Smoking Cessation In Vulnerable Populations Dr. Milan Khara MBChB, CCFP, Dip. ABAM Physician Lead, Smoking Cessation Clinic, Vancouver General Hospital Clinical Assistant Professor, Faculty of Medicine, University of British Columbia [email protected] Disclosure Disclosures I have received unrestricted research funding/grants, speakers honoraria, consultation fees or product from the following in the previous 12 months:
Health Canada Interior Health Authority Provincial Health Services Authority Northern Health Authority Pfizer Johnson and Johnson Janssen Ottawa Heart Institute TEACH (Centre for Addiction and Mental Health) Government of Nunavut Context Research Mitigating Potential Bias Content includes ALL smoking cessation medications Peer reviewed, published research Invitation to discuss or challenge content Learning Objectives
To recognize and challenge misconceptions relating to these populations and tobacco To increase confidence regarding tobacco treatment in these populations To become aware of specific caveats relating to tobacco treatment in these populations Smoking Prevalence Trends in Canada (1965-2013) Reid JL et al. Tobacco Use in Canada: Patterns and Trends, 2015 Edition. Waterloo, ON: Propel Centre for Population Health Impact, University of Waterloo. Prevalence of Smoking: Psychiatric and Substance Use Disorders From Kalman, Morissette and George (2005), Am. J. Addict., 14: 106-123
Smoking and Schizophrenia: Patient Perceived Benefits Cigarette smoking in schizophrenia may be reinforcing because it may: Improve psychiatric symptoms (self medication hypotheses) Improve cognitive functioning Reduce medication side effects Mental Health Service culture? Williams et al. Addict Behav. 2004;29:1067-1083; http://www.fotosearch.com/IDX015/558904. Accessed October 19, 2007. Management of Smoking in People with Psychiatric Disorders and SUD Limited efforts to treat this population Providers rarely screen and mostly not trained
Needs to be seen as a co-occurring disorder Integrated, intensive treatment Lasser K, Wesley BJ, Woolhandler S et al. Smoking and Mental Illness JAMA 2000 A Wake Up Call For Psychiatrists: Reasons To Treat Tobacco Use Tobacco use kills half our patients Tobacco use limits full recovery Tobacco use disorder is in the DSM Tobacco use has a negative impact on treatment Callaghan RC; et al: Patterns of tobacco-related mortality among individuals diagnosed with schizophrenia, bipolar disorder, or depression. Journal of Psychiatric Research 2014 Allen MH; et al: Effect of nicotine replacement therapy on agitation in smokers with schizophrenia: a double-blind, randomized, placebo-controlled study. Am.Journal of Psychiatry 2011 Taylor G; et al: Change in mental health after smoking cessation: systematic review and meta-analysis. BMJ 2014 Smoking Cessation and
Psychiatric Disorders Change in mental health after smoking cessation: systematic review and meta-analysis. Taylor G et al BMJ 2014 Changes in mental health after smoking cessation: systematic review Investigate change in mental health after cessation v continuing to smoke Studies that assessed mental health before and after cessation Smoking cessation is associated with REDUCED depression, anxiety and stressIMPROVED positive mood and quality of life...effect equal for those with psychiatric disorders as without Taylor, Gemma et al. Change in mental health after smoking cessation: systematic review and meta-analysis BMJ 2014; 348 :g1151
Smoking and Psychotropic Drug Levels Metabolized by CYP 1A2 Chlorpromazine Haloperidol Clozapine Olanzapine Caffeine Spina & de Leon Basic Clin Pharmacol Toxicol. 2007;100:4-22. Not Metabolized Bupropion Risperidone Quetiapine Ziprasidone Aripiprazole
13 Smoking Cessation and Substance Use Disorders Tobacco-free clients maintain longer periods of sobriety after inpatient treatment for alcohol/drug dependence than tobacco users. Stuyt, 1997 Smoking cessation interventions result in effective drug and alcohol treatmentProchaska, outcomes,2004 including reducing the risk of relapse and increasing long term sobriety. Smoking and tobacco craving are strongly associated with the use of and craving for cocaine and heroin. Epstein, 2010
Cessation Treatment For Patients with PD/SUD All smokers with psychiatric disorders, including substance use disorders, should be offered tobacco dependence treatment and clinicians must overcome their reluctance to treat this population Brief Intervention Individual, group and telephone counselling Pharmacotherapy Fiore MC et al. Treating Tobacco Use and Dependence: 2008 US DHHS Cessation Treatment For Patients with PD/SUD Summary Statement #2 Health care providers should offer counseling and pharmacotherapy treatment to persons who smoke and who have a mental illness and/or addiction to
other substances. GRADE: 1A CAN-ADAPTT http://www.can-adaptt.net/ A Brief Smoking Cessation Intervention ASK: about tobacco use ADVISE: every tobacco user to quit ASSESS:assess readiness to quit ASSIST: self-help material pharmacotherapy counselling/quit lines ARRANGE: follow up or referral Fiore MC et al. Treating Tobacco Use and Dependence: 2008 Update. Clinical Practice Guideline.U.S. Department of Health and Human
Services. Public Health Service. May 2008 NRT Combinations Common to combine patch + gum/lozenge/inhaler/oral spray More efficacious than monotherapy Considered safe (FDA 2013) 1.Mills E.J. et al. Comparison of high-dose and combination NRT, varenicline and buproprion for smoking cessation: a systematic review and multiple treatment analysis. Ann Med 2012 Sep; 44(6): 588-97 2. Cahill K et al. Pharmacological interventions for smoking cessation: an overview and meta-analysis. Cochrane Database Syst. Rev 2013 May 31 FDA Proposed Label Changes NRT use permitted whilst still smoking Use of multiple NRT products allowable Safe to extend treatment beyond label recommendation Food and Drug Administration (2013b). Nicotine replacement therapy labels may change. FDA Consumer Health Information. Silver Spring, MD: U. S. Department of Health and Human Services.
