Treatment Development and Delivery Program
Despite the fact that cigarette smoking continues to be the greatest preventable cause of morbidity and mortality, there are currently only three FDA-approved medications for nicotine dependence: nicotine replacement therapy (NRT; transdermal nicotine (TN), nasal spray, gum, lozenge), bupropion, and varenicline. Although these treatments are effective for some smokers, nearly 75% relapse within a year. There is a clear need to identify novel treatment approaches to help more smokers quit.
The Treatment Development and Delivery Program within CIRNA is guided by the following goals: (1) to develop and evaluate novel behavioral and pharmacological interventions for nicotine dependence; (2) to develop novel methods to improve the efficacy and effectiveness of FDA-approved treatment for nicotine dependence; (3) to expand the use of treatments for nicotine dependence to under-served populations.
Project Descriptions and Grants
Pharmacogenetics of Nicotine Addiction Treatment (National Institute on Drug Abuse; 2005-2015):
Personalizing the selection of medications to treat nicotine dependence based on genetically-informed information about an individual smoker may help to increase overall response rates to treatments for nicotine dependence. Over the past decade, we have characterized genetic variants altering nicotine pharmacokinetics as well as pharmacodynamic genetic variants influencing response to pharmacotherapies for smoking cessation treatment. We have shown that the CYP2A6 enzyme is critical in the metabolic inactivation of nicotine, and inherited variation in nicotine clearance influences smoking behavior and cessation. With a vision toward translation of our research to practice, we have characterized a genetically-informed biomarker of CYP2A6 activity, specifically the nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine), which reflects both genetic and environmental influences on CYP2A6 activity and nicotine clearance. The NMR is measured noninvasively in smokers with established reliability, stability, analytic validity, and efficacy as a predictor of therapeutic response in multiple independent (retrospective) clinical trials. In this study, conducted across 4 clinical sites (3 in the United States and 1 in Canada), 1246 smokers characterized as slow or fast metabolizers of nicotine were randomized to: placebo patch and placebo pill, nicotine patch and placebo pill, or varenicline and placebo patch. We selected varenicline as the non-nicotine medication that we hypothesized to be efficacious for fast metabolizers since it was (and remains) the most efficacious medication for nicotine dependence, even compared to bupropion. Our results (Lerman et al., 2015; Lancet Respiratory Medicine) showed that at both the end of treatment and at a 6-month follow-up, fast metabolizers of nicotine had significantly higher quit rates if treated with varenicline vs. nicotine patch and that slow metabolizers of nicotine exhibited similar quit rates across the two active treatments, but reported a significant increase in side effects if treated with varenicline. This study provides critical evidence that validates the NMR as a genetically-informed diagnostic tool which clinicians can use to optimize treatment decisions for their patients who wish to quit smoking.
An Effectiveness Trial of Maintenance Therapy for Nicotine Dependence (National Institute on Drug Abuse; 2009-2015):
The FDA adopted labeling for nicotine patches to allow use beyond standard 8-weeks based, in part, on data showing increased efficacy from 24-weeks of treatment. Few studies have examined whether use of nicotine patches beyond 24-weeks provides additional therapeutic benefit. This trial (N = 525) compared 8- (standard), 24- (extended), and 52- (maintenance) weeks of nicotine patch treatment for promoting tobacco abstinence (Schnoll et al., 2015; JAMA Internal Medicine). In a multivariate model, at 24-weeks, participants in extended and maintenance treatments reported significantly greater abstinence rates, vs. participants who were in standard treatment, had a longer duration until relapse, reported smoking fewer cigarettes/day if not abstinent, and reported more abstinent days. At 52-weeks, participants in maintenance treatment did not report significantly greater abstinence rates, vs. participants who were on standard and extended treatment. There were no significant effects of treatment duration on side effects but maintenance treatment participants reported lower nicotine patch adherence, vs. standard and extended treatment participants. These results support the safety of long-term use of nicotine patch treatment, though they do not support the efficacy beyond 24 weeks of treatment in a broad group of smokers.
A Placebo-Controlled Trial of Varenicline for Smoking among those with HIV/AIDS (National Institute on Drug Abuse; 2012-2017):
Among people diagnosed with HIV/AIDS, the widespread use of antiretroviral therapy has greatly improved survival rates and changed the leading causes of death, from AIDS-related diseases (e.g., non-Hodgkin’s lymphoma, Kaposi sarcoma), to cardiovascular disease and lung cancer. As such, addressing modifiable risk factors for disease mortality among those with HIV/AIDS, including tobacco use, has become a critical priority. To date, remarkably few smoking cessation clinical trials have been conducted with those with HIV/AIDS and no study has investigated the safety and efficacy of varenicline for treating nicotine dependence in this sub-group of smokers. In collaboration with the PENN health system and Philadelphia community organization, we are conducting a randomized, double-blind, placebo-controlled trial of varenicline with smokers with HIV/AIDS (N = 310). The trial results may support the use of varenicline for the treatment of nicotine dependence among those with HIV/AIDS, thereby reducing tobacco-related morbidity and mortality in this under-served population.
