Current advances in research in treatment and recovery: Nicotine addiction – Science Advances

As discussed, tobacco dependence is characterized as a physiological dependence (addiction to nicotine) and behavioral (or conditioned) habit of using tobacco. Hence, for maximal effectiveness, as recommended by U.S. Clinical Practice Guidelines, tobacco dependence treatment engages a multipronged approach (98). Addiction can be treated with FDA-approved medications for smoking cessation; the behavioral habit can be treated through counseling and behavior change programs, and policy interventions can promote smoke-free environments, discussed in the Tobacco Control Population-Based and Policy Approaches section.

Brief cessation advice. With 7 in 10 tobacco users seeing a healthcare provider in a given year, opportunities exist for brief cessation clinical advice. Treating smoking is relevant to all areas of medicine, and the evidence in support of brief clinical cessation advice is strong (99). The U.S. Preventive Services Task Force gives a grade A recommendation for clinician-delivered brief tobacco cessation interventions (100). Counseling by nonphysician health providers, including nurses (101), oral health professionals (102), and pharmacists (103), also increases quit rates.

The gold standard for brief cessation advice is the National Cancer Institutes (NCI) 5As to (i) ask all patients about use of all forms of tobacco; (ii) advise tobacco users to quit; (iii) assess patient readiness to quit; (iv) assist in the quit attempt with counseling, medications, and referrals; and (v) arrange follow-up. The 5 As increase patient treatment engagement, quit attempts, and tobacco abstinence (104).

Recognizing time constraints in the clinical setting, an alternate approach with evidence is Ask-Advise-Refer (AAR), whereby clinicians ask about tobacco use, advise tobacco users to quit, and then refer patients to an outside entity for assistance and follow-up, such as a tobacco quitline (1-800-QUIT-NOW) (105, 106). Further adaptation is Ask-Advise-Connect (AAC), the distinction being that the referral is provided in the form of a direct connection, such as a fax or other electronic referral (107). Comparison of AAR to the 5 As delivered in 68 dental clinics found comparable quit rates, and both approaches were better than usual care (106). Sustained quit rates at long-term follow-up, however, were under 4% in all three study arms. A recognized standard of care, brief provider advice is effective for engaging patients in treatment and supporting quitting (98); however, to further improve sustained abstinence rates, more intensive interventions are needed.

Intensive counseling. Clinical practice guidelines recommend intensive cessation counseling offered in person, individually or in groups, in clinical, behavioral, or community settings for treating smoking (98). The counseling framework tends to be cognitive behavioral and motivational, although, increasingly, other clinical approaches (e.g., mindfulness, acceptance, and commitment therapy) are being incorporated. A systematic review of 49 randomized trials with some 19,000 participants concluded that intensive counseling only (without medications) delivered by a cessation counselor on a one-to-one basis was more effective than minimal contact (i.e., brief advice and self-help materials) and had greater effects when combined with cessation medications (108). Intensive individual and group counseling treatments also have demonstrated effectiveness in workplace settings (109). Access to intensive counseling may be limited because of travel, time, cost, or privacy concerns. To overcome these barriers, tobacco quitlines were developed to improve accessibility and reach of tobacco cessation counseling treatment.

Tobacco quitlines. Tobacco quitlines are staffed by trained counselors or coaches who provide information, individual counseling, local referrals, self-help materials, and, in some cases, limited supplies of free cessation medications. The effectiveness of tobacco quitlines is well demonstrated (110). Quitline services are available at no cost to U.S. residents and accessed via a toll-free national portal (1-800-QUIT-NOW or 1-855-DJELO-YA), which links callers to their state quitline based on their area code. While specific services vary by state, by county, and over time, most state quitlines provide at least one counseling session to any adult tobacco user who calls, and many states provide a multi-call program that includes reactive and proactive calls. The reactive approach relies upon smokers to initiate the calls, whereas the proactive approach makes outbound calls to engage tobacco users. In meta-analyses, better outcomes are seen with multi-call versus single-call protocols (110) and with proactive versus reactive quitline services (111).

