Mechanisms and Clinical Features of Co-occurring Opioid and Nicotine Use

Abstract

Purpose of review:

To review the literature addressing shared pathophysiological and clinical features of opioid and nicotine use to inform etiology and treatment, and highlight areas for future research.

Recent findings:

Opioid and nicotine use co-occur at an alarmingly high rate, and this may be driven in part by interactions between the opioid and cholinergic systems underlying drug reward and the transition to dependence. Pain, among other shared risk factors, is strongly implicated in both opioid and nicotine use and appears to play an important role in their co-occurrence. Additionally, there are important sex/gender considerations that require further study. Regarding treatment, smoking cessation can improve treatment outcomes in opioid use disorder, and pharmacological approaches that target the opioid and cholinergic systems may be effective for treating both classes of substance use disorders.

Summary:

Understanding overlapping etiological and pathophysiological mechanisms of opioid and nicotine use can aid in understanding their co-occurrence and guiding their treatment.

Introduction

Both opioid and nicotine use independently represent enormous public health problems, associated with staggering morbidity and mortality worldwide. Furthermore, opioid and nicotine use often co-occur, and their comorbid presentation has implications for their progression and treatment prognosis. Here, we review what is known about shared pathophysiological mechanisms of co-occurring opioid and nicotine use, including factors implicated in the etiology, illness course, and treatment of these conditions, and recommend directions for further research.

Opioid epidemic

The prevalence of nonmedical opioid use has risen dramatically over the past decade, for example, increasing by greater than 300% in the U.S. [1]. These rates are highest among young adults ages 25 to 34—with 1 in 5 deaths in this age group attributable to opioids—and opioid misuse in older adults also continues to rise [1, 2]. Rates of perinatal opioid exposure and of opioid-associated neonatal abstinence syndrome have also increased in recent years [2]. Thus, the current opioid epidemic is a pervasive public health problem affecting individuals of all ages.

While opioid use is particularly prevalent in the U.S. and Canada, opioid use disorder (OUD) is the second most prevalent illicit drug use disorder worldwide, effecting 15.5 to 16.8 million people globally [3, 4]. In addition to its increasing prevalence, the clinical profile of OUD has changed in recent decades. Within the U.S., this has included a sharp increase over the past two decades in the number of individuals reporting misuse of opioid analgesics prior to heroin initiation [5, 6], as well as a more recent increase in the intentional and unintentional misuse of synthetic opioids with very high overdose potential, such as fentanyl [7, 8].

Tobacco use

Tobacco smoking is a leading cause of preventable death worldwide [9], and costs the global economy $422 billion in healthcare expenditures annually due to smoking-attributable diseases [10]. Despite knowledge of severe health consequences, less than half of smokers worldwide have attempted to quit in the past year [11]. Smokers with comorbid medical conditions (e.g. substance use disorders, SUD) have been identified as important targets for treatment [12], and some medical conditions (e.g. pain) may serve to maintain tobacco dependence [13]. Furthermore, as with OUD, the clinical and demographic profile of tobacco/nicotine use may be changing with emerging products such as electronic cigarettes (e-cigarettes), which have both potential for harm reduction and abuse liability [14].

Co-occurrence of smoking and opioid misuse

Smoking and opioid misuse co-occur at strikingly high rates. Approximately 85% of patients in methadone treatment for OUD smoke cigarettes [15]—a much higher rate than those with alcohol use disorder [16]. Additionally, tobacco-related disease and mortality rates are high among individuals who use opioids [17]. Furthermore, nicotine and opioid use are thought to be mutually reinforcing, such that individuals with OUD are more likely to smoke [18, 19] and smokers are likely to misuse opioids [20].

