Achieving smoking cessation among persons with opioid use disorder

Abstract

While prevalence of tobacco use in the U.S. general population is declining, prevalence among persons with opioid use disorder (OUD) remains high and results in excessive tobacco-related disease and premature mortality. Among smokers with OUD, tobacco cessation rates are negligible without treatment. However, both low-intensity behavioral interventions and more intensive motivational interventions yield negligible cessation rates. While contingency management has potent short-term cessation effects, effects are not maintained at post-intervention follow-up. Evidence-based smoking cessation pharmacotherapies, such as nicotine replacement therapy, bupropion, and varenicline, result in very modest cessation rates among smokers with OUD. Intensification of pharmacotherapy, such as high-dose and combination nicotine replacement therapy or extended medication treatment, has failed to improve cessation outcomes compared to standard treatment regimens. Targeting the unique challenges faced by smokers with OUD, including nicotine-opioid interactions and poor medication adherence, has potential to improve cessation outcomes, but further research is needed to optimize intervention efficacy among smokers with OUD.

1. Introduction

1.1. Burden of tobacco use among persons with opioid use disorder (OUD) and substance use disorder (SUD).

The prevalence of opioid use disorder (OUD) in the United States is escalating. With over two million persons in the U.S. with OUD [1] and over three-quarters of persons in OUD treatment being cigarette smokers [2–8], there is an urgent need to reduce tobacco use among persons with OUD. The prevalence of smoking is even higher among persons with OUD who are not in OUD treatment, with estimates of 92% among persons who use heroin and are not in OUD treatment [9] and 95% among syringe exchange program participants [6]. Even persons with chronic pain taking opioid analgesics without misuse are nearly twice as likely to smoke as persons without opioid prescriptions [10–12]. Additionally, the prevalence of tobacco use among persons with OUD has increased over time, and is now nearly five times higher than the 15.5% smoking prevalence in the general U.S. population [13, 14]. These findings are replicated in international samples: in an international review of substance use disorder (SUD) treatment samples, 85% of persons receiving medications for OUD smoked cigarettes. These rates were higher than those seen among persons receiving treatment of alcohol or other SUD, and nearly triple the 31% pooled estimate of population-based prevalence [15].

The disproportionate prevalence of tobacco use puts smokers with OUD at increased risk of relapse to opioids, poor quality of life, adverse neonatal outcomes, and premature mortality [16–22]. In a national U.S. sample of persons with opioid- and other SUD in recovery, those who initiated or maintained tobacco use were more likely than non-smokers to relapse to SUD [16]. Among pregnant people receiving OUD treatment, tobacco use is associated with adverse neonatal outcomes, including low birth weight, and both greater morphine doses and days of treatment needed to treat neonatal abstinence syndrome [20–22]. Tobacco use is a leading cause of death among persons with opioid- and other SUD [23, 24, 19], with the death rate of smokers four times that of non-smokers [18].

Despite the high prevalence, smokers with OUD consistently report interest and motivation to quit at levels comparable to the general population of smokers [3, 4, 25–27]. The majority of smokers with OUD have made multiple prior quit attempts [25, 26, 28], which are a critical prerequisite to successful long-term cessation [29]. This provides an important opportunity for OUD treatment providers.

1.2. Limited evidence to guide cessation interventions for smokers with OUD.

Despite the burden of tobacco use and interest in quitting among smokers with OUD, there is limited evidence to inform efficacious treatment of their tobacco use. Due to common exclusion criteria in clinical trials of cessation interventions, results generalize to only approximately half of the daily smoking population [30]. This yields large gaps in the evidence base for tobacco use treatment among smokers with OUD. As an example, even trials including persons in sustained full remission from SUD for 12 months excluded persons receiving opioid agonist treatment with methadone or buprenorphine for OUD [31–33]. Such stringent exclusion criteria prevent knowledge generation about efficacious interventions for smokers with OUD.

Extant evidence on tobacco cessation interventions among smokers with OUD has focused primarily on daily smokers who are in treatment with methadone [34–43] or buprenorphine [40, 44] and are motivated to quit smoking. Few studies have evaluated persons with OUD outside of treatment; one study evaluated outcomes in a medically-supervised injecting facility [45] and none have evaluated persons not in treatment. Little is currently known about engagement or treatment of smokers with OUD who are not yet ready to quit; only two trials to date have enrolled smokers with OUD regardless of intention to quit [36, 46]. Though nearly a third of U.S. smokers report intermittent (non-daily) tobacco use [47], only one clinical trial has included non-daily smokers with OUD [34].

1.3. Smokers with OUD face multiple barriers to cessation.

Smokers with OUD face multiple, intersecting challenges to smoking cessation. At systems-and social levels, these include lack of access to evidence-based smoking cessation medication, and pro-smoking social norms. In national surveys of opioid treatment programs (OTPs), fewer than 40% provide smoking cessation counseling, and fewer than one-third provide pharmacotherapy; among those that do, services are not sustained over time [48–53]. Pro-smoking social norms among treatment providers, including providers and patients smoking together, is associated with lower provision of tobacco treatment services [54]. Persons with OUD also have relatively small social networks [55, 56], which are predominantly comprised of other smokers; this is negatively associated with quitting self-efficacy [56] and cessation success [57].

Persons with OUD also face multiple individual-level challenges. The high burden of chronic medical illness among persons with OUD [58] may limit utilization of evidence-based cessation pharmacotherapy, by increasing pill burden, increasing side effects, and through risk perceptions that prioritize other medical concerns over tobacco-related risks [59]. These cessation challenges may be further exacerbacted by psychiatric comorbidity and psychological distress [60–63], high perceived stress [64], low smoking cessation self-efficacy [65], and intolerance of withdrawal discomfort [66, 67]. Chronic pain and OUD are also highly co-morbid—80% of methadone-maintained patients report past-week pain, and over one-third report chronic, severe pain [68–72]. Among persons without OUD, pain intensity is associated with nicotine withdrawal, distress intolerance, negative affect, and urges to smoke [73–75]. Across studies, smokers with OUD adhere to fewer than 50% of smoking cessation counseling sessions, and often fail to initiate or to adhere to the prescribed amount or duration of nicotine replacement therapy (NRT), bupropion, or varenicline [37, 38, 43, 65, 66, 76, 77]. In large smoking cessation trials among smokers with OUD, adherence to cessation interventions was associated with improved cessation outcomes [28, 65, 76, 78, 79].