Although free, convenient, and confidential, quitlines in most states reach an average of only 1% of smokers annually (112). Even among smokers aware of quitlines and making a quit attempt, reach is only about 8% (113). The Centers for Disease Control and Preventions (CDC) Tips From Former Smokers (Tips) tobacco education campaign, developed to encourage quitting and raise awareness of state quitline services and conducted annually since 2012, has generated hundreds of thousands of additional calls to state quitlines (114). The Tips campaign and its impact on quitting are discussed under media campaigns in the Tobacco Control Population-Based and Policy Approaches section. To further expand reach, some state quitlines have incorporated mobile health technologies.

Mobile technologies: Internet, text, and social. Mobile technologies, such as internet interventions, email, chat, and texting, are being leveraged for health promotion at a low cost, with broad reach potential and with evidence of efficacy.

Internet-delivered tobacco cessation interventions have existed for more than 25 years and have continued to develop in sophistication, level of interaction, and complexity of functionality, as well as treatment efficacy. In 2011, the Community Preventive Services Task Force deemed the evidence insufficient to recommend internet-based interventions for tobacco cessation (115). Two years later, a 2013 review concluded that internet-based interventions can assist in achieving long-term smoking cessation, particularly interactive programs tailored to the individual (116). A 2016 review noted significant improvements in internet-based smoking cessation interventions with evidence of superior efficacy relative to print materials and equivalent efficacy to telephone and in-person counseling (117). Relative to quitlines, internet-delivered interventions have 27 times greater national reach [annually, 11 million for internet versus 400,000 for quitlines (112)] and at a lower cost per quit [e.g., $291 for internet versus $900 for quitlines (118)].

A model example of an internet-delivered tobacco cessation program is NCIs Smokefree.gov, which combines evidence-based guidelines for quitting smoking, tailored to readiness to quit, with availability of professional assistance via instant messaging and telephone (1-877-44U-QUIT). The site has also tailored offerings for veterans, women, adolescents, Spanish-speaking smokers, and older adults. SmokefreeTXT is an additional mobile service that provides encouragement, advice, and tips for young adults to quit smoking. Smokefree smartphone apps are offered to provide motivational reminders and help with tracking progress with quitting smoking. The Smokefree.gov site had 3.6 million visitors in 2016 (118) and received high user satisfaction ratings (119). Randomized trial evidence supports Smokefree.gov as a population-based intervention for smoking cessation (118, 120).

Mobile phonebased tobacco cessation interventions that send automated low-cost messages (i.e., texts) were deemed to have sufficient evidence of efficacy to be recommended by the Community Preventive Services Task Force (121). Trials in New Zealand and the United Kingdom evaluated text messages sent daily up to the quit day that tapered to a maintenance phase; texts included general information, motivational messages, quitting advice, and distraction strategies, and effects on quit rates were significant relative to no-text controls (122, 123). A 2016 review found significant short-term effects of text-based smoking cessation interventions, although they were not sustained at long-term (>6 months) follow-up (124). Given the chronic, relapsing nature of nicotine addiction, more intensive extended interventions may be needed.

With the potential for more dynamic interactions, smoking cessation apps (applications) are available for download from digital marketplaces (e.g., iTunes and Google Play) for use on smartphones, tablets, and other handheld devices. A 2014 search identified 546 smoking cessation apps in the Apple Store and on Google Play that were downloaded some 3.2 million times in the United States and 20 million times worldwide (125). Broad reach and high scalability make apps particularly well suited for serving remote and resource-poor settings. Advantages include low or no cost to the user, self-tracking and tailored feedback functionalities, and use of images and video for enhanced health literacy. However, a 2015 review of 225 Android apps for quitting smoking found that most provide simplistic tools (e.g., calculators and trackers); use of tailoring was limited, although positively related to app popularity and user ratings of quality (126). Evaluation of intervention effects on quitting smoking is sorely needed. Notably, one randomized trial found that a simpler, direct texting program outperformed a smoking cessation app (127).