In addition to a more general link between smoking and opioid use, smoking status is a strong predictor of risk for nonmedical use of prescription opioids in particular [18], and tobacco smokers have a high frequency of non-medical use of prescription opioids [21]. While the greatest risk factor for nonmedical use of prescription opioids is a history of substance or polysubstance abuse [22], recent evidence has singled out tobacco smoking as the strongest predictor [18]. Daily/intermittent smokers are three times more likely to report past-year nonmedical prescription opioid use compared to never smokers [23]. Likewise, a population-based survey found that the odds ratios for prescribed opioids increased with severity of nicotine dependence (OR=3.1) [24]. In line with this, smoking rates are higher among individuals who use prescription opioids than in the general population [24, 19, 25]. A recent study using the U.S. National Survey on Drug Use and Health found that opioid-dependent smokers exhibited greater severity of nicotine dependence compared to non-opioid dependent smokers [26]. Taken together, these studies suggest that smoking is a risk factor for prescription opioid use. Tobacco smoking may increase risk for opioid misuse because of the prior establishment of nicotine use as a “gateway” to illicit drug use [27], especially among adolescents [28].

Interactions between the endogenous opioid and cholinergic systems

Smoking might also be a risk factor for opioid dependence because of neurobiological interactions between the endogenous opioid and cholinergic system. Preclinical and clinical evidence point to a neurobiological link between nicotine- and opioid-related neurotransmitter systems [29]. With respect to nicotine dependence, nicotinic-acetylcholine receptors (nAchRs) mediate nicotine reinforcement by stimulating the release of dopamine as well as opioid neuropeptides in the striatum that act on mu-opioid receptors (MORs), which facilitate psychological nicotine dependence [30, 31], and act on delta-(DORs) and kappa-opioid receptors (KORs), which facilitate physical nicotine dependence [32]. With respect to opiates, in vitro studies show that prescription opioids bind to MORs and DORs [33] and interact with nAchRs [34] suggesting possible mechanisms by which opioids might produce reinforcing/euphoric effects. One in vivo mouse study showed that opioid-induced striatal dopamine release, locomotor activity, and reinforcement is enhanced by nicotine treatment [35]. Thus, nicotine reinforcement is partly dependent on the opioid system and opioid reinforcement is partly regulated by the nicotinic-acetylcholine system. Furthermore, nicotine use may enhance the rewarding properties of opioids in the brain [36], promoting nicotine and opiate co-use. These complex nicotine-opioid interactions may explain why nicotine and opioids independently prime the use of other drugs of abuse [27] and might bidirectionally prime one another.

Pain as a candidate mechanism underlying co-occurring smoking and opioid misuse

Opioid use disorder and pain

It has also been shown that chronic nicotine exposure dysregulates the endogenous opioid system and leads to greater pain and cross-tolerance to opioids [37, 38], suggesting that pain may contribute to comorbidity between smoking and opioid misuse, particularly among individuals with chronic pain. However, it is important to note that rates of tobacco smoking are also elevated among individuals with OUD without chronic pain. Both the therapeutic (i.e., analgesic) and rewarding (e.g., euphoric) effects of opioids are largely due to their activation of MORs [39]. Within the brain, MORs are widely expressed and overlap with regions implicated in both nociceptive and reward processes; e.g., insula, thalamus anterior cingulate, striatum [39]. These brain regions are activated in response to painful stimuli and these effects are reduced following administration of opioid agonists [40, 41]. However, despite significant evidence for short-term efficacy of opioid analgesics for acute pain management, the evidence for the efficacy of these medications to treat chronic pain is limited [42]. In addition, in some individuals, repeated opioid exposure can result in the development of hyperalgesia—heightened pain sensitivity (see Smoking and pain section for nicotine-induced hyperalgesia) [39].

OUD is relatively common among individuals with chronic pain. Recent data indicates that approximately 35% of patients receiving opioid treatment for non-cancer chronic pain also meet criterial for OUD [43]. Despite this, the majority of individuals who are prescribed opioids do not develop OUD [39]. Similarly, chronic pain is common among individuals with OUD, with estimates indicating that between 37–61% of individuals engaged in medication-assisted treatment (MAT) for OUD have a form of chronic pain [44–47]. Among MAT patients, chronic pain is associated with negative clinical symptoms including anxiety, depression, overall psychiatric distress, sleep disturbances and trauma [48, 49]. As each of these factors are also associated with poorer clinical outcomes in OUD, further work to address chronic pain in MAT patients is urgently needed.