Cessation can be more challenging for smokers with OUD due to neurobiological interactions between nicotine and opioids [67, 88]. Nicotine releases endogenous opioids by binding to nicotinic receptors of neurons containing opioid peptides [89, 90]. In preclinical and human laboratory studies, administration of the opioid antagonists naloxone and naltrexone precipitates signs of nicotine withdrawal and craving [91–93], whereas administration of opioid agonists morphine and methadone is associated with decreases in nicotine withdrawal [94, 92]. In a qualitative study, smokers with OUD reported smoking cigarettes to balance the sedating effects of methadone, and experiencing more pleasurable effects when cigarettes and methadone are taken concurrently [82]. Clinically, smokers with OUD smoke most daily cigarettes at the time of peak opioid effect [82], increase cigarettes smoked per day (CPD) with increasing opioid agonist treatment dose, and decrease CPD with opioid agonist treatment dose taper [83–87].

Because of the enormity of these challenges, smokers with OUD have difficulty establishing initial abstinence and maintaining abstinence over time [28, 35, 39]. Given the resulting low rates of smoking cessation observed among smokers with OUD treated with existing evidence-based interventions, it is unclear whether our current interventions are effective among smokers with OUD [95].

1.4. Narrative review overview

The purpose of this narrative review is to describe the evidence base for behavioral and pharmacological treatment of tobacco use among smokers with OUD. We searched PubMed with the assistance of a reference librarian, using the search terms: “smoking cessation,” “tobacco cessation,” “methadone maintenance,” “buprenorphine,” and “opioid use disorder.” We included studies (including uncontrolled studies, open label studies, and randomized controlled trials) that describe interventions to treat tobacco use among persons with OUD that were published prior to December 20, 2019 (Table). We included trials with persons with other SUD that report the proportion of participants with OUD, and did not include trials among persons receiving chronic opioid analgesics without OUD, or that address systems-level or policy-level interventions.

Table 1.

Descriptions of studies testing smoking cessation intervention among smokers with OUD