Social media, such as Twitter and Facebook, are being explored for delivering cessation treatment. In the United States, 74% of online adults use social media, 80% of whom are seeking health information, and a majority access the sites daily (128). A promising technology, efforts to sustain engagement are key and can be challenging; like predecessor technologies such as bulletin boards and listservs, initial interest may be high but then tends to wane (129, 130). There is preliminary evidence, however, of good acceptability and efficacy. Using Twitter, small, private groups of 20 smokers, who interact for 100 days, have been studied. The intervention (Tweet2Quit) seeds the groups with twice-daily automessages to encourage group sharing and support. In a randomized trial, the Tweet2Quit Twitter groups added to Smokefree.gov and the nicotine patch fostered peer-to-peer support for quitting and significantly doubled the likelihood of reported sustained abstinence relative to the website and patch alone (131). Similar efforts are being developed on Facebook, with a focus on engaging young adults into cessation treatment. In a randomized trial, a novel Facebook smoking cessation intervention increased abstinence at the end of treatment, although effects were not sustained out to 1-year follow-up (132).

Social media can provide varying degrees of anonymity, which may be attractive. Having tried and failed to quit smoking in the past, smokers may not initially publicize their quit attempts within their main social circle (133). With social media sites that are largely uncurated or expert moderated, however, users should be forewarned that inaccurate information may be posted. For example, online communities may encourage use of nonevidence-based treatments (e.g., laser, herbs, acupuncture, or hypnosis for quitting smoking) (129). A heterogeneous group of emerging applications and knowledge gaps remain concerning best strategies for maximizing the reach and efficacy of mobile technologies for treating nicotine addiction as well as the comparative effectiveness relative to in-person approaches.

Monetary incentives. Monetary incentives that reward outcome (i.e., quitting smoking) or engagement (e.g., treatment participation) have been evaluated in 33 trials, with a meta-analysis finding evidence of increased abstinence that persisted after the incentives ceased (134). The level of the incentives ranged from zero (self-deposits) to between $45 and $1185, with no clear direction of effect by level of incentive. Conditional payments (i.e., payment for abstinence) outperformed nonconditional payments. Findings from a subgroup analysis of eight trials conducted with smokers with substance use problems were consistent with the overall analysis. A summary of nine trials with pregnant smokers reported more than twofold greater odds of abstinence at longest follow-up assessment (up to 24 weeks postpartum). The findings are particularly important given the substantial health harms of smoking to mother and baby and that, currently, there is no other effective cessation intervention for pregnant smokers.

While counseling and psychosocial treatments help promote cessation, medications that address the neuropharmacological effects of nicotine and nicotine withdrawal further enhance the likelihood of quitting. E-cigarettes, which allow continued self-administration of nicotine without combustion, can also promote quitting smoking.

Smoking cessation guidelines, such as those from the U.S. Public Health Service and National Cancer Center Network, recommend smoking cessation medications for all daily smokers where feasible and safe (98, 135). Pharmacotherapy can be considered for nondaily smokers as well, although there are few clinical trials to guide treatment in this group. The mechanism of benefit in nondaily smokers would be reduction of nicotine reward from cigarettes by nicotinic receptor desensitization or antagonism, as discussed below. Table 2 presents the FDA-approved smoking cessation medications, including dosing guidelines, advantages, disadvantages, adverse effects, and precautions. FDA-approved medications are NRT in the form of gum, patches, lozenge, nasal spray and inhaler, varenicline, and bupropion. Nicotine gums, lozenges, and patches are available over the counter in the United States, while the nicotine nasal spray, nicotine inhaler, varenicline, and bupropion are by prescription only. Nicotine mouth spray is available outside of the United States and has evidence of acceptability, efficacy, and safety, including with minimal behavioral support (136).