Smoking and pain

There is also a significant association between smoking and pain [e.g., 50]. Smoking prevalence among pain patients is twice that observed in the general population [e.g., 51]. Whereas smoking rates have declined in recent years in the general population, rates do not appear to have declined among persons with chronic pain [52]. Smoking is associated with increased risk of chronic pain [53], and tobacco smokers report pain in more locations and at a higher intensity than nonsmokers [20], and also experience more pain-related disability [50]. Furthermore, smokers with significant pain consume more cigarettes per day [54], are more dependent on tobacco, and are less confident in their ability to quit smoking [55] than smokers who do not report significant pain symptoms.

Pain and smoking have been proposed to interact in a reciprocal manner in a positive feedback loop that results in greater pain and increased smoking [13]. In this proposed model, effects of pain on smoking include: psychosocial factors; smoking expectancies for pain coping and affect regulation [56]; negative reinforcement (e.g. relief from pain, stress, negative affect [57]); positive reinforcement (e.g. positive affect, energy/arousal, cognitive enhancement); activation of the mesolimbic dopamine reward system and neural stress system; and other pain-related factors [13]. In line with this, an ecological momentary assessment study has provided evidence that pain triggers smoking [58], and a number of studies have provided evidence for a positive association between pain intensity and cigarettes per day [13]. Pain manipulation has also been associated with greater smoking urge and higher likelihood of smoking [59].

The proposed model likewise accounts for the effects of smoking on pain, including: psychosocial factors; interactions with other risk factors for pain; pain from tissue damage from smoking; modulation of neurological processes related to pain; and altered pain processing, the latter involving activation of nAChRs and endogenous opioid systems, cardiovascular pressor actions, changes in attention, and nicotine withdrawal effects [13]. Nicotine administration has acute analgesic effects [reviewed in 13], and this is heightened in men [60]. Despite these short-term analgesic effects, chronic smoking may sensitize pain receptors and increase pain sensitivity over time (i.e., nicotine-induced hyperalgesia). In fact, greater nicotine dependence is associated with more severe pain symptoms [61], likely contributing to greater opioid use [20, 62].

Furthermore, nicotine withdrawal is associated with a blunted stress response and increased pain sensitivity [50, 63]. Even among smokers who do not report pain, those who abstained from smoking reported greater pain intensity and were nearly 3.5x more likely to endorse pain following a pain manipulation [64]. Therefore, there may be specific challenges to smoking cessation for pain patients. There is an association between positive pain status, reduced self-efficacy, and greater difficulty quitting smoking [65]. Pain-related anxiety is associated with greater smoking severity and barriers to quitting [66], and anxiety and depression may worsen the effects of pain on smoking cessation due to more severe withdrawal and increased pain sensitivity [67]. Nevertheless, smokers with chronic pain appear to be motivated to quit and amenable to pharmacologic intervention [68]. Other studies are testing cognitive behavioral therapy for smoking cessation in treatment for chronic pain [69] to address these issues.

Interactions between pain, smoking, and opioid misuse

Critically, smokers with chronic pain are more likely to use opioids and at higher doses (among men) [56], and smoking status may indicate risk for problems with prescription opioids [50]. One study found that pain patients who smoked perceived fewer problems with prescription opioid use, despite higher odds of having an OUD and using opioids at greater doses (among men) [50]. Another study of pain patients found that smoking was associated with greater pain intensity and less decline in daily opioid use at follow-up [70]. Smokers as well as former smokers using nicotine have been found to use opioids more frequently and at higher doses versus never smokers or former smokers not using nicotine [51]. Finally, although smoking abstinence may complicate short-term efforts to treat pain, smoking cessation does not cause poorer opioid treatment outcomes [50] (see Quitting smoking improves OUD treatment outcomes section). However, medications for smoking cessation may be less effective among opioid-dependent smokers [71]. Together the data suggest that pain plays an important role in opioid misuse, as well as smoking maintenance and escalation, and may also relate to the high co-occurrence of smoking and opioid misuse.