Author & Date	Setting	Participants	Sample Size	Intervention	Control	Intervention adherence	Biochemically verified abstinence at end of intervention, n(%)a	Cessation Outcome at Follow-up, n (%)a
Campbell, 1995 [97]	Outpatient and residential SUDTPb (one OTPc)	In SUD treatment (37% methadone maintenance), interested in smoking cessation treatment	111 (intervention: 90, control: 21)	Weekly group motivational & relapse prevention counseling with contingency management x 16 weeks, optional nicotine patch x 10 weeks	Delayed treatment control	Intervention: 17% Controls: 14% completed 16 weeks of treatment	Intervention: 7 (11%), Control: 0%, p=0.19	N/A
Cooperman, 2017 [34]	OTP	On methadone ≥ 3 mo, smoking every/most days, interested in quitting	83 (intervention: 41, control: 42)	8 individual, motivational & cognitive behavioral skills counseling sessions x 12 weeks, free NRT	Facilitated referral to quitline	Intervention: 51% used NRT, 24% completed 8 of 8 scheduled counseling sessions; Control: 57% had ≥ 1 quitline contact	Intervention: 3 (7%), Control: 0% (p=0.23)	Intervention: 1 (2%), Control: 1 (2%), 6 mo, p= 0.96
Cooperman, 2019 [147]	OTP	On methadone ≥ 3 mo, ≥ 100 lifetime cigarettes, smoking every/most days, interested in quitting	7 (intervention only, no control group)	12 weekly, 90-minute, dialectical behavioral therapy training sessions, nicotine patches x 8 weeks	N/A	57% reported patch use 7d/week, 86% attended at least 50% of intervention sessions	Intervention: 1 (14%)d	N/A
Dunn, 2008 [41]	OTP	Stable methadone dose x 30 d, without regular opioid or cocaine use, smoking ≥10 CPD for ≥ 1 year, interested in quitting	20 (intervention: 10, control: 10)	Brief smoking cessation education, contingent monetary vouchers x 2 weeks	Brief smoking cessation education, yoked, non-contingent monetary vouchers	% scheduled samples missing: Intervention 29%, Control 2%	% abstinent samples: Intervention: 55%, Control: 5%, p<0.01	Intervention vs Control: 3 (30%) vs 0%, 30 d; 2 (20%) vs 0%, 60 d; 2 (20%) vs 0%, 90 d, all p=0.10
Dunn, 2010 [107]	OTP and OBOTe	Stable methadone or buprenorphine dose, without regular heroin or cocaine use, marijuana negative urine at intake, smoking ≥10 CPD for ≥ 1 year, interested in quitting	40 (intervention: 20, control: 20)	Contingent monetary vouhersc x 2 weeks, optional bupropion	Yoked, non-contingent monetary vouchers x 2 weeks, optional bupropion	Initiation of bupropion: Intervention: 45%, Controls: 30%	Intervention: 9 (45%), Control: 2 (10%), p<0.01	Intervention vs Control: 2 (10%) vs 0%, 30 d; 2 (10%) vs 0%, 60 d; 1 (5%) vs 0%, 90 d, all p=0.15
Fallin-Bennett, 2019 [148]	Academic prenatal and postpartum treatment program for persons with OUD	≥ 100 lifetime cigarettes, past month cigarette smoking, interested in quitting	50 (intervention only, no control group)	Smoking cessation counseling, assessment of cessation barriers, referral to social services to address those barriers, referral to clinic smoking cessation group	N/A	100% referred to cessation class, but adherence/participation not reported	Self-reported 30-day point prevalence abstinence: Intervention: 2 (4%)d	N/A
Felicione, 2019 [129]	OTP	Buprenorphine treatment, no drug use for ≥ 90 d, smoking ≥10 CPD for ≥ 1 year, interested in quitting	25 (intervention: 14, control: 11)	Second generation tank electronic cigarette, 18 mg/ml nicotine liquid (tobacco or menthol) ad libitum x 2 weeks	Second generation tank electronic cigarette, 0 mg/ml nicotine liquid (tobacco or menthol) ad libitum x 2 weeks	80.6% (active), 91.2% (placebo) reported daily electronic cigarette use; mean of 4.7 ml (active) and 7.6 ml (placebo) liquid used	CO < 8 p.p.m. at Day 14 or 28: Intervention: 0%, Control: 2 (18%)f	CO < 8 p.p.m. at Day 14 or 28: Intervention: 0%, Control: 2 (18%)f
Hall, 2018 [46]	Urban public health department buprenorphine program	Buprenorphine ≥ 3 mo, smoking ≥5 CPD for the past week, interest in quitting unnecessary	175 (intervention: 85, control: 90)	Precontemplative participants given self-help workbook. Those expressing desire to quit offered: individualized motivational feedback (4 sessions over 12 months); individual cognitive behavioral therapy (10 sessions over 6 months); nicotine patch (≥ 10 CPD: 24 weeks, < 10 CPD: 12 weeks); gum or lozenges (24 weeks)	Written information about self-quitting techniques, help lines, and cessation medications	54% of intervention group participants initiated treatment. Mean number CBT sessions 4.7 of 10; Mean NRT dispensed: patches 72.9 (max 264), gum 313 (max 2290), lozenges 67.2 (max 576)	Intervention: 9 (11%), Control: 9 (11.3%), p=0.96	Intervention: 5 (6.3%), Control: 10 (12.7%), 12 mo, p=0.17; Intervention: 13 (16.5%), Control: 11 (14.3%), 18 mo, p=0.71
Haug, 2004 [105]	Hospital-based perinatal program	Pregnant women ≤26 weeks gestational age, on methadone treatment, smoking ≥5 CPD	63 (intervention: 30, control: 33)	4 motivational enhancement therapy (MET) sessions x 10 weeks, standard care advice given by research staff and printed cessation material	Standard care advice given by research staff, printed cessation material	Average 3.4 of 4 MET sessions attended	No significant differencesg	N/A
Heydari, 2014 [101]	OTP in Iran	All subjects men, ≥ 1 year of hookah/cigarette smoking, 1 year of opiate/narcotic/hashish/recreational drug use, interested in quitting smoking, 5–10 mg of methadone twice a day	424 (intervention: 212, control: 212)	NRT (step down patch: 30 to 20 to 10 mg, and supply of 4 mg gum/1 mg lozenges) x 6 weeks & minimal behavioral therapy (5 A’s)	Placebo & minimal behavioral therapy (5 A’s)	Not reported	Intervention: 0%, Control: 0% (week 4 of 6)f	Intervention: 15 (7.1%), Control: 1 (0.5%), 6 mo, p<0.0001
Holbrook, 2011 [149]	SUDTP	Nicotine dependent, pregnant or parenting women, on methadone treatment, receiving comprehensive outpatient SUD treatment	91 (pregnant: 44, parenting: 47)	Group counseling, based on 5As, for six weeks	N/A	Not reported	Mean cigarettes per day (baseline to end of intervention): Pregnant women 18.8 to 8.3, Nonpregnant women: 13.2 to 9.3j	Mean cigarettes per day: Pregnant women 7.9, Nonpregnant women: 8.5, 3 mo post-interventionj
Mooney, 2008 [44]	Veteran’s Affairs opioid treatment research center	Smoking ≥10 CPD for past year, seeking treatment for OUD, interested in quitting smoking	40 (intervention: 20, control: 20)	Bupropion (titrated to 150 mg BID) x 10 weeks + post-intervention taper; weekly motivational counseling; contingent reinforcement for tobacco, opioid and cocaine abstinence; buprenorphine titration to 24 mg x 10 weeks followed by post-intervention taper	Placebo bupropion x 10 weeks; weekly motivational counseling; contingent reinforcement; buprenorphine titration to 24 mg x 10 weeks followed by post-intervention taper	Intervention: 58%, Control: 90% completed 10 weeks of treatment	Intervention: 2 (13.7%), Control: 2 (11.4%), p=0.5	N/A
Nahvi, 2014 [35]	OTP	Smoking ≥5 CPD, stable methadone treatment, interested in quitting smoking	112 (intervention: 57, placebo: 55)	Varenicline (titrated to 1 mg BID) x 12 weeks, 5 sessions of brief in-person counseling, quitline referral	Placebo varenicline x 12 weeks, 5 sessions brief in-person counseling, quitline referral	Intervention: mean of 1.96, Control: mean of 1.85 counseling sessions completed (of five); 22% utilized quitline	Intervention: 6 (10.5%), Control: 0% (p=0.03)	Intervention: 3 (5.3%), Control: 0%, 6 mo, p=0.24
Nahvi, 2014 [135]	OTP	Smoking ≥5 CPD, stable methadone treatment, interested in quitting smoking	100	Directly observed varenicline (titrated to 1 mg BID) x 12 weeks, administered by OTP nurses with methadone doses; brief cessation and adherence counseling	Self-administered varenicline x 12 weeks; brief cessation and adherence counseling	N/A	N/Ah	N/Ah
Poling, 2010 [42]	OTP	Smoking ≥10 CPD for ≥ one year, seeking treatment for OUD	31 (intervention: 13, control: 18)	Varenicline (titrated to 1 mg BID) x 11 weeks, weekly cognitive behavioral therapy, methadone initiation	Placebo varenicline x 11 weeks, weekly cognitive behavioral therapy, methadone initiation	Not reported	Self-reported 7-day point prevalence abstinence: Intervention: 2 (15.4%), Control: 1 (5.5%)f	N/A