In general, medications serve to make smokers more comfortable while they learn to live and cope with daily cues/triggers and life stressors without smoking cigarettes. There are three main mechanisms by which medications can facilitate smoking cessation: (i) reduction of nicotine withdrawal symptoms, (ii) reduction of the rewarding effects of nicotine from smoking by blocking or desensitizing nicotine receptors, and (iii) providing an alternative source of nicotine with the desired pharmacologic effect previously provided by nicotine from cigarettes. NRT medications are not as satisfying as cigarette smoking because of slower absorption of nicotine; nicotine delivery from e-cigarettes can resemble that of a cigarette, and these devices tend to be much more satisfying. Most smoking cessation medications are recommended for 8 to 12 weeks, although use for 6 months or longer may be necessary to achieve optimal quit rates. It makes sense to use medications to support smoking cessation for as long as the individual feels at risk for relapse. For those switching to e-cigarettes as a less harmful substitute for cigarette smoking, use sometimes continues for many months or years.

Nicotine replacement therapy. Nicotine medications consist of purified nicotine that is administered to ameliorate symptoms of physical dependence on nicotine. The particular actions of different products vary according to route of administration and rate of nicotine absorption into the bloodstream. For example, nicotine patches deliver nicotine slowly, relieving nicotine withdrawal symptoms and reducing positive effects of cigarette smoking, without providing much, if any, direct positive effects of nicotine. Nicotine gums, lozenges, sprays, and inhalers deliver nicotine more rapidly, providing some acute nicotine effects that may serve as a substitute for smoking a cigarette. Combining a short-acting (gum, lozenge, spray, or inhaler) with a long-acting (nicotine patch) NRT results in superior quit rates compared to any NRT product alone and is recommended as a first-line treatment (137).

NRT products are marketed in different strengths, with higher doses recommended for more dependent smokers based on the number of cigarettes smoked per day or time to first cigarette upon wakening. A 2019 Cochrane review concluded that 4-mg gum is more effective than 2-mg gum in more highly dependent smokers and that 21-mg patch is more effective than 14-mg patch in general (137). While clinical trials do not demonstrate superiority of 42- to 21-mg dose nicotine patch, some clinicians do use high-dose patch for smokers with particularly severe withdrawal symptoms. Tapering of nicotine doses over time is an option for nicotine patches but does not appear to affect outcome in clinical trials.

All forms of NRT have shown similar efficacy in clinical trials (137), increasing quit rates by 50 to 100% compared to behavioral treatment alone. For the NRTs, compliance is greatest with nicotine patches, lower with gum and lozenge, and lowest with the nasal spray and inhaler. Nicotine patches are usually placed on the skin in the morning and deliver nicotine over 16 to 24 hours. Some smokers experience nicotine patchrelated insomnia and/or abnormal dreams and do better removing the patch at bedtime. Use of patches for 16 or 24 hours is equally effective in promoting quitting smoking. The pharmacokinetics of nicotine gum, lozenge, and inhaler are similar, with gradual absorption of relatively low doses of nicotine over 15 to 30 min. Use every 1 to 2 hours provides the best pharmacologic response. The nicotine inhaler is a plastic device inhaled like a cigarette but delivers nicotine to the oropharyngeal area rather than to the lungs, which explains its slow absorption. The main advantage of the inhaler is providing a hand-to-mouth experience similar to smoking. All oral nicotine products have an alkaline pH, which results in a high proportion of nicotine in the free base form, which is rapidly absorbed across mucous membranes. Acidic beverages (e.g., coffee, citrus juice, sodas, and many alcohol beverages) reduce the pH and reduce nicotine absorption and should be avoided for >10 min before using oral NRT products. The nicotine nasal spray is absorbed much faster than the other rapid-release products, most closely resembling a cigarette. More dependent smokers may find nicotine nasal spray to be more effective than other NRT products for smoking cessation. The spray is associated with more local toxicity, including a burning sensation, watery eyes, and sneezing; however, tolerance develops to these effects with regular use of the spray over 1 to 2 days.