Extended Duration Varenicline for Smoking among Cancer Patients: A Clinical Trial (National Cancer Institute; 2012-1017):
Upwards of 33-50% of cancer patients who smoked prior to diagnosis continue to smoke following diagnosis and treatment. Continued smoking by cancer patients reduces survival time, medical treatment efficacy, and quality of life (QOL). To date, studies of smoking cessation interventions for cancer patients have failed to yield significant treatment effects. As such, currently, there is no evidence-based treatment model for addressing tobacco use in this population. With medical advances in cancer care yielding a growing constituency of cancer survivors - close to 12 million today - addressing nicotine dependence in this population is a priority. A recent NCI meeting called for the evaluation of novel treatments for nicotine dependence among cancer patients which address the unique barriers to cessation evident in this population, including: a high level of nicotine dependence, high levels of psychological distress and cognitive impairment, and a protracted relapse timeline. Thus, using a double-blind placebo-controlled design with 374 cancer patients, this study will compare standard varenicline treatment (12-weeks active + 12-weeks placebo) to extended varenicline treatment (24-weeks active) for increasing cessation rates. This study may help guide efforts to implement effective smoking cessation programs for cancer patients and help determine the benefits of extended treatment duration for nicotine dependence more broadly.
Behavioral Activation and Varenicline for Smoking Cessation in Depressed Smokers (National Cancer Institute; 2014-2019):
The prevalence of cigarette smoking among adults with current mental health disorders is 2-3 times higher than the rate among the U.S. population (40-60% vs. 19%). Up to 43% of persons with major depressive disorder (MDD) are smokers, and they are more likely to smoke heavily, perceive smoking as more pleasurable than many other traditionally rewarding activities, show greater tobacco dependence, and suffer more severe withdrawal (including cigarette craving) than smokers without MDD. Little is known about treatment strategies that optimize cessation outcomes for smokers with current or recent MDD, largely because almost all randomized clinical trials (RCTs) excluded these smokers. While varenicline is promising for this subgroup of smokers, data are limited on its efficacy and safety for smokers with current or recent MDD. Further, standard behavioral smoking cessation interventions has had limited long-term impact on smoking. A treatment that helps overcome limited efficacy of standard behavioral counseling is behavioral activation therapy (BA), which focuses on increasing engagement in rewarding activities, a problem for smokers with MDD who find smoking especially rewarding. Thus, the primary aim of this 2x2 RCT is to enroll and randomize 630 daily smokers with current or recent (past year) MDD to receive 12 weeks of either: 1) Standard behavioral cessation treatment + placebo; 2) BA + placebo; 3) Standard behavioral cessation treatment + varenicline; or 4) BA + varenicline. The results of this trial may help identify a unique approach to using combination behavioral therapy and pharmacotherapy to address nicotine dependence in an under-served population of smokers.
Placebo-controlled Trial of Bupropion for Smoking Cessation in Pregnant Women (National Cancer Institute; 2014-2019):
Cigarette smoking during pregnancy is one of the most important modifiable causes of poor pregnancy outcomes in the US and doubles the risk of delivering a low-birth-weight neonate which exponentially increases infant morbidity and mortality. Ten percent of pregnant women continue to smoke, with higher rates among women in lower socioeconomic groups and in those with depression. Behavioral treatments for smoking during pregnancy are only modestly effective in producing cigarette abstinence and first-line treatments for smoking cessation (effective in the general population of smokers), have not been adequately tested for their safety and efficacy for smoking cessation during pregnancy. Bupropion, a first-line treatment for smoking cessation in non-pregnant adults, may be a good option for smoking cessation in pregnant women because: 1) pregnancy increases nicotine metabolism, which is associated with a poorer response to nicotine replacement therapy but does not influence response to bupropion; 2) bupropion is currently used by practitioners to treat depression in pregnant women; and 3) pregnancy increases the activity of the CYP2B6 enzyme, thereby potentially increasing bupropion metabolism, which by increasing the concentration of the metabolite hydroxybupropion can produce better smoking cessation outcomes. Moreover, data indicate that bupropion can be used safely after the first trimester of pregnancy. Thus, using a double-blind clinical trial design, we are testing bupropion (vs. placebo) for treating nicotine abstinence among 360 pregnant smokers. Safety and birth outcomes (e.g., birth weight) are also being assessed. This will be the first adequately powered clinical trial of the efficacy and safety of bupropion for nicotine dependence in pregnant smokers. The results of the trial could translate into important advances in the clinical care of pregnant smokers (for whom there is currently no efficacious smoking cessation treatment), thereby reducing the rate of poor pregnancy outcomes in the United States.