Raich, 2018 [150]	Specialty tobacco addiction units in SUDTP in Spain	Nicotine dependence, smoking ≥10 CPD for ≥ one year; with OUD on methadone, alcohol use disorder or psychotic disorder; interested in quitting smoking	90 (OUD n=30)	Varenicline (titrated to 1 mg BID) x 12 weeks, multimodal psychological therapy x 12 months	N/A	30 (33%) attended all eight therapy sessions	Intervention: 17.7% abstinent (cohort with OUD) 23.7% (alcohol use disorder), 25.4% (psychotic disorder)	N/A
Reid, 2008 [43]	5 OTP and 2 outpatient SUDTP	Smoking ≥10 CPD, enrolled in SUD treatment ≥ 30 d, interested in quitting smoking	225 (intervention: 153, control: 72)	Nicotine patch x 8 weeks, 9 group counseling sessions (cognitive behavioral therapy and mood management), SUD treatment as usual	SUD treatment as usual	Intervention: 83% used patches for at least 1 week, 58% for at least 4 weeks, 34% for all 8 weeks; 86% attended at least 1 counseling session, 47% at least 5, 1% all 9	Intervention: 10–11%, Control: 0%,i wks 2–7, p<0.01	Intervention: 5.5%, Control 0%,i 13 wks, p=0.065; Intervention: 5.7%, Control: 5.2%, 26 wks, p=0.963
Richter, 2005 [38]	OTP	Smoking ≥ one year, smoking ≥10 CPD, in methadone treatment ≥ 3 mo, interested in quitting smoking	28 (intervention only, no control group)	Bupropion (titrated to 150 mg BID) x 7 weeks, 4 mg nicotine gum x 12 weeks, 6 motivational interviewing sessions, quit smoking printed materials	N/A	Mean 10.5 pieces nicotine gum/day (of the 8–24 daily recommended); 53% used bupropion less than prescribed	Intervention: 2 (7%), wk 12d	Intervention: 4 (14%), 6 mod
Rohsenow, 2017 [79]	University offices	Smoking ≥10 CPD for past 6 mo, with SUD diagnosis (34% with OUD), enrolled in outpatient SUD treatment, interest in quitting unnecessary	137 (intervention: 77, control: 60)	Varenicline (titrated to 1 mg BID) x 12 weeks, placebo nicotine patch x 12 weeks, 10 brief counseling sessions	Placebo varenicline, active nicotine patch x 12 weeks, 10 brief counseling sessions	Intervention: 37.4%, Control 42.4% capsules taken; Intervention: 40%, Control 43.3% patches used; 4.2 of 10 counseling sessions completed (both groups)	Intervention: 10 (13%), Control: 2 (3%), p<.05	Intervention: 7 (9%), Control: 2 (3%), 6 mo, p > .05
Schmitz, 1995 [151]	Methadone maintenance treatment-research program	Smoking ≥10 CPD, for ≥ one year, enrolled in a methadone maintenance treatment-research program	5	Within subject A-B-A-B design. Two-week baseline period, followed by two cycles of two-week non-contingent reinforcement (A), followed by two-week contingent reinforcement (B)	Within subject A-B-A-B design with two two-week non-contingent A periods	Not reported	Non significant treatment effect on CO level, p=0.38g	N/A
Shoptaw, 1996 [106]	OTP	Cigarette smokers, in methadone treatment, interested in participation	17 (intervention only, no control group)	Contingent voucher-based reinforcement for CO levels ≤4 three times weekly x 4 weeks	N/A	Not reported	Intervention: 0%d	N/A
Shoptaw, 2002 [39]	OTP	Smoking ≥10 CPD, in methadone treatment, interested in quitting smoking	175 [Relapse Prevention (RP), Contingency Management (CM) + patch: 47; RP+patch: 42; CM+patch: 43; patch alone: 43]	Weekly, group relapse prevention counseling (RP), contingent voucher-based reinforcement for CO levels ≤8 (up to $447.50; CM), nicotine patch, all x 12 weeks	RP + patch x 12 weeks; CM + patch x 12 weeks; Patch alone x 12 weeks	Average 68.1 of 84 patches used (similar across conditions); RP groups: average of 5.9 of 12 sessions attended; CM groups: average of 44.3% of total possible earnings	RP+CM+patch: 13 (28%), RP+patch: 9(22%), CM+patch: 15 (35%), NRT alone: 6 (14%); CM vs. non-CM conditions, p=0.003	RP+CM+patch: 2 (4.5%), RP+patch: 1 (2%), CM+patch: 1 (2%), NRT alone: 4 (9%), 6 mo, p=NS
Sigmon, 2016 [40]	Outpatient research clinic	Smoking ≥10 CPD for ≥ one year, stable in methadone or buprenorphine treatment, interested in quitting smoking	Phase 1: 88; Phase 2: 63 total (intervention: 31, control: 32)	Phase 1: contingent monetary vouchers x 2 weeks; Phase 2: extended contingent reinforcement x 10 weeks, bupropion offered	Phase 1: contingent monetary vouchers x 2 weeks; Phase 2: yoked, extended noncontingent reinforcement x 10 weeks, bupropion offered	Intervention: 29%, Control: 34% initiated bupropion; Intervention: Mean earnings $353.40 (of $570)	Percent biochemically abstinent samples: Intervention: 46.7%, Control: 23.5%; Abstinent at last study visit: Intervention: 11 (35%), Control: 5 (16%), p=.07	N/A
Stein, 2006 [36]	OTP	Smoking ≥10 CPD x 3 mo, enrolled in methadone treatment ≥ 6 mo, interest in quitting not necessary	383 (intervention: 191, control: 192)	Three tailored motivational counseling sessions; nicotine patch based on baseline CPD: if ≥ 40 CPD, 12 weeks of patch starting at 42 mg daily; if < 40 CPD, 8 weeks of patch starting at 21 mg daily	Brief counseling using 4A’s model; nicotine patch based on baseline CPD: if ≥ 40 CPD, 12 weeks of patch starting at 42 mg daily, < 40 CPD, 8 weeks of patch starting at 21 mg daily	Intervention: average 2.23 (of 3), Control: 1.88 (of 2) counseling sessions attended; Participants used nicotine patches on 44.1% of days	Intervention: 11 (5.8%), Control: 16 (8.3%), p=0.325	Intervention: 10 (5.2%), Control: 9 (4.7%), 6 mo, p=0.805
Stein, 2013 [37]	OTP	Smoking ≥10 CPD, in methadone treatment ≥ 1 mo, willing to set quit date in next week	315 (varenicline: 137, NRT: 133, placebo: 45)	Varenicline: Varenicline (titrated to 1 mg BID), monthly brief counseling x 6 mo Combination NRT: Patch (starting at 42 mg daily for ≥ 30 CPD, and 21 mg daily for <30 CPD), 4 mg gum (up to 24 daily), monthly brief counseling x 6 mo	Placebo: placebo varenicline BID, monthly brief counseling x 6 mo	Varenicline: 34.2%, Combination NRT: 48.8%, Placebo: 34.4%	Varenicline: 5 (3.7%), Combination NRT: 11 (8.3%), Placebo: 1 (2.2%), p=0.168	N/A
Stein, 2016 [128]	OTP	Smoking ≥10 CPD ≥ 1 year, current methadone treatment ≥ 3 mo, ready to make quit attempt, without current e cigarette or smoking cessation medication use	12 (intervention only, no control group)	One NJOY e cigarette daily (providing nicotine equivalent of 20–30 tobacco cigarettes) x 6 weeks, telephone quitline referral	N/A	% days self-reported use 92.9% at end of treatment	Intervention: 1 (8.3%)d	Intervention: 0%, wk 9d
Story, 1991 [84]	OTP	Smokers in methadone treatment, enrolled in a smoking cessation course	22 (intervention: 11, control: 11)	20% methadone dose increase, four group cognitive smoking cessation counseling sessions	1 mg methadone dose increase, four group cognitive smoking cessation counseling session	Intervention: 1, Control: 2 subjects requested decrease in methadone dose	Intervention: 0%, Control: 2 (18%), p=0.11	N/A
Tuten, 2012 [152]	Drug and alcohol treatment program for pregnant people	Pregnant, ≤30 weeks gestation, nicotine dependent or smoking ≥10 CPD, on methadone treatment	102 (Contingent incentives:42, Non-contingent incentives: 28, Treatment as usual: 32)	Contingent voucher incentives for meeting smoking reduction targets from baseline x 12 weeks, brief motivational feedback session	Control 1: Yoked, non-contingent incentives x 12 weeks, brief motivational feedback session Control 2: program treatment as usual, brief motivational feedback session	Contingent incentives: $156.85 (of $736), Non-contingent incentives: $96.98 (of $384) mean voucher earnings	CO < 4 p.p.m,: Continent incentives: 13 (31%), Non-contingent incentives: 0%, Treatment as usual: 0%f	N/A
Winhusen, 2016 [80]	OTP	Smoking ≥10 CPD for ≥ 3 mo, smoking ≥40% of daily cigarettes during 4-hour period post daily methadone dose, stable methadone dose ≥ 1 month	20 (5 participants in each of the 4 groups)	Within-subject cross over study, with randomization to sequence of active/placebo medication, nicotine nasal spray (1 week each of active/placebo) preceding varenicline (2 weeks each of active/placebo, each followed by wash out period x 1 week)	Within subject cross over study: Placebo nicotine nasal spray x 1 week, Placebo varenicline x 2 weeks followed by wash out period x 1 week	N/A	N/Ah	N/Ah