Overall, NRT products are well tolerated and present few safety concerns. Safety concerns with NRT are primarily skin irritation with patches, gastrointestinal symptoms with oral products, and nasal/throat burning and irritation with nasal spray. Nicotines cardiovascular effects raised concern about NRT cardiovascular safety. Nicotine enhances sympathetic neural activity, resulting in increased heart rate, constriction of blood vessels, induction of proatherogenic lipid profiles (lower high-density lipoprotein cholesterol), development of insulin resistance, and possible promotion of arrhythmias (138). Cigarette smoke delivers not only nicotine but also many oxidants, prothrombotic and other toxic chemicals, making smoking much more toxic than nicotine alone. Clinical trials and other studies of NRT in patients with cardiovascular disease find no increase in adverse cardiovascular events due to NRT (139, 140).

Varenicline. Varenicline is a partial agonist at the nicotinic 42 receptor, the major receptor mediating nicotine addiction. Varenicline both activates (about 50% of the maximal effect of nicotine) and blocks the effects of nicotine on the 42 receptor (141). The agonist effect serves to reduce withdrawal symptoms, while the antagonist effects reduce the rewarding effects of nicotine from cigarette smoke. Varenicline treatment before smoking cessation is often associated with reduced smoking, presumably because smoking is less satisfying, an effect that can promote subsequent cessation.

In clinical trials, varenicline is more effective than bupropion or nicotine patch in promoting smoking cessation and is comparably effective to combined NRT (142). The EAGLES trial, the largest smoking cessation trial conducted with 8000 smokers, directly compared varenicline, bupropion, nicotine patch, and placebo. Varenicline outperformed all conditions; bupropion and nicotine patch were comparable to each other and were significantly better than placebo (143). EAGLES included smokers without and with psychiatric diagnoses. Quit rates were higher in those without psychiatric diagnoses, but the relative efficacy of the various treatments was similar. Extended treatment with varenicline for 6 months is superior to the standard 12-week treatment and is recommended for smokers who feel at risk of relapse (144).

The most common adverse effect of varenicline is nausea, which is dose related and to which tolerance develops over time. Concern about nausea is the rationale for starting at lower doses (0.5 mg once to twice daily) for a week before starting the full dose (1.0 mg twice daily). Some smokers cannot tolerate the normal dose but do well on continued use of the lower dose. Anecdotal reports of neuropsychiatric adverse effects of varenicline used for smoking cessation have been reported, prompting a black box warning in the label after the drug was marketed (for both varenicline and bupropion). The putative neuropsychiatric side effects included depression, psychosis, and suicide, with potentially higher risk in smokers with psychiatric disease. However, the EAGLES trial found no evidence of increased neuropsychiatric adverse events for varenicline or bupropion relative to nicotine patch or placebo, in smokers with or without psychiatric illness, and in 2016, the black box warnings were removed for both varenicline and bupropion (143). Varenicline has been shown to enhance smoking cessation in patients with cardiovascular disease, including stable coronary heart disease and acute coronary syndrome (145, 146). Concern was raised about possible cardiovascular toxicity due to the nicotine-like effects of varenicline and anecdotal reports of adverse cardiovascular events, but several meta-analyses, a large retrospective cohort study, and clinical trials in smokers with cardiovascular disease, as well as the EAGLES trial, showed no increase in cardiovascular risk (147, 148). Varenicline has also been found efficacious for cessation of smokeless tobacco use (149).