Additional risk factors for opioid and nicotine use and co-use

Additionally, several other factors have been implicated in risk, illness course, and treatment prognosis of comorbid opioid and nicotine use disorder, including adverse childhood experiences, stress, and depression, reviewed below.

Adverse childhood experiences

Adverse childhood experiences (ACEs), including household dysfunction, physical, sexual, and emotional abuse, are robustly associated with a wide range of substance use behaviors, as well as other mental and physical health problems across the lifespan [72]. In particular, exposure to ACEs has been linked to increased risk for opioid use [73] and smoking [74], and a strong body of evidence demonstrates that individuals exposed to multiple ACEs are at particularly high risk for both [73, 75]. A recent meta-analysis reports that individuals with multiple ACEs are approximately 3 times more likely to smoke and 10 times more likely to engage in problematic drug use (including intravenous substance use, heroin, or crack cocaine use) [76]. Increased impulsivity has been proposed as one potential mechanism whereby ACEs give rise to later substance abuse [77]. Another potential mechanism is suggested by studies indicating that severe child abuse is associated with epigenetic changes in opioid receptor expression [78]. However, additional research elucidating factors mediating these relationships is needed. Beyond risk for substance use/abuse, ACEs have also been associated with a more severe course of illness. ACEs have been linked to higher likelihood of overdose among individuals with OUD [73], more withdrawal symptoms and distress among newly abstinent smokers [79], and adverse psychosocial and health outcomes among inpatients with comorbid substance use and mental health disorders [80].

Stress

Stress has also been linked with the development of both opioid and nicotine use disorders [81], as well as poorer treatment engagement and outcomes in OUD [82]. In particular, stress has been robustly associated with relapse in opioid, nicotine, and other SUDs [83], and opioid administration reduces acute stress responses [84]. It has been proposed that learned associations between opioid use and relief from aversive states of opioid withdrawal potentiate individuals’ vulnerability to relapse when faced with stressful life events [85]. Nicotine use may exacerbate this vulnerability, as nicotine withdrawal increases acute stress responses among smokers [86] and higher stress severity has been linked to increased opioid craving [87]. Notably, the relationship between stress and drug reinstatement may be stronger among women compared to men, as greater associations between stress and opioid craving [87] and heightened stress-induced negative affect, stress, and nicotine craving [88] have been reported among women. Additional research is necessary to delineate potential mechanisms of sex differences in stress-induced reinstatement [83], as well as sex differences relevant to co-occurring opioid and nicotine use more broadly (see Sex Differences section).

Depression

Depression is frequently comorbid with both OUD [89, 90] and smoking [91], and may be an important contributor to their high rate of co-occurrence. Individuals with depression are significantly more likely to abuse prescribed opioid medication [92, 93], and depressive symptoms are associated with greater opioid craving and use among individuals with OUD [94, 95]. Similarly, negative affect predicts craving to smoke among current smokers [96]. Furthermore, comorbid mood disorders are associated with reduced opioid pharmacotherapy adherence among individuals in treatment for OUD [97] and poorer quit outcomes for individuals taking nicotine replacement therapy [98]. Among individuals with OUD, comorbid mood disorders are associated with smoking status [99], and depressive personality features are associated with fewer smoking quit attempts [100].

Pain may be another important mechanism linking depression with opioid and nicotine use. One study [100] found that higher depressive symptoms and current smoking status were both associated with higher opioid dose among pain patients, yet the effect of depressive symptoms was no longer significant when pain severity was included in the model, suggesting that altered pain perception may be a potential mechanism linking depressive symptomatology to opioid use, as described above. However, these findings could alternatively be interpreted as evidence that pain and depression explain common variance in opioid use. Nonetheless, negative mood has been shown to increase pain sensitivity among healthy volunteers [101], and individuals with depression display lower thresholds for certain types of pain [102] and poorer responses to opioid pain treatment [103]. Negative affect induction increases withdrawal-related pain sensitivity among individuals with heroin dependence [104] and nicotine withdrawal has also been associated with acute increases in pain sensitivity among daily smokers [64]. Collectively, these results suggest that depression plays an important role in the etiology and treatment of opioid and nicotine use, which may be mediated in part by negative mood related alterations in pain perception.