^aTobacco abstinence, biochemically verified with expired CO, cotinine, or anatabine/anabasine levels, except as noted

^bSUDTP= substance use disorder treatment program(s)

^cOTP= opioid treatment program(s)

^dSingle-arm study, p value not reported

^eOBOT= office based opioid treatment program(s)

^fp-value not reported

^gStudy does not specify abstinence rates but reports no significant differences between groups

^hManuscript reports study design and rationale, and does not report outcomes

ⁱn not reported

^jn (%) abstinent not reported

These studies share common findings, which we detail in this review. First, treatment is critical; without smoking cessation treatments, smokers with OUD do not quit smoking. Second, low-intensity behavioral interventions are insufficient to achieve tobacco abstinence among smokers with OUD. Third, evidence-based smoking cessation treatments yield modest cessation rates. Finally, we review potential intervention strategies—addressing nicotine-opioid interactions, supporting adherence to cessation interventions, and reducing tobacco toxicant exposure—that have potential to decrease the burden of tobacco use among persons with OUD.

2. Evidence-based smoking cessation treatment is critical.

Without smoking cessation treatment, persons with OUD who smoke cigarettes do not quit smoking. This is a consistent finding in observational studies and among control groups of clinical trials. In a trial of OUD treatment strategies among persons with OUD not receiving treatment, 92% of participants reported smoking at baseline, and of those, only one participant was abstinent from tobacco at one-year follow-up [9]. Similarly, in a trial among persons with opioid- and other SUD that included SUD treatment interventions that did not address tobacco use, participants’ tobacco use was high, and did not change over time [96]. In trials comparing smoking cessation treatments to OUD treatment alone, to wait-list controls, or to cessation brochures, control condition participants have had negligible cessation [43, 97, 46]. Though the efficacy of evidence-based smoking cessation treatments among smokers with OUD is disappointingly modest, without treatment, persons with OUD will continue to smoke at high rates, and suffer from tobacco-related disease and premature death.

3. With evidence-based smoking cessation treatments, cessation rates are modest.

3.1. Behavioral interventions

3.1.1. Low-intensity behavioral interventions alone are insufficient to achieve tobacco abstinence among smokers with OUD.

Brief cessation counseling and telephone quitline counseling are low-intensity, scalable, evidence-based cessation interventions that increase tobacco abstinence among smokers without OUD [98, 99]. Brief counseling includes 5 A’s: (1) ask the patient if s/he uses tobacco (2) advise patient to quit (3) assess willingness to make a quit attempt (4) assist with behavioral and pharmacological treatments, and (5) arrange for follow-up [98]. Telephone quitlines are available in all 50 states and may offer telephone counseling, mailed educational materials, cessation medications, and information about local treatment resources. Quitlines have a broad reach and flexible structure, thereby potentially reducing treatment barriers [100].

Among smokers with OUD, those receiving low-intensity behavioral smoking cessation interventions without pharmacotherapy have negligible rates of cessation. In separate randomized trials among smokers with OUD, control condition participants receiving low-intensity behavioral interventions (including facilitated referral to a tobacco quitline [34]; brief cessation counseling [101]; or brief cessation counseling and telephone quitline referral [35]) had cessation rates of 0%. This is in contrast to the 13% cessation at six months seen with brief counseling and quitline counseling among smokers without OUD [98]. There are multiple potential reasons for this abysmal cessation rate: first, interventions may not be sufficiently potent; second, interventions may not address the many challenges to cessation faced by smokers with OUD; third, unstable telephone access may deter quitline use [102, 100]; finally, adherence to in-person counseling is low [43, 35]. These findings show that with minimal behavioral treatment alone, continued smoking is ensured, and highlight the need for the development of robust, evidence-based smoking cessation interventions for smokers with OUD.

3.1.2. Motivational interviewing does not outperform brief counseling among smokers with OUD.

Motivational interviewing (MI) is designed to enhance motivation for change [103]. Among smokers without OUD, compared to usual care or brief advice, MI is associated with a 26% increase in cessation [104]. Among smokers with OUD, however, MI effects are modest. For example, a trial of 383 smokers in methadone-maintenance treatment (MMT) compared motivational counseling to brief cessation counseling, both with nicotine patches. At the end of the intervention period, biochemically-verified cessation rates were similar and low among intervention and control groups (5.8% and 8.3%, p=0.325) [36]. Similarly, in trials of MI among pregnant smokers with OUD [105], among smokers with OUD receiving individualized motivational counseling [34], and among buprenorphine treatment patients receiving extended MI [46], abstinence rates were modest and comparable to outcomes associated with brief cessation counseling or quitline referral. One common finding in all of these trials was that adherence to counseling interventions was modest, highlighting both a challenge to treatment implementation and a potential therapeutic target.