Bupropion. Bupropion is a stimulant drug originally marketed as an antidepressant. Bupropion blocks neuronal uptake of dopamine and norepinephrine and has antagonist activity on the 42 nicotinic receptor. By blocking reuptake, bupropion increases brain levels of dopamine and norepinephrine, simulating effects of nicotine. Bupropion is marketed for smoking cessation as a sustained-release preparation. The drug works in both depressed and non-depressed smokers. The usual duration of bupropion treatment is 12 weeks, but extended bupropion therapy for a year reduces relapse and enhances long-term quit rates (150). With lower quit rates, bupropion is considered to be second-line, after combination NRT and varenicline.

The main adverse effects of bupropion relate to its nervous system stimulant actions. Some smokers are intolerant to bupropion because of anxiety, agitation, and insomnia. Bupropion reduces the seizure threshold and should not be used in smokers who are at risk for seizures. In overdose, bupropion causes tachycardia and hypertension, but there is no evidence of increased cardiovascular events in smokers with preexisting stable cardiovascular disease (151, 152).

Combination pharmacotherapy. Combined NRT with patch and a more immediate acting product results in higher quit rates than single NRT [Cochrane meta-analysis: risk ratio (RR), 1.34; 95% confidence interval (CI), 1.18 to 1.48] (137). The combination of varenicline and nicotine patch has been evaluated with mixed results (153). The mechanism for why NRT should augment effects of varenicline is unclear, but the combination appears to be safe. The combination can be considered in a smoker who does not quit with dual NRT or varenicline. Bupropion in combination with nicotine patch or dual NRT increases quit rates compared to these drugs given alone (154). One trial reported promising results with the combination of varenicline and bupropion, although neuropsychiatric adverse effects were greater in the first 2 weeks compared to varenicline alone (155).

Preloading pharmacotherapy. Many smokers would like to quit but are not prepared to commit to a quit date when seen by a healthcare provider. Starting pharmacotherapy while the smoker is still smoking with the expectation that quitting will be easier at a later date has been studied with the use of nicotine patches and varenicline. The pharmacological basis for this approach is that NRT, by desensitizing nicotinic receptors and reducing withdrawal symptoms between cigarettes, and varenicline, by antagonizing effects of nicotine from cigarettes and also providing relief of withdrawal symptoms, will reduce satisfaction from smoking and decrease the number of cigarettes smoked per day. Preloading trials with nicotine patches have shown mixed benefit on quitting with a weak overall effect, although some trials showed large beneficial effects (156, 157). Varenicline trials have shown benefit with a flexible quit date, and this approach is approved by the FDA (158). The attraction of precessation pharmacotherapy is that the clinician can now approach every patient who smokes, regardless of whether they are prepared to quit at the time of the visit, with a pharmacological intervention along with communication that this will help with quitting smoking in time, just as the clinician would advise every patient with hypertension to take medication to prevent future disease. In this regard, a small trial involving heavy smokers with COPD, who were initially unprepared to quit, prescribed varenicline for as long as they wanted, without a fixed quit date, and by 18 months, most had quit (159).

Gradual reduction. Meta-analysis finds similar quit rates for gradual reduction in cigarettes smoked per day before quitting as compared to abrupt quitting (160). Even in trials that found that abrupt quitting resulted in higher quit rates, many in the gradual reduction group successfully quit. Precessation varenicline with instructions to reduce cigarettes per day by 50% at 4 weeks, 75% at 8 weeks, and completely quit at 12 weeks showed substantial benefit compared to placebo (161).

