that smokers who suffer from opioid misuse may constitute such a "high-risk group"15,16.

B.2. Prevalence of Comorbid Opioid Misuse and Tobacco Smoking. Like smoking, opioid misuse, defined as opioid use without a prescription, at a dose or frequency higher than prescribed, or for a non-medical purpose (e.g., getting high)3, is a critical national health problem that burdens over 11.5 million American adults17, with annual direct medical treatment and lost productivity costs in excess of $504 billion17. Opioid misuse often leads to hypervigilance for somatic perturbation, significant emotional distress, physical deconditioning, and functional disability18-20. According to NIH, the deleterious effects of opioid misuse have been demonstrated in morbidity, immune function, sleep, cognition, eating, mobility, and affective distress11. Clinical and epidemiological population estimates indicate that the prevalence of smoking among persons misusing opioids (upwards of 48%21) may be greater than twice the rate (19%) observed in the general population22-24. Daily smokers are 5 times more likely than non-smokers to meet criteria for past year opioid misuse16.

B.3. Complex Interrelations between Opioid Misuse and Tobacco Smoking. Although interrelations between opioid misuse and smoking have been of clinical interest for decades25, research in this area has only begun to develop. Studies provide evidence of covariation between tobacco smoking and the development and maintenance of opioid misuse16. Chronic nicotine exposure may result in dysregulation of the endogenous opioid system, leading to greater somatic perturbation (e.g., pain) and cross-tolerance to prescription opioids26. There is also evidence that nicotine may sensitize the neural system to enhance the rewarding properties of opioid medications27, which is consistent with incentive-sensitization theories of addiction28,29. Although limited, available work has begun to model the interrelations between opioid misuse and tobacco smoking. One recent study using a representative sample, for example, found that smokers were more likely than non-smokers to report past year opioid misuse, as well as meet criteria for opioid use disorder, and these results were evident over and above depression and alcohol use16. Further, initiating tobacco use prior to the age of 14 and reporting greater tobacco dependence were robustly associated with past-year opioid misuse16.

B.4. Limitations of Opioid Misuse-Tobacco Research. Despite the public health importance of the comorbidity between opioid misuse and smoking, there are substantive gaps in extant research and knowledge. Without such knowledge, it is difficult to develop or adapt smoking cessation treatments to meet the needs of this neglected population. First, despite the established association between opioid misuse and smoking16,24, there are no data addressing the impact of opioid misuse on smoking cessation. There is a clear need to develop research to understanding the extent to which opioid misuse may impair successful smoking cessation. To address this gap, the present proposal seeks to test the extent to which opioid misuse interferes with smoking cessation and theoretically and empirically established factors of negative affect states and nicotine withdrawal/craving that occur over the course of a cessation attempt. This limitation impedes the ability to begin to understand the possible linkages between opioid misuse and key affective and drug-state processes. It is unfortunate theoretically and clinically because numerous studies have documented that smokers, especially those with greater degrees of nicotine dependence or higher smoking rates, report negative affect and problematic physical and affective nicotine withdrawal symptoms during quitting30-32.

Second, it is yet unknown what specific processes account for poor smoking cessation outcomes among smokers with opioid misuse. Identifying these processes is important for at least two reasons: (a) understanding of the pathway(s) through which opioid misuse affects smoking cessation outcomes so that we can develop a process-based theoretical model of opioid misuse-smoking cessation relations; and (b) explicating such explanatory mechanisms is essential to translating basic research knowledge about opioid misuse and smoking to advances in specialized behavioral and pharmacologic smoking cessation interventions for smokers misusing opioid33. The present proposal is therefore innovative in exploring mechanisms that affect opioid-smoking linkages.

Third, there is a need to identify possible moderators of smoking-opioid relations. Although many possible moderators exist, comorbid pain is one leading candidate. Symptoms of (current) moderate to severe pain are more prevalent among both smokers and persons misusing opioids16,34, often doubling rates observed in the general population. Among persons with chronic pain, such comorbidity has been associated with overall greater pain intensity and chronicity, increased functional impairment, and reduced pain-treatment efficacy35,36. Theoretically, chronic pain is therefore apt to increase the severity of nicotine withdrawal and craving and decrease quit success, especially among smokers with opioid misuse. Additionally, sex is another potential candidate as a moderator of smoking-opioid relations37. Specifically, females relative to males often report more difficulty quitting smoking,38,39 due in part to holding more positive expectancies for smoking effects on mood and appetite40-42. In terms of opioid misuse, although less is known, females compared to males receive less treatment for opioid misuse43,44 and report more mood disturbances45-47. Theoretically, these data may suggest that sex differences could exist among tobacco smokers with opioid misuse, such that females may have greater difficulty reducing their tobacco use in the context of opioid misuse.

B.5. Integrative Model. Although presently no integrative model of smoking-opioid co-use has been offered, several mechanisms may be involved. Such mechanisms could include genes central to regulating certain brain chemical systems48-50, neurobiological mechanisms involved in the cross-tolerance and cross-sensitization to both drugs51,52; conditioning mechanisms (e.g., craving for opioids or nicotine elicited by certain environmental cues)53, or individual differences in psychosocial factors (e.g., personality characteristics)54. There is highly limited research addressing these mechanisms. Drawing from past work (see B.3.), I have theorized that smokers with opioid misuse, compared to those without, may be more cognitively, affectively, and behaviorally reactive to aversive internal cues (e.g., nicotine withdrawal, negative emotional states) during periods of smoking deprivation. For example, individuals who misuse opioids may be more apt to engage in catastrophic thinking toward these aversive internal cues (e.g., "I cannot tolerate this distress!")55,56 and experience greater change in the intensity of negative affect, nicotine withdrawal symptoms (e.g., more intense restlessness ), and craving (e.g., "I need to smoke now"). As a result, opioid misuse may drive the affective and drug-state experiences (negative affect and withdrawal symptoms) experienced during a quit attempt. Consequently, individuals with misuse opioids may tend to rely on smoking to cope with such aversive internal distress. From this perspective, aversive internal states (negative affect and nicotine withdrawal symptom)57, may mediate the relation between misuse and lapse/relapse to smoking. Further, individual differences factors, such as severity of pain and sex, could moderate opioid-smoking relations.