Influences of Sex/gender on opioid and nicotine use and co-use

Sex/gender differences (with the understanding of the American Psychiatric Association’s [105] definitions of sex as a person’s biological status such as male or female, and gender as the attitudes, feelings and behaviors associated with biological sex such as men and women) in tobacco smoking and smoking-related behaviors are well-established [106], whereas the literature on sex/gender-related differences in opioid use has yielded mixed findings [107]. With respect to tobacco smoking, men are better able to detect nicotine in cigarettes [108, 109] and women are more reinforced by nicotine-associated sensory cues and stress than nicotine itself [110, 109]. Women also metabolize nicotine and cotinine faster (partially due to estrogen) [111], which may explain why women typically experience more adverse nicotine-related effects [112] and worse smoking cessation outcomes [113]. With respect to opioid use, there is evidence that women’s progression to opioid dependence is “telescoped” relative to men—women initiate use of opioids at an older age but progress to disease faster than men [114]. For women, emotional problems conferred risk for opioid misuse among individuals with chronic pain, whereas legal and behavioral problems predicted opioid misuse among men with chronic pain [115]. Gender-specific factors also predict non-pain-related opioid use—alcohol and illicit drug use predict opioid use in men while tobacco smoking and psychological stress predict opioid use in women [116, 117]. As mentioned above, among women, former daily smokers were more likely to have met criteria for past-year OUD than never smokers [23], and among men, smokers report higher daily doses of opioids than nonsmokers [21]. More research on the neurobiological bases of these sex/gender differences is needed to advance sex/gender-appropriate screening and treatment options for tobacco smoking, OUD and nicotine-opioid co-use.

Effects of early exposure to nicotine and opioids

Perinatal nicotine and opioid exposure

Perinatal nicotine and opioid exposure have significant negative health consequences for mother and infant, though the negative effects of smoking on fetal development may exceed those of opioid exposure [118]. Within the U.S., approximately 14–22% of women are estimated to use tobacco during pregnancy [119], however smoking prevalence estimates among pregnant women receiving treatment for OUD are markedly higher at 88–95% [118, 120, 121]. In addition to numerous adverse physical health consequences, perinatal tobacco use is also linked to increased depression during pregnancy in the general population, as well as among individuals receiving MAT [99, 122]. MAT is recommended to treat opioid use in pregnant women and recognized to improve pregnancy outcomes, but does not address co-occurring tobacco smoking [118, 123]. Thus, further interventions to address the high rates of tobacco use in MAT patients during pregnancy are urgently needed (for a review of existing treatments, see [118]).

Adolescent nicotine exposure increases OUD susceptibility in adulthood

A growing body of preclinical literature suggests that adolescent nicotine exposure may increase risk for opioid use in adulthood. In one report [124], mice exposed to nicotine in early adolescence displayed enhanced conditioned place preference for morphine in adulthood, whereas nicotine exposure in late adolescence and adulthood was not associated with the same effect. These results are consistent with a larger literature implicating adolescence as a sensitive period when nicotine exposure can exert long-lasting effects on neurodevelopment, with substantial implications for addiction vulnerability in adulthood [for review, see: 125]. Adolescent nicotine exposure may also potentiate risk for opioid use in adulthood via alterations in MOR expression [126], increased sensitivity to stress, and heightened depressive symptomatology [127–129]; effects that may vary by sex [126–128]. However, additional research is necessary to clarify these mechanisms, and to establish these findings in human subjects.

