Integrating Pain Assessment in Nicotine and Tobacco Research and Treatment to Improve Cessation Outcomes

Introduction

Chronic pain, typically defined as pain that is present most days for 3 months or more, affects ~24% of adults in the United States.¹ Pain is a primary feature of several chronic disorders; such as migraine, chronic back pain, and fibromyalgia; and a common symptom of other health conditions, including cancer and HIV. Chronic pain is also highly comorbid with commercial nicotine/tobacco use. Across population-based and clinical samples, ~33%–44% of individuals who currently smoke cigarettes report chronic pain, and ~24%–42% of adults with chronic pain report smoking cigarettes^2–7; both rates exceeding general population estimates. Individuals with chronic pain are more likely to use nicotine/tobacco products and experience greater difficulty quitting. In turn, nicotine/tobacco product use is associated with more severe pain, greater functional disability, and increased use of opioid medications.^8–11 Despite this documented overlap, complex interrelations between pain and nicotine/tobacco use remain understudied and insufficiently addressed.

We presented a symposium at the 2025 Society for Research on Nicotine and Tobacco annual meeting titled “Novel translational research on pain and tobacco use: Examining relationships from laboratory to clinical research.” Presentations highlighted emerging methods and findings emphasizing the need for integrated assessment and treatment to improve both pain and nicotine/tobacco cessation. This commentary aims to provide an overview of the bidirectional relationship between pain and nicotine/tobacco use, discuss the importance of assessing pain in the context of nicotine/tobacco research and treatment, and to briefly describe pain measures that can be easily incorporated into clinical settings and research protocols.

Reciprocal Model of Pain and Nicotine/Tobacco Use

The Reciprocal Model of Pain and Nicotine/Tobacco Use describes a bidirectional feedback loop where each condition exacerbates the other over time.^8–11 In this model, pain functions as a potent driver of nicotine/tobacco use, partly due to acute analgesic effects of nicotine.¹² The presence and severity of pain has been linked to heavier smoking, increased use of e-cigarettes and other tobacco products, and more pronounced craving. Conversely, tobacco smoking is a well-established risk factor in the onset and worsening of chronic pain conditions, including low back pain and rheumatoid arthritis.^8,9 Nicotine/tobacco-induced inflammatory and neuroplastic changes (eg, allostatic load on pain-processing neural circuits) may also contribute to the persistence and intensification of pain.¹¹ This cyclical relationship presents a significant challenge for nicotine/tobacco cessation, as individuals with pain report lower cessation self-efficacy and greater difficulty quitting,¹³ with smoking abstinence also shown to induce hyperalgesia (increased sensitivity to pain), which may contribute to relapse.¹⁴

Beyond human research, preclinical models have advanced our understanding of bidirectional pain-nicotine/tobacco effects. Animal research has shown that nicotine produces pain relief; including antinociceptive, antihyperalgesic, and antiallodynic effects; in acute and chronic pain models.^15–19 However, chronic nicotine exposure also leads to tolerance, requiring higher doses to achieve the same level of pain relief.^15,18 Nicotine withdrawal further induces hyperalgesia and allodynia,^18,20,21 which mirrors the increased sensitivity to pain observed in humans during early tobacco abstinence. These findings underscore the bidirectional nature of the relationship where pain potentiates nicotine use, and nicotine withdrawal exacerbates pain, creating a vicious cycle of reinforcement.

Call to Action: The Importance of Integrating Pain Assessment into Nicotine/Tobacco Research and Treatment

The growing body of human and preclinical work highlights the need to integrate pain considerations into nicotine/tobacco research and treatment, including developing interventions that address the unique challenges faced by individuals with both nicotine/tobacco use and pain. Strategies that simultaneously address both pain management and nicotine/tobacco cessation offer potential to enhance both outcomes. However, pain assessment in nicotine/tobacco research remains limited, and few cessation interventions incorporate pain-specific content or explicitly target both pain and nicotine/tobacco use. For example, a small feasibility study in veterans piloted a brief telephone-delivered CBT protocol that targeted both chronic pain and smoking.²² Preliminary signals were encouraging, but the single-arm design and small sample underscore the need for adequately powered randomized trials.

Additional research is necessary to inform the development of integrated treatments for nicotine/tobacco use and chronic pain. For example, preclinical models that account for the comorbidity of pain and nicotine use, including the inclusion of females, are needed to advance understanding of their reciprocal interplay. In rodent studies, chronic pain has been shown to alter nicotinic acetylcholine receptor function without affecting nicotine self-administration,²³ highlighting a gap in understanding neurobiological changes that accompany co-occurring pain and nicotine use. Although approved cessation treatments like varenicline (Chantix) have been shown to block nicotine reward and reduce withdrawal-induced hyperalgesia in rodents,²⁰ their efficacy in the context of chronic pain remains unknown. Addressing these gaps in preclinical research will be critical in the conceptualization and development of integrated treatments.

