Interrelations between pain, nicotine, and tobacco smoking are of increasing interest due to their prevalence, public health impacts, and significant comorbidity (Fig. 1). Approximately one-third of American adults suffer from chronic pain,46,91 and over two-thirds endorse lifetime nicotine use.14 Although the prevalence of cigarette smoking in the general population has declined to approximately 14%,67 this trend has not been observed among pain patients.68 Indeed, smoking rates remain substantially higher among individuals with co-occurring pain (∼24%-68%),3,13,63,68,86,100,101 and there is emerging evidence that smokers with pain are more likely to also use e-cigarettes and other nicotine products.74 Moreover, recent estimates indicate that nearly 60% of individuals with tobacco use disorder meet criteria for chronic pain.48 Pain and substance use are hypothesized to operate in a reciprocal manner, contributing to the progression of both conditions over time.32 Consistent with this perspective, smoking can lead to the development of chronic pain, and pain can motivate nicotine/tobacco use and impede cessation.22,24,98 The goals of this narrative review are to provide a critical update on the extant literature on pain, nicotine, and tobacco smoking, and to outline clinical applications and next steps for future research.
2. Effects of nicotine/tobacco use on pain
2.1. Smoking as a risk factor for chronic pain
Cigarette smoking has been identified as a risk factor in the onset of back pain,85 sciatica,84 rheumatoid arthritis,89 headache,1,93 oral pain,76 and diabetic peripheral neuropathy.15 Moreover, lifetime exposure to cigarettes has been positively associated with risk for developing persistent pain,73,89 pain severity,20,81 and experimental pain reactivity.20 Pain patients who smoke also tend to report greater pain intensity/impairment than nonsmokers.9,40 Smoking may lead to dysregulated pain processing and poorer outcomes through both nicotine/tobacco-specific (eg, tissue degeneration/healing impairment24) and general neurobiological effects (eg, allostatic load on overlapping pain, stress, and reward neurocircuitry36).
2.2. Acute analgesic effects
A 2016 meta-analysis of 13 studies revealed small- to medium-sized analgesic effects of nicotine (delivered through tobacco and other methods) on experimental pain threshold (k = 15; N = 339) and tolerance (k = 21; N = 393).27 Gender was a significant moderator of threshold outcomes, such that analgesic effects were more robust among samples that included a greater number of men. Notably, smoking status and method of nicotine administration were not found to moderate threshold outcomes, suggesting that analgesia may be achieved regardless of delivery method or smoking history.
2.3. Abstinence-induced hyperalgesia
Nicotine-deprived smokers demonstrate greater sensitivity to laboratory pain than both nonsmokers5,66,72 and nondeprived smokers.30 Daily smokers have also reported greater spontaneous pain intensity after 12 to 24 hours of nicotine deprivation,11,57 and it has been suggested that deprived states may increase pain through both central (eg, enhanced excitability of spinal dorsal horn neurons, release of pain-related neurotransmitters, and nAChR availability) and peripheral (eg, vasodilation caused by neuropeptide release from peripheral C-fiber activation) processes.18,30 One implication is that increased pain during the initial phases of smoking cessation may precipitate relapse. Greater pain reactivity is a well-established characteristic of nicotine withdrawal in the animal literature,41,47 and covariation between pain and withdrawal severity has been observed among smokers.11,30
2.4. Effects of smoking cessation on pain
Although one early study found that cessation may not be associated with changes in pain,82 more recent prospective work has shown cessation (vs continued smoking) to be associated with improved pain outcomes among patients with axial/radicular pain,9 geriatric populations,10 and veterans with chronic illness.8 One cross-sectional study further revealed that 34% of pain patients reported decreased pain after a reduction in smoking.50
3. Effects of pain on nicotine/tobacco use
3.1. Pain as a motivator
Situational pain can be a potent motivator of smoking urge and behavior. For example, laboratory pain induction has been shown to increase urge/latency to smoke,22,23,69 with effects partially explained by pain-induced negative affect22,23,52 and expectancies for pain coping.69 Ecological momentary assessment (EMA) data have further shown that pain often precedes smoking,21 and cross-sectional data indicate positive associations between pain and heaviness of smoking/e-cigarette dependence.6,102
3.2. Use of nicotine/tobacco to cope with pain
Pain patients readily identify pain coping (eg, behavioral distraction from pain and distress) as a primary reason for smoking.44 A cross-sectional study of 151 chronic pain patients further showed that nearly 50% of smokers reported using cigarettes for pain coping and that those who endorsed smoking to cope with pain reported greater pain intensity/interference and fear of pain.70 Thus, the behavioral response of using nicotine/tobacco to cope with pain is both common and associated with deleterious pain outcomes. A recently developed measure of pain and smoking (PSI) includes 3 items assessing expectations for pain coping through smoking,29 and higher scores on this subscale have been prospectively associated with lower odds of achieving 6-month smoking abstinence.37
3.3. Pain as a barrier to quitting