Treatment implications for co-occurring opioid and nicotine use disorders

Quitting smoking improves opioid use treatment outcomes

Smoking accounts for a significant proportion of mortality among individuals with SUD, yet nicotine dependence is rarely addressed in SUD treatment [17]. There is evidence to suggest that both providers [130] and patients [131] may abstain from addressing smoking based on concerns that it will interfere with sobriety from their primary drug of abuse. Contrary to this perceived barrier, smoking cessation appears to improve outcomes in SUD treatment overall [132], and among individuals with OUD specifically [133]. A meta-analysis of seven studies with long-term follow-up data found that receiving a smoking cessation intervention during SUD treatment was associated with a 25% higher likelihood of long-term abstinence from alcohol and other substance use, including but not limited to opioids [133]. Other indirect evidence supports that smoking cessation may benefit OUD treatment. For example, among smokers with OUD, those who smoked during detoxification reported significantly higher opioid craving and had lower rates of retention as compared with those who were not allowed to smoke during detox as well as nonsmokers [134]. Similarly, among methadone-maintained individuals, there is a positive association between smoking and opioid use [135, 136], and individuals who smoked more cigarettes on a preceding day were more likely to report that their methadone dose was inadequate [137]. In line with this, one small study has found smoking status to be a stronger predictor of opioid use during methadone maintenance than daily methadone dose [135]. Together these data provide support for smoking abstinence to improve opioid treatment outcomes, and argue for smoking cessation interventions to be provided with OUD treatment [17].

Implications for pharmacological treatment of opioid and nicotine use disorders

The functional interactions between the cholinergic and endogenous opioid systems described above have important implications for pharmacological treatments of opioid and nicotine use disorders [138, 139]. For example, medications targeting the cholinergic system have been found to be effective for smoking cessation [140, 141]. Animal research suggests that cholinergic medications may also be effective for treating OUD, however there is very limited literature in humans [138]. Nonetheless, preliminary data suggest that cholinergic agents are well-tolerated [142], attenuate opioid withdrawal symptoms [142], increase time to relapse [143], and may also reduce symptoms of depression and anxiety [143], in human subjects in treatment for OUD [138].

Similarly, preclinical literature indicates that manipulation of various opioid receptor subtypes may aid smoking cessation, but human data is also limited [139]. There are currently no medications approved by the U.S. Food and Drug Administration that specifically target DORs or KORs, and research with MOR manipulation has yielded mixed results. Meta-analyses have reported that there is not strong evidence for the efficacy of MOR antagonists for smoking cessation across studies [144, 145]. However, there is data to suggest that MOR antagonists may be more effective among subpopulations, including heavy drinkers [146] and individuals with comorbid depression [147]. Therefore, additional research is necessary to identify who may benefit most from medications targeting MORs, as well as to evaluate the safety, tolerability, and efficacy of medications that selectively target DORs and KORs, to aid in smoking cessation. Nevertheless, these promising preliminary findings suggest that further investigation into the potential of cholinergic and opioidergic agents for the treatment of opioid and nicotine use disorders is warranted.

Conclusions

There have been a number of recent advances in our understanding of the magnitude and mechanisms of co-occurring nicotine and opioid use and misuse. The available literature emphasizes pain as a critical mechanism underlying co-use and contributing to negative treatment outcomes for either disorder, in particular the interaction of pain and smoking with opioid use and treatment. Also highlighted are the roles of depression, stress, sex/gender, early exposure, and other factors that impact the effects of acute exposure, chronic use, treatment, and withdrawal/relapse of either substance (Figure 1). Continued development in our understanding of nicotine and opioid use and co-use, including at neurobiological and genetic levels, should inform the development of more optimal prevention and treatment. In particular, continued consideration should be given to the impact of tobacco smoking on individuals in treatment for opioid use disorder, and the potential role of smoking cessation in improving opioid treatment outcomes. Such efforts may have substantial public health benefits in both domains.

Figure 1. Interactive pathophysiological mechanisms of opioid and nicotine use.

Highlights selected findings related to mechanisms underlying opioid and nicotine use and their co-occurrence. nAChR–nicotinic acetylcholine receptor; OUD–opioid use disorder.