Furthermore, incorporating pain assessment into nicotine/tobacco research and treatment will allow investigators to: (1) quantify pain-related variance in use patterns, cessation response, and relapse risk that would otherwise be missed; (2) test mechanisms (eg, abstinence-induced hyperalgesia, pain-related outcome expectancies) as modifiable targets; (3) stratify and tailor interventions based on pain impact (eg, high-impact chronic pain) and align the timing of supports with pain-related fluctuations; and (4) identify subgroups for whom integrated approaches are likely to yield the greatest benefit.

Mechanistically, integrated protocols that pair standard cessation pharmacotherapy with basic pain management and target negative reinforcement (pain relief, withdrawal-related hyperalgesia), pain-related expectancies, and affective dysregulation may improve quit outcomes without substantial added burden. Cognitive behavioral approaches aimed at increasing distress tolerance and pain-related coping could be adapted to also address nicotine cravings. Similarly, neuromodulatory approaches, such as repetitive transcranial magnetic stimulation, could be employed to simultaneously treat both chronic pain and nicotine/tobacco dependence. Given the high prevalence and reciprocity of comorbid pain and nicotine/tobacco use, combined interventions that target both conditions may leverage overlapping mechanistic pathways to yield synergistic benefits.

Finally, it is essential to assess and consider pain in non-treatment studies, as pain can contribute important variance to nicotine/tobacco-related behaviors. Recent studies, including those using ecological momentary assessment methods,²⁴ have shown that changes in pain can influence urge to smoke and nicotine/tobacco use behaviors. Such information could also be leveraged to provide real-time feedback as part of comprehensive interventions. Including pain assessment across diverse types of nicotine/tobacco research (eg, clinical, survey, human laboratory, preclinical) would provide a more accurate understanding of its role in nicotine/tobacco use behaviors and cessation outcomes.

Practical Suggestions for Incorporating Pain Assessment in Nicotine/Tobacco Research and Treatment

Self-report remains the gold standard for pain assessment, and many aspects of pain experience (eg, type, location, intensity, frequency) can be efficiently assessed in both research and clinical settings using a few key items (see Table 1). An additional pain-related variable that may provide important information is pain interference which refers to the extent to which pain disrupts daily activities (eg, work, social participation, household tasks, concentration) and impacts emotions (eg, irritability) and is important for understanding the broader impact of pain on functioning in the context of nicotine and tobacco use.²⁵

There are many well-established pain measures that can be easily integrated into nicotine/tobacco research and clinical treatment protocols. For example, the 5-item Graded Chronic Pain Scale Revised (GCPS-R)²⁶ evaluates the frequency of pain and impact on life or work activities over the past three months, past 7-day pain intensity, interference with enjoyment of life, and interference with general activity. GCPS-R scoring further permits assessment of chronic pain presence (Grade 0 = no chronic pain) and differentiation of mild, bothersome, and high-impact chronic pain. The NIH-developed Patient-Reported Outcomes Measurement Information System pain measures²⁵ provide adaptable items for assessing pain intensity and interference across various populations and settings. The NIH Common Data Elements²⁷ further offer a comprehensive set of standardized pain domains and recommended instruments. Although these are some commonly used tools, this list is not exhaustive and researchers and clinicians may prefer to use other pain measures or focus on specific pain-related constructs and potential transdiagnostic factors (eg, catastrophizing), depending on the given study design and target population.

It is important to note that pain assessment items vary by time frame (eg, past 24 hours, past 3 months), so aligning the pain assessment and nicotine/tobacco use time frames can help ensure consistency and meaningful data interpretation. Including even a few key pain assessment items into research and applied clinical settings can offer valuable insights into how pain impacts nicotine/tobacco use behaviors and outcomes. Incorporating and considering pain data will also help account for variance in outcomes, ultimately informing the development of more precise and personalized treatment strategies for individuals with co-occurring pain and nicotine/tobacco dependence.

Conclusions

Pain impacts a sizable proportion of the population and is closely linked with poorer nicotine/tobacco cessation outcomes. Despite this relationship, there is little research on integrated treatments that simultaneously address both nicotine/tobacco dependence and pain. Incorporating pain assessment into research and treatment is needed to better understand and account for the influence of pain on nicotine/tobacco use and cessation. By intentionally integrating pain considerations, we can develop more precise, personalized, and effective treatment strategies to improve cessation success, pain-related functioning, and overall quality of life for the millions of individuals living with the dual challenge of comorbid chronic pain and nicotine/tobacco dependence.

Author Contributions

Deniz Bagdas (Conceptualization, Writing—original draft, Writing—review & editing [equal]), Jessica M. Powers (Conceptualization, Writing—original draft, Writing—review & editing [equal]), Dana Rubenstein (Conceptualization, Writing—original draft, Writing—review & editing [equal]), Maggie M. Sweitzer (Conceptualization, Writing—original draft, Writing—review & editing [equal]), Joseph W. Ditre (Conceptualization, Writing—original draft, Writing—review & editing [equal]), Andrea H. Weinberger (Conceptualization, Writing—original draft, Writing—review & editing [equal])

Funding

Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under Award Numbers K01-DA056854 to D.B. and R21-DA052729 to M.M.S.), and by a Hollander Faculty Fund Award to A.H.W. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Hollander Faculty Fund.

Declaration of Interests

The authors report no potential conflicts of interest.