Targeted pharmacotherapy. Personalized medicine aims to use individual patient characteristics to select the most effective and/or safest medications for their medical problem. With long-term quit rates of 30% or less in most smoking cessation trials, there is interest in individualizing treatment to enhance efficacy. A promising approach involves phenotyping based on an individual rate of nicotine metabolism. Rapid metabolizers of nicotine, on average, smoke more cigarettes and take in more nicotine per day compared to slower metabolizers, presumably to maintain desired levels of nicotine in the body (35). Rapid metabolizers also have more severe withdrawal symptoms when not smoking (97). The nicotine metabolite ratio is a phenotypic marker of the rate of nicotine metabolism, which can be measured in blood, saliva, or urine (162, 163). In a prospective clinical trial, smokers were stratified as slow or normal metabolizers and treated with nicotine patch, varenicline, or placebo. In slow metabolizers, varenicline and nicotine patch were equally effective [odds ratio (OR), 1.13; P = 0.56], but in rapid metabolizers, varenicline was more effective (OR, 2.17; P < 0.001) (164). Side effects were greater for varenicline in slow metabolizers. The results indicate that slow metabolizers can be successfully treated with nicotine patch, at lower cost and with fewer side effects, but normal metabolizers are better treated with varenicline. More research is needed for confirmation.

Cytisine. Cytisine is an alkaloid extracted from the seeds of Cytisus laburnum, commonly known as golden chain or golden rain, a common garden plant in central and southern Europe. Cytisine has been used for smoking cessation in eastern and central European countries for more than 50 years. Cytisine, like varenicline, is a partial agonist at the 42 nAChR. Thus, it has nicotine-like effects, while at the same time it desensitizes and/or blocks the effects of nicotine from tobacco on the 42 nAChR. The recommended treatment regimen involves tapering doses over 25 days, a treatment course that is shorter than the 12 weeks recommended for most other smoking cessation medications, with significant effects relative to placebo (meta-analysis; RR, 1.74; 95% CI, 1.38 to 2.19) (165). The cost of cytisine in Europe is several-fold less than that of other smoking cessation medications. The drug is well tolerated, with the most common side effects being nausea, vomiting, dyspepsia, and dry mouth. Clinical trials of cytisine for FDA-approved use in the United States are underway.

Second-line smoking cessation medications. While not approved by the FDA, nortriptyline and clonidine have demonstrated efficacy in clinical trials for smoking cessation (166, 167). These drugs are used primarily by smoking cessation specialists for patients who have not responded to other treatment. Nortriptyline is a tricyclic antidepressant that blocks neuronal reuptake of norepinephrine, thereby increasing levels of the neurotransmitter in the brain. These actions simulate some of the actions of nicotine on brain neurotransmitters. Clonidine is a central 2 adrenergic receptor agonist that reduces sympathetic activity, resulting in sedation and anxiolysis. The benefit of clonidine is thought to be mediated by its anxiolytic and calming effects and appears to be most useful in smokers with anxiety as a major withdrawal symptom.

Smoking cessation pharmacotherapies in development or that have failed. A number of medications have been considered as possible candidates for smoking cessation (168). While animal and/or small studies in people show effects on nicotine reward or smoking behavior, none of these medications alone has been shown in adequately sized clinical trials to be effective in promoting cessation, including (i) serotonin agonists (lorcaserin), (ii) acetylcholinesterase inhibitors (galantamine and rivastigmine), (iii) drugs affecting GABA receptors (baclofen, topiramate, and gabapentin), and (iv) N-methyl-d-aspartate (NMDA) receptor modulators (cycloserine, memantine, and N-acetylcysteine).

A promising new medication is lorcaserin, a selective 5-hydroxytryptamine 2c receptor agonist. The drug induces food satiety by increasing pro-opiomelanocortin production in the hypothalamus and is FDA approved for weight loss in overweight individuals. Lorcaserin has also been reported to reduce nicotine self-administration in rodents. Because weight gain after stopping smoking is common and sometimes triggers relapse, lorcaserin alone or in combination with other smoking cessation medications has been of interest. In a placebo-controlled trial combining lorcaserin (10 mg twice daily) with varenicline, the combination significantly increased 3-month continuous abstinence (OR, 3.0; 95% CI, 1.5 to 6.2) versus placebo (169), and weight gain was significantly less.