3.1.3. Contingency management for smokers with OUD has potent short-term effects that are not maintained.

Contingency management (CM), in which financial incentives are used to reinforce tobacco abstinence, is the one behavioral treatment shown to increase short-term tobacco abstinence among smokers with OUD, even in the absence of pharmacotherapy. In pilot studies of short-term (2–4 weeks) CM for tobacco abstinence, CM had potent short-term abstinence effects among smokers with OUD [106, 41, 107], but these effects were not maintained at post intervention follow-up [41, 107]. Two large trials of 12 weeks of CM have also demonstrated the efficacy of this approach in achieving initial abstinence [39, 40]. The first was a 2x2 factorial, randomized trial of CM and relapse prevention among 175 methadone-maintained smokers [39]. CM groups had significantly higher abstinence rates than those not receiving CM at the end of the intervention period. However, at post-intervention follow-up, CM condition participants showed a steep rate of return to smoking. In another trial of 12 weeks of CM among 88 buprenorphine- or methadone-maintained smokers, cessation rates at the end of treatment were 46.7% and 23.5% (p=0.02) in the intervention and control groups, respectively, but post-intervention effects were not assessed [40]. Taken together, these trials show that CM interventions have potent effects at establishing initial abstinence among smokers with OUD while interventions are in place. This is an important therapeutic strategy among smokers with OUD given their challenges establishing initial abstinence [28, 35, 39]. Novel strategies, such as extended CM, or contingent reinforcement of cessation medication adherence, may be necessary to maintain CM effects long-term.

3.2. Smoking cessation pharmacotherapies have modest effects among smokers with OUD.

There are seven smoking cessation medications approved by the U.S. Food and Drug Administration (FDA) with demonstrated efficacy to promote tobacco cessation among smokers without OUD [98]. These include NRT: nicotine patch, gum, lozenge, inhaler and nasal spray; bupropion; and varenicline. Among smokers without OUD, these treatments increase the likelihood of cessation compared to placebo controls 1.5 to 3.6-fold at six month follow-up [98]. Cytisine is a partial agonist of nicotinic receptors that is associated with smoking cessation and used in Europe and Asia [108]; its effects among smokers with OUD have not yet been described.

3.2.1. How does nicotine replacement therapy (NRT) work among persons with OUD?

Trials testing the effects of nicotine replacement monotherapy among smokers with OUD highlight several common findings: cessation effects with NRT are modest; adherence is a major mediator of cessation success; and strategies are needed to maintain abstinence long-term [39, 34, 43]. In one trial of smokers in outpatient SUD treatment (including but not limited to methadone maintenance), 225 participants were randomly assigned to receive smoking cessation treatment (eight weeks of nicotine patch, and smoking cessation group counseling) and SUD treatment, or to receive SUD treatment alone [43]. Abstinence rates were 0% among controls, and 10–11% over the intervention period in the intervention group. Adherence to counseling and to NRT were associated with total number of weeks abstinent during treatment. Unfortunately, intervention group cessation effects were not sustained when active interventions ceased. In another trial, 83 methadone-maintained smokers were randomized to receive nicotine patch and a motivational intervention, or referral to the state quitline [34]. Similar to the other trial, abstinence rates at three months were 0% among controls, and 7% in the intervention group; at the six-month follow-up, cessation rates in the intervention group dropped to 2%. Among smokers with OUD, cessation rates at the end of treatment with nicotine replacement monotherapy are under half of that seen at six months post-quit among smokers without OUD [98]. Though these modest cessation rates are higher than the negligible rates seen without smoking cessation interventions, or with low-intensity interventions, they are not maintained over time.

3.2.2. Does NRT intensification improve outcomes among smokers with OUD?

Increasing the dose and the duration of NRT are evidence-based strategies that have been shown to enhance efficacy among smokers without OUD [109]. Combination NRT (patch in combination with gum, lozenge, inhaler or nasal spray) and “high-dose” patch (starting at doses of 42, 35, or 28 mg daily) have been shown to significantly increase abstinence rates over standard NRT dosing [109]. Compared to the standard two months of NRT, extended (six month) NRT courses are associated with increased abstinence and decreased relapse [110–113]. Unfortunately, the potency of these interventions is not observed among smokers with OUD; in trials (described below) that have employed combination and extended NRT, cessation rates remain modest [36, 37, 46, 101].

Though higher patch dosing has not been directly compared to standard dosing among smokers with OUD, it has been utilized in one trial testing two behavioral interventions, both with nicotine patch [36]. Patch duration and dosing was guided by baseline CPD: participants smoking 10–39 CPD received eight weeks of patch starting at 21 mg daily, and participants smoking ≥40 CPD received 12 weeks of patch starting at 42 mg daily. Across the behavioral treatment conditions tested, cessation rates were modest at end of treatment (5.8% and 8.3%) and declined to 5.2% and 4.7% at six month follow up [36]. Another randomized trial compared open-label combination NRT (patch, gum and lozenges for six weeks, with brief cessation counseling) to brief counseling alone among methadone-maintained men in Iran. Cessation rates in both groups were 0% at one month, but increased to 7.1% (intervention) and 0.5% (control) (p<0.0001) at six months [101]. Findings from this trial highlight that combination NRT is efficacious as an aid to initial abstinence among smokers with OUD. Though cessation rates are a quarter those seen with combination NRT among smokers without OUD [98], they are higher than the negligible rates among controls.

Trials to date that have used extended (24-week) NRT suggest that low intervention adherence may limit this approach among smokers with OUD [37, 46]. In a trial [46] among buprenorphine-maintained smokers that tested extended combination NRT and counseling compared to written cessation resources, only 54% of extended treatment group participants initiated NRT; those who did completed under half of all counseling sessions, and used only a small fraction of the NRT offered. Ultimately, cessation rates with extended treatment (11%) were modest, and similar to those seen in the control condition (11.3%). Another randomized trial [37] tested six months of combination NRT with patch and gum, or varenicline, or placebo. Adherence to extended treatment at six months was modest: 48.8% with NRT, 34.2% with varenicline and 34.4% with placebo. Cessation rates at the end of treatment were correspondingly low and did not differ between groups: 8.3% with combination NRT, 3.7% with varenicline and 2.2% with placebo.

Taken together, trials employing NRT among smokers with OUD highlight important common findings. First, without pharmacotherapy, cessation is negligible [101, 46, 34, 43]. Second, NRT is associated with rates of cessation which are under half that seen among smokers without OUD. These low rates of cessation decline further when active treatment ceases. Though trials among smokers with OUD have not directly compared combination NRT and monotherapy, cessation effects with combination NRT are comparable to those previously reported with monotherapy. Third, high-dose NRT, combination NRT, and extended NRT achieve cessation rates under a quarter that seen among smokers without OUD. Given the potency of these interventions among smokers without OUD, these findings raise questions about how interventions could be further optimized to enhance cessation effects.