Smokers with pain (vs no pain) report being less confident in their ability to quit,33,97 anticipate more severe withdrawal during future quit attempts,28 and are nearly 3.5 times more likely to identify pain as a barrier to cessation.29 Pain severity has most recently been positively associated with perceived barriers to e-cigarette cessation.102 The presence/severity of pain may also influence the subjective experience of quitting. For example, smokers with pain (vs no pain) have been shown to report more severe nicotine withdrawal,28,33,75 and the presence of pain has been positively associated with difficulties experienced during previous quit attempts (eg, nausea and insomnia).7,87 Most recently, greater pain severity was shown to predict increased negative affect during a self-guided smoking cessation attempt.71
3.4. Pain as a predictor of cessation outcomes
Greater pain-related anxiety and experimental pain sensitivity have each been associated with early relapse to smoking.55,65 In addition, greater pain-related disability has been shown to predict quicker latency to lapse in a laboratory paradigm of cessation.75 However, only 2 studies have examined pain severity/status as predictors of cessation outcomes. One study of 474 smokers living with HIV/AIDS found that less pain was associated with a greater likelihood of 7-day point prevalence abstinence at 12-month follow-up.2 A more recent study of 301 smokers who were motivated to quit found that those who endorsed past 2-week pain (vs no pain) were approximately 50% less likely to initiate a quit attempt.33 Results further indicated that, among a second sample of 242 smokers who recently initiated a quit attempt, those with past 2-week pain (vs no pain) were nearly 10 times more likely to lapse and over 25 times more likely to relapse during the 2-month study period.33 Indeed, learned associations between smoking and pain relief may lead to pain becoming a conditioned interoceptive cue that can elicit craving and precipitate relapse by triggering the behavioral response of smoking.24,32
4. Emerging mechanisms and transdiagnostic factors
Anxiety and depression have been implicated in the promotion of bidirectional pain-smoking effects,98 and negative affect has been identified as a central mechanism in pain-smoking reciprocity24,71,77 and the effects of pain on smoking.22,23,52 A transdiagnostic approach to examining interplay between pain and nicotine/tobacco use may further aid in the identification of shared mechanisms.32,53,58 The authors of a 2018 review proposed a transdiagnostic conceptualization in which anxiety sensitivity and pain-related fear/anxiety were hypothesized to exacerbate both chronic pain and nicotine dependence.58 For example, pain-related anxiety (ie, tendency to respond to pain with anxiety/fear) has been linked to greater pain severity/interference61 and has been positively associated with heaviness of tobacco use,25,26 use of nicotine to cope with aversive states,70 and early lapse/relapse to smoking.55 Other emerging transdiagnostic candidates include distress tolerance/intolerance,56 catastrophizing,52 and social-cognitive factors (eg, outcome expectancies and self-efficacy).23,32,59,69
5. Treatments for comorbid pain and nicotine/tobacco use
The authors of a 2018 evidence synthesis observed mixed findings across 2 trials examining the utility of standard smoking cessation interventions among individuals with chronic pain and concluded that treatments should be adapted to better meet the needs of smokers with pain.80 Indeed, such work is already underway, with 4 additional studies describing effects of tailored treatments.31,34,45,99 Three of these incorporated a novel pain-smoking psychoeducation component and focused on the motivational phase of cessation.31,45,99 First, Hooten et al.45 conducted a trial in which 99 chronic pain patients were randomized to either a brief pain-smoking intervention (BPS) or a brief control intervention that addressed the “5A's” of smoking cessation. Results indicated that BPS participants were subsequently 7.5 times more likely to endorse willingness to consider quitting and nearly 5 times more likely to consider participating in an intensive smoking cessation program.
A second randomized controlled trial (RCT) of 76 daily smokers with chronic pain tested the effects of a brief (∼30 minutes) motivational intervention that integrated personalized feedback and pain-smoking psychoeducation to help participants develop discrepancy between continued smoking and desired pain outcomes.99 Participants who received the tailored intervention (vs control) subsequently reported increased knowledge of pain-smoking interrelations, motivation to quit, and intention to engage cessation treatment. At 1-month follow-up, those who received the tailored treatment were also more likely to have talked to their health care provider about smoking cessation.
A third study developed and pilot tested a computer-based personalized feedback intervention (PFI) for smokers with comorbid pain and HIV.31 Participants (N = 68) were recruited from an outpatient infectious disease clinic and randomized to either integrated pain-smoking PFI (addressed pain-smoking perceptions/expectancies) or time-matched control PFI. Results showed that participants who received the pain-smoking PFI subsequently demonstrated greater knowledge of pain-smoking interrelations, with heavier smokers also reporting increased confidence/intention to quit.
Finally, a feasibility study of a telephone-based intervention for Veteran smokers with chronic pain showed that 4/7 participants successfully completed the 5-session protocol.34 At 10-week follow-up, 2/7 participants reported having quit smoking, and 5/7 reported clinically meaningful improvements in pain intensity/interference. Collectively, findings from these 4 treatment studies indicate that smokers may become increasingly motivated to quit and engage cessation treatment because they come to understand how continued use of nicotine/tobacco may interfere with their goals for pain management/reduction.