Repurposing Cholinesterase Inhibitors for Smoking Cessation (National Institute on Drug Abuse; 2013-2018):
Despite advances in treatment for nicotine dependence, most smokers relapse within the first week of abstinence. Thus, there is a need to screen new medications to aid smokers during this critical period. Three lines of research suggest that pharmacotherapies that modulate endogenous acetylcholine (ACh) levels may be effective treatments for nicotine dependence: (1) nicotine withdrawal is associated with cognitive deficits, which in turn predict relapse to smoking; (2) variation in genes that modulate ACh has been associated with smoking cessation and nicotine dependence; and (3) acetylcholinesterase inhibitors (ACHEIs), which enhance ACh, improve cognitive function in Alzheimer’s disease. We recently demonstrated that the ACHEI, donepezil, improved working memory and was well tolerated among non-treatment seeking smokers. The proposed proof-of-concept study takes the next step by evaluating the effects of the ACHEI, galantamine (GAL), on short-term abstinence among treatment-seeking smokers. In this double-blind, randomized phase II study, 80 smokers (40 GAL, 40 placebo (PLA)) will undergo a 7-day quit attempt following a 2-week drug run-up. Because most smokers relapse in the first week following a quit attempt, this short-term cessation model is predictive of long-term relapse. Thus, the primary outcome is the number of days abstinent out of seven. Secondary outcomes include: smoking rate during the run-up and abstinence period, cognitive performance, medication adherence, side effects, and withdrawal symptoms. The results of this project may lead to the availability of a potential treatment alternative that can help more smokers quit.
Ashare RL, Schmidt HD. Optimizing treatments for nicotine dependence by increasing cognitive performance during withdrawal. Expert Opin Drug Discov. 2014;9(6):579-94. PMCID: PMC4287224.
Ashare RL, Falcone M, Lerman C. Cognitive function during nicotine withdrawal: Implications for nicotine dependence treatment. Neuropharmacology. 2014;76 Pt B:581-91. PMCID: PMC3779499.
Lerman C, Schnoll RA, Hawk LW, Jr., Cinciripini P, George TP, Wileyto EP, et al. Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, double-blind placebo-controlled trial. Lancet Respir Med. 2015;3(2):131-8. PMCID: PMC4480925.
Schnoll RA, Goelz PM, Veluz-Wilkins A, Blazekovic S, Powers L, Leone FT, Gariti P, Wileyto EP, Hitsman B. Long-term nicotine replacement therapy: A randomized clinical trial. JAMA Internal Medicine. 2015:175:504-511. PMCID: PMC4410859.
Kaufmann A, Hitsman B, Goelz PM, Veluz-Wilkins A, Blazekovic S, Powers L, Leone FT, Gariti P, Tyndale RF, Schnoll RA. Rate of Nicotine metabolism and smoking cessation outcomes in a community-based sample of treatment-seeking smokers. Addictive Behaviors. In Press.
Mrazek DA, Lerman C. Facilitating clinical implementation of pharmacogenomics. Journal of the American Medical Association, 2011; 306(3):304-305.
Schnoll RA, Patterson F, Wileyto EP, Heitjan D, Shields AE, Asch D, Lerman C. Effectiveness of extended duration transdermal nicotine therapy: a randomized trial. Annals of Internal Medicine, 2010; 152(3):144-151.
Lerman C, Jepson C, Wileyto EP, Patterson F, Schnoll R, Mroziewicz M, Benowitz N, Tyndale RF. Genetic variation in nicotine metabolism predicts the efficacy of extended duration transdermal nicotine therapy. Clinical Pharmacology and Therapeutics, 2010; 87(5):553-557.
Tyndale RF, Zhu AZX, George TP, Cinciripini P, Hawk LW, Schnoll RA, Swan GE, Benowitz NL, Heitjan DF, Lerman C. Lack of associations of CHRNA5-A3-B4 genetic variants with smoking cessation treatment outcomes in Caucasian smokers despite associations with baseline smoking. PLOS One, 2015; 10(5):e0128109.
Perkins KA, Lerman C. Early human screening of medications to treat drug addiction: novel paradigms and the relevance of pharmacogenetics. Clinical Pharmacology and Therapeutics, 2011; 89(3):460-463.
Perkins KA, Mercincavage M, Fonte C, Lerman C. Varenicline’s effects on acute smoking behavior and reward and their association with subsequent abstinence. Psychopharmacology, 2010; 210(1):45-51.
Volpp K, Troxel A, Pauly MV, Glick HA, Puig A, Asch DA, Galvin R, Zhu J, Wan F, DeGuzman J, Corbett E, Weiner J, Audrain-McGovern J. A randomized controlled trial of financial incentives for smoking cessation. New England Journal of Medicine. 2009; 360 (7): 699-709.
Audrain-McGovern J, Wileyto EP, Ashare R, & Strasser A. Affective regulation and reward processing in depression-prone smokers. Biological Psychiatry. 2014; 76(9): 689-697.
Halpern SD, French B, Small DS, Saulsgiver K, Harhay MO, Audrain-McGovernJ, Loewenstein G, Brennan TA, Asch DA, & Volpp KG. A randomized trial of four financial incentive programs for smoking cessation. New England Journal of Medicine. 2015; 372(22): 2108-2117.