3.2.3. Limited evidence to inform use of bupropion among persons with OUD.

There is limited evidence informing the use of bupropion for smoking cessation among persons with OUD. In the only randomized trial testing bupropion among smokers with OUD, 40 smokers initiating buprenorphine treatment for OUD were randomized to receive active or placebo bupropion for smoking cessation, in combination with weekly counseling [44]. Here, differences between groups were negligible: 13.7% of bupropion participants achieved abstinence compared to 11.4% of controls by the end of the trial. Of concern, retention in OUD treatment was lower among bupropion-treated participants: 59% in the intervention group and 90% in the control group. This trial raises questions about bupropion efficacy among smokers with OUD, and highlights the challenges of initiation of smoking cessation treatment at the same time as initiation of medication treatment of OUD.

In a small, uncontrolled open-label study of smokers with OUD receiving MMT, all participants received bupropion, nicotine gum, and motivational counseling [38]. Though the 14% abstinence rate is among the highest rates of abstinence at six months reported to date among smokers with OUD, the modest sample size and lack of controls limit these findings. Two trials conducted among smokers in MMT made bupropion optional for participants [107, 40]; uptake of bupropion was low–only 28.6% of participants initiated bupropion in one trial [40], and 37.5% in the other [107]. Though there was no difference in abstinence among participants who did and did not initiate bupropion in both trials, the modest bupropion uptake limits power to detect a bupropion effect.

Taken together, there are limited data to inform the use of bupropion for smoking cessation among persons with OUD. Though bupropion, in combination with nicotine gum and motivational counseling, may yield cessation among smokers with OUD, the limited controlled data, potential adverse impact on retention, and comparable effects to non-bupropion treated controls raises questions about use of bupropion for smoking cessation among smokers with OUD.

3.2.4. How efficacious is varenicline among smokers with OUD?

Varenicline is a partial agonist of the α4β2 nicotinic acetylcholine receptor, which is a major mediator of nicotine dependence. Among smokers without OUD, varenicline has been shown to be more efficacious than bupropion, nicotine patch and placebo [114, 115, 31], and to prevent relapse (when continued for a total of six months) among smokers who establish initial abstinence [116, 117]. Given the efficacy and potency of varenicline among smokers without OUD, and the modest efficacy of NRT and bupropion among smokers with OUD, several trials have tested efficacy of varenicline for smoking cessation among smokers with OUD [42, 35, 37]. Three trials tested varenicline against placebo controls [37, 42, 35], two tested varenicline against NRT [79, 37], and one trial used an extended (24-week) course of therapy [37].

In a randomized, placebo-controlled trial of varenicline, participants receiving varenicline were more likely than those receiving placebo to achieve abstinence (10.5% vs 0%, p =0.03), but these effects were not maintained after varenicline treatment ceased [35]. These findings were echoed in a trial of smokers receiving outpatient SUD treatment (of whom 34% had OUD): varenicline was efficacious as an aid to cessation (compared to nicotine patch), with 13% abstinence at three months; again, this effect was not maintained at post-intervention follow-up [79]. In this trial, compared to smokers with other SUD, smokers with OUD had significantly fewer days adherent to varenicline (with 35 vs 47 days of capsules taken of 91), and a lower rate of tobacco abstinence that did not reach statistical significance [66].

Varenicline did not increase rates of tobacco abstinence over combination NRT or placebo in a separate randomized trial among 315 smokers in MMT treated with six months of pharmacotherapy [37]. Cessation rates were 3.7% with varenicline compared to 8.3% with combination NRT and 2.2% with placebo (p > .05). These findings are partially attributable to the low rates of treatment adherence at six months – only 34.2% of varenicline group participants reported past-week varenicline use at six months. Though extended varenicline has been shown to increase cessation over the standard three months of treatment among smokers without OUD [116, 117], including among smokers with serious mental illness [117], these findings raise questions about whether challenges with medication adherence limit the feasibility of an extended treatment approach in smokers with OUD.

Overall, as with other cessation medications among smokers with OUD, varenicline had modest effects as an aid to cessation, and effects were not sustained when active treatment ceased [37, 42, 35, 79]. Extended varenicline treatment was associated with limited medication adherence, and modest cessation rates that were comparable to those of combination NRT and placebo.

4. Interventions targeting unique challenges faced by smokers with opioid use disorder

4.1. Interventions to reduce tobacco exposure and harm

Given that cessation interventions in smokers with OUD have resulted in substantially lower quit rates than in smokers without OUD [95, 35, 118, 39, 43, 46, 34], traditional cessation-focused treatment approaches may be inadequate for smokers with OUD. If smokers with OUD are unable to achieve tobacco abstinence despite evidence-based treatments, novel treatment approaches are necessary to reduce tobacco use and reduce risk of tobacco-related harm.

Few trials to date have included smokers with OUD regardless of readiness to quit [36, 46, 34, 119]. Across the heterogeneous interventions offered in these studies, participants reduce CPD, advance stages of change, and make quit attempts. These results suggest that it is feasible to recruit smokers with OUD who are not initially ready to quit into tobacco treatment trials, and that tailored approaches may increase long-term cessation by reducing CPD [34, 36], and enhancing motivation [46, 36] and treatment engagement [119].

An alternate approach to promoting cessation is to reduce the harm of tobacco products; the United States FDA is currently exploring a regulatory strategy to decrease nicotine content, and in turn, the addictiveness of combustible cigarettes [120]. Compared to standard nicotine cigarettes, cigarettes with reduced nicotine content reduce CPD and nicotine dependence among smokers without OUD [121, 122]. However, research on effects of reduced nicotine content cigarettes among smokers with OUD is sparse. In a double-blind, within-participant laboratory assessment of acute effects of reduced nicotine content cigarettes among 60 smokers with OUD, reducing nicotine content of cigarettes decreased both the reinforcing effects of smoking and nicotine withdrawal [123]. Reducing the nicotine content of cigarettes may thus decrease their addictive potential, and research on long-term effects among smokers with OUD is warranted.

Electronic nicotine delivery systems (ENDS), such as electronic cigarettes, may have potential to reduce cigarette use among smokers with OUD. In separate samples, between 18% and 34% of persons with OUD report past-month use of electronic cigarettes [124, 125], but few (6–8%) report daily use [125, 126]. The majority of persons with OUD using electronic cigarettes are current cigarette smokers [126]; this pattern of dual use, rather than switching from combustible to e-cigarettes, puts smokers at greater risk of toxicant exposure than use of either product alone [127]. In two small pilot studies of ENDS effects among persons with OUD, participants self-reported adherence to e-cigarettes [128, 129], but the volume of liquid used was low [129]. Participants also reported reductions in CPD while using ENDS, but did not achieve tobacco abstinence with their use [128, 129]. The potential benefits (e.g., whether these observed short-term reductions in CPD persist long-term, and can prompt quit attempts and switching from combustible cigarettes to ENDS) and harms (e.g., toxicant exposure, lung injury) of ENDS among smokers with OUD warrant empiric evaluation.