6. Clinical Implications and future directions
Patients/providers would likely benefit from increased assessment of both pain and nicotine/tobacco use in the context of treatment for either condition. It is further recommended that pain programs begin to integrate treatment for nicotine dependence and that nicotine/tobacco interventionists monitor pain-related factors over the course of treatment. Similarly, researchers who work in the areas of pain and nicotine should take steps to examine how these conditions may influence study outcomes. For example, RCTs for smoking cessation should incorporate pain measures (eg, chronic pain severity, duration/persistence, intensity, and impairment16,92) at baseline and follow-up, and information regarding current and historical nicotine/tobacco use should be collected in the context of studies involving clinical and experimental pain assessment.
6.1. Tailored and integrated treatment approaches
Although initial findings indicate that brief pain-smoking interventions can increase motivation to quit and engagement of smoking cessation treatment,31,45,99 no research to date has tested the efficacy of protocols specifically designed to support long-term abstinence in the context of pain. This represents a major gap in the literature, and it is critical that future studies assess lapse, relapse, and point-prevalence/prolonged abstinence outcomes. Randomized controlled trials have demonstrated the efficacy of behavioral treatments for smoking cessation (eg, skills training),39 and these approaches could be tailored to better account for the antithetical influence of pain. For example, integrated treatments may benefit from addressing pain-nicotine perceptions/expectancies,29,37,95 and teaching more adaptive pain-coping techniques (eg, progressive muscle relaxation, distraction, and mindfulness38,51,60). Given that nicotine deprivation can increase pain sensitivity30 and that pain has been associated with more severe withdrawal,11,33,75 smokers with pain may also benefit from high-dose or combination nicotine replacement therapy.43,64,96 Varenicline, nicotinic receptor partial agonist, may also have utility in the context of pain because it has been shown to reduce hyperalgesia in rodent models4 and is among the most efficacious cessation pharmacotherapies.64 Finally, future treatments should address comorbid psychopathology and target emerging transdiagnostic factors (eg, pain-related anxiety) that likely promote behavioral tendencies to ameliorate pain and negative affect through self-administration of nicotine/tobacco.32,58
6.2. Translational, laboratory, and momentary assessment paradigms
Future translational/multimethod research approaches will be central to the identification of efficacious treatment targets. For example, laboratory paradigms designed to examine pain as a motivator of nicotine/tobacco use22,23 and dynamic pain responses in the context of abstinence (eg, through quantitative sensory testing30) offer great potential to further our understanding of cognitive-behavioral and neurobiological mechanisms. In addition, EMA paradigms may clarify temporal pain-smoking microprocesses and enhance ecological validity.21,83 Finally, the application of widely used imaging modalities (eg, functional magnetic resonance imaging) may advance our understanding of neural correlates in bidirectional pain-nicotine effects.54,79
6.3. Examination of third variables
Future work should continue to investigate biopsychosocial and lifestyle factors (ie, potential confounding or third variables) that are common to both pain and nicotine dependence. For example, pharmacological treatments for chronic pain include opioid- and cannabis-based medicines,12,78 there is evidence of covariation between smoking rate and use of opioid medications,44 and rates of cigarette-cannabis co-use are higher in states where medical cannabis is legal.94 Important next steps include quantifying the prevalence of co-use among individuals with chronic pain, and assessing pain-related perceptions/expectancies and reasons for use. In addition, several health behaviors have been implicated in both chronic pain and nicotine dependence (eg, exercise and sleep)17,35,49,88,90 and may contribute to bidirectional pain-nicotine effects. For example, sedentary behavior is associated with an increased likelihood of developing chronic pain88 and is greater among current smokers (vs nonsmokers),49,90 and it is possible that extended sitting and/or physical inactivity may amplify pain-smoking reciprocity. Future work is needed to identify casual or moderating links between chronic pain, nicotine use, and lifestyle factors.
6.4. Electronic cigarettes and alternative nicotine products
Given that e-cigarette use has increased over the past decade19,62 and that smokers with co-occurring pain are more likely to use e-cigarettes and other nicotine products,74 there is a need to examine whether smokers with chronic pain use other products to supplement their exposure to nicotine.74 Future research would also benefit from examining acute analgesic effects of novel nicotine delivery systems (eg, heat-not-burn products) that may support smoking cessation in the context of pain.42
The transdisciplinary study of complex interrelations between pain and nicotine/tobacco use is rapidly evolving and of great clinical significance. Converging evidence indicates that pain and nicotine/tobacco use interact in a reciprocal fashion to influence their respective trajectories and outcomes. It is recommended that researchers and clinicians increasingly assess both pain and nicotine/tobacco use when working with populations that present with either condition. It is also recommended that future research use translational, laboratory, and EMA paradigms to further elucidate bidirectional pathways. Finally, there is a critical need to develop treatments that target emerging transdiagnostic factors and better address the specific needs of millions of individuals who suffer from both chronic pain and nicotine dependence.
Conflict of interest statement
The authors have no conflicts of interest to declare.
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