Medications evaluated in clinical trials and judged ineffective for quitting smoking include mecamylamine, serotonin-specific uptake inhibitors, anxiolytics (benzodiazepines and buspirone), MAO inhibitors (moclobemide and selegiline), modafenil, naltrexone, rimonabant, silver acetate, ondansetron, lobeline, nicotine vaccines, and Nicobrevin (quinine, methyl valerate, camphor, and eucalyptus oil).

E-cigarettes. A general discussion of e-cigarettes and other tobacco products for harm reduction, including consideration of benefits versus risks, is presented in the Discussion: What Evidence Is Needed section. Here, we specifically discuss evidence regarding e-cigarettes for smoking cessation. To date, no e-cigarette company has undergone FDA review and approval for use of e-cigarettes as a therapeutic aid for quitting smoking. Less than a handful of randomized controlled trials of e-cigarettes for smoking cessation have been published, and none has been conducted in the United States; hence, most of the evidence to date is observational.

E-cigarettes produce an aerosol from a liquid that typically contains nicotine. The e-cigarette concept is to deliver nicotine by an inhaled route without generating products of tobacco combustion. NRT medications can aid cessation as discussed previously, but most smokers do not find NRT very satisfying, and quit rates are modest. The performance of e-cigarettes as nicotine delivery devices has evolved over time. The earliest devices looked like cigarettes but delivered very low levels of nicotine. The two clinical trials performed with these devices were encouraging, but the quality of evidence was low (170). Recently, a randomized clinical trial with 886 smokers treated in the United Kingdoms National Health Service evaluated a second-generation e-cigarette refillable tanktype device to patients choice of NRT provided free of cost for up to 3 months (171). All received standard behavioral support. At 1 year, the sustained abstinence rate in the e-cigarette group was twofold greater than the NRT group (RR, 1.83; CI, 1.30 to 2.58). Among participants randomized to the e-cigarette arm who quit smoking, 80% were still using e-cigarettes at 1 year; in comparison, among those randomized to the NRT arm, continued use of NRT was 9% for those who quit smoking. While e-cigarettes were found to significantly increase smoking cessation, some have expressed concern about the unknown health risks of long-term e-cigarette use. Adverse effects reported during the trial included greater throat or mouth irritation in the e-cigarette group and more nausea in the NRT group. Overall, adverse effects were minor in severity.

Population-based observational studies report different results depending on the intention of the smokers to quit, how e-cigarettes are used, and where the study was conducted. A four-country comparison found the likelihood of quitting with e-cigarettes to differ by the regulatory environment (172). In Canada and Australia, which have more restrictive e-cigarette regulations, e-cigarette use was associated with a significantly lower likelihood of quitting smoking relative to unassisted quitting (i.e., no medication or e-cigarette use), whereas in the United States and United Kingdom, which have less restrictive e-cigarette regulatory environments, e-cigarette use was associated with increased quitting, consistent with other reports (173, 174). The United Kingdom estimates that, annually, 22,000 to 57,000 long-term cigarette quitters are associated with e-cigarette use, more than quits attributed to NRT or other forms of pharmacotherapy (175). In the United States and United Kingdom, daily use of e-cigarettes is associated with a greater likelihood of quitting smoking than nondaily use (176, 177). In a study from France, e-cigarette use was associated with not only higher smoking cessation rates but also greater relapse to smoking (178).

In conclusion, with respect to e-cigarettes, there is evidence that e-cigarettes can aid smoking cessation. This can occur both in the general population, where e-cigarette use is adopted as an acceptable and safer alternative to cigarette smoking, and in the context of a health service. The risks of long-term e-cigarette use are still unknown, and some medical professionals oppose the use of e-cigarettes for that reason. As discussed in the Discussion: What Evidence Is Needed section, there are also concerns about the use of e-cigarettes by children possibly creating a new epidemic of primary nicotine addiction, leading some U.S. public health professionals to conclude that the potential benefits of e-cigarettes for smoking cessation in adults are outweighed by the risks to youth.

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Current advances in research in treatment and recovery: Nicotine addiction - Science Advances