4.2. Interventions targeting unique challenges faced by smokers with opioid use disorder: nicotine-opioid interactions and medication adherence

The limited efficacy of potent, evidence-based smoking cessation treatments underscores the need to investigate novel strategies to reduce tobacco use among smokers with OUD. Among the multiple structural and individual-level barriers to cessation among persons with OUD described above, ongoing trials are targeting two: the interaction between nicotine and opioids [82–87], and the limited adherence to smoking cessation medication [76, 65, 43, 77, 38, 37, 80].

Neurobiological and clinical interactions between nicotine and opioids challenge the achievement of tobacco abstinence among persons with OUD, but few trials to date have targeted that interaction. Given that smokers with OUD smoke most daily cigarettes at the time of peak opioid effect [82], an ongoing trial will test effects of nicotine nasal spray, varenicline, and their placebos, on tobacco use behavior in the period of peak methadone effect [80].

Despite robust associations between medication adherence and smoking cessation, little research has evaluated the efficacy of interventions to improve adherence to smoking cessation pharmacotherapy [130]. Directly observed therapy (DOT) has been shown to improve medication adherence and outcomes among persons with OUD with HIV or tuberculosis [131–134]. In a pilot trial of methadone-clinic based varenicline DOT compared to self-administered treatment (SAT), we found higher levels of varenicline adherence with DOT compared to SAT [135, 118]. This laid the groundwork for an ongoing trial to test whether DOT varenicline promotes tobacco abstinence among smokers with OUD.

5. Remaining clinical and research questions

Research evidence is clear that treatment of tobacco use and OUD does not adversely impact OUD treatment outcomes [136–138]. But the optimal timing of tobacco use treatment among persons in OUD treatment--at treatment initiation or following a delay--remains an open clinical question. Much of the data to answer this question come from research among persons with alcohol use disorder. In clinical trials among persons with alcohol use disorder, concurrent (vs delayed) tobacco cessation treatment was associated with lower rates of abstinence from alcohol [139] and greater relapse to alcohol [140]. Among persons with OUD, one placebo-controlled trial tested bupropion at initiation of buprenorphine treatment; fewer bupropion group participants than placebo group participants were retained in treatment [44]. Unfortunately, a delay in the provision of smoking treatment may result in a missed opportunity to treat tobacco use, particularly if patients are not retained in treatment [141, 97]. From a pragmatic perspective, clinicians may elect to defer treatment of tobacco use until patients have reached stable doses of opioid agonist treatment.

There are also multiple research opportunities to address the gaps in our knowledge of challenges faced by smokers with OUD. To what extent are these challenges driven by issues of SUD more broadly, or specific to OUD? Limited research to date has compared processes and determinants of smoking cessation among persons with OUD vs persons with other SUD [66]. Do differences in opioids used, i.e., heroin or prescription opioids, impact tobacco use behavior? Though there are demographic and clinical differences between persons with heroin use disorder and prescription opioid use disorder [142–144], there are few data to inform whether there are differences in tobacco use behavior in these groups. What is the interaction of pain, tobacco use, and OUD? Though pain is highly prevalent among persons with OUD, smokers were more tolerant of withdrawal discomfort that persons with other SUD in one study [66]; the impact of pain on mechanisms of tobacco cessation warrants further investigation. Nicotine dependence is associated with initiation of opioid analgesics, chronic opioid analgesic use and high-dose opioid analgesic use [10–12, 145, 146], and research is needed to characterize the impact of tobacco use on the development on of opioid misuse and OUD.

There are also multiple remaining questions with regard to optimizing tobacco treatment among smokers with OUD. First, how can we best engage smokers with OUD who are not yet ready to quit? Are there strategies that can reduce nicotine exposure and tobacco-related harms long-term? Second, how can we enhance the efficacy of cessation interventions among smokers with OUD? Can combining CM with combination NRT enhance long-term cessation effects? Do interventions to increase adherence to cessation interventions increase tobacco abstinence? What are the best strategies to address interactions between nicotine and opioids? Finally, how can OTPs enhance and sustain the provision of cessation services?

6. Conclusion

Despite the high burden of tobacco use among persons with OUD, evidence-based tobacco cessation interventions have only modest effects among smokers with OUD. But without smoking cessation interventions, tobacco use rates remain high and unchanged. Low-intensity behavioral interventions alone, including brief counseling and telephone quitline referral, are insufficient to achieve tobacco abstinence among smokers with OUD. More intensive behavioral interventions, including individualized motivational enhancement and extended counseling, do not outperform low-intensity behavioral interventions. CM has potent short-term effects as an aid to cessation, but effects dissipate when incentives cease.

NRT, bupropion and varenicline have modest effects among smokers with OUD that are approximately one quarter that reported among smokers without OUD. Strategies to optimize pharmacotherapy effects, including combination therapy and extended therapy, do not enhance cessation rates over standard interventions.

Given these data, where do we go from here? First, smokers with OUD need evidence-based smoking cessation pharmacotherapy. Without treatment, smokers will continue to smoke at high rates, and will suffer high rates of tobacco-related disease and premature death. Second, low-intensity behavioral interventions alone, such as brief counseling or quitline referral, are unlikely to change tobacco use among smokers with OUD; though scalable, these will need to be coupled with pharmacotherapy. Third, novel strategies are needed to optimize the modest rates of cessation seen with smoking cessation therapies, and to maintain abstinence effects long-term [7, 137]. Fourth, further research is needed to evaluate the efficacy of approaches to reduce tobacco exposure and tobacco-related harm. Finally, the efficacy of interventions that target challenges unique to smokers with OUD warrant evaluation. Without delivery of evidence-based treatments, and without enhancing efficacy of interventions, smokers with OUD will remain at risk for OUD relapse, tobacco-related disease, and premature death.

Key Points.

1. Without smoking cessation pharmacotherapy, cessation rates are negligible among smokers with opioid use disorder (OUD).

2. Even when evidence-based smoking cessation medications are used, cessation rates among smokers with OUD are modest and only a quarter that of the general adult population.

3. Smokers with OUD are confronted by a unique set of challenges regarding smoking cessation, including nicotine-opioid interactions and poor medication adherence.