EAGLES Study Design Main Objectives Safety: Characterize the neuropsychiatric safety profiles of varenicline and bupropion vs. placebo in subjects with and without a diagnosis of psychiatric disorder Efficacy: Compare smoking abstinence rates of varenicline and bupropion relative to placebo in subjects with and without a diagnosis of psychiatric disorder Design: Randomized, double-blind, 24week, and NRT and placebo-controlled week, and NRT and placebo-controlled Four Treatment Arms: varenicline, bupropion, nicotine patch (NRT), placebo Primary comparisons: varenicline vs. placebo and bupropion vs. placebo Nicotine replacement therapy (NRT) was used as an active control
Triple dummy design: all 3 active study drugs were blinded 12 weeks of active treatment followed by 12 weeks of non-treatment follow-up All participants received counseling of up to 10 minutes at each clinic visit Targeted Sample Size: 8000 total randomized subjects 2000 per treatment arm, including 1000 with and 1000 without psychiatric disorder Anthanelli et al. Lancet April 2016 EAGLES Study Diagram Primary Efficacy Endpoint: Week 9-12 Continuous Abstinence Rate Begin dosing bupropion and varenicline Secondary Efficacy Endpoint: Week 9-24 Continuous Abstinence Rate Begin 0.5 mg BID Day 4 Begin 1 mg BID Day 8
clinic visits Placebo BL=Baseline Target Quit Date Study Contacts (Week) BL 1 2 Anthanelli et al. Lancet April 2016 3
4 5 6 7 8 Treatment Phase 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Non-treatment Follow-up Key Endpoints Primary Outcome Measure: The percentage of subjects reporting at least one of the following Neuropsychiatric (NPS) adverse events (AEs) during treatment and up to 30 days after last dose:
Anxiety Depression Feeling abnormal Hostility Classified as Severe Agitation Panic Aggression Paranoia Delusions Psychosis Hallucinations Suicidal ideation Homicidal ideation
Suicidal behavior Mania Completed suicide Classified as Moderate or Severe Main Efficacy Measure: CO-confirmed 4-week continuous abstinence rates (CAR) for Weeks 912 Anthanelli et al. Lancet April 2016 Primary Outcome Measure: Neuropsychiatric AE Composite Endpoint Participants with Events n/N, % Varenicline Bupropion
4.0% 90/2006 4.5% 78/2022 3.9% 74/2014 3.7% Cohort AEs reported during treatment and 30 days after last dose. * One additional participant (Psychiatric/NRT group) who reported suicidal ideation was identified after clinical database lock and was not included in the analysis Benowitz N et al. Presented at Society for Research on Nicotine and Tobacco Annual Meeting, Symposium
5B, Chicago Ill, March 3, 2016 Con tin uo us A b stin ence Rate (% ) Efficacy: Continuous Abstinence Rates (CARs) All Treated Subjects (Both Cohorts Pooled) Odds Ratios* CAR Weeks 9-12 Main Efficacy Measure OR (95% CI) 40 35 Varenicline (N=2,037) Bupropion (N=2,034) NRT (N=2,038)
Placebo (N=2,035) 33.5 30 25 Varenicline vs. placebo* 3.61 (3.07-4.24) Bupropion vs. placebo* 2.07 (1.75-2.45) NRT vs. placebo Varenicline vs. NRT
Bupropion vs. NRT Varenicline vs. bupropion 2.15 (1.82-2.54) 1.68 (1.46, 1.93) 0.96 (0.83, 1.11) 1.75 (1.52, 2.01) 23.4 22.6 21.8 20 Odds Ratios* CAR Weeks 9-24 16.2
15.7 OR (95% CI) 15 12.5 9.4 10 Varenicline vs. placebo* 2.74 (2.28-3.30) Bupropion vs. placebo* 1.89 (1.56-2.29)
NRT vs. placebo Varenicline vs. NRT Bupropion vs. NRT Varenicline vs. bupropion 5 0 Weeks 912 Weeks 924 * Primary comparisons West, R et al. Presented at Society for Research on Nicotine and Tobacco Annual Meeting, Symposium 5C, Chicago Ill, March 3, 2016. 1.81 (1.49, 2.19)
1.52 (1.29, 1.78) 1.04 (0.88, 1.24) 1.45 (1.24, 1.70) Authors Limitations Findings may not generalize to smokers with untreated or unstable psychiatric disease Light smokers not included Smokers with imminent suicidality risk were excluded Low power for rare NPS events Benowitz N et al. Presented at Society for Research on Nicotine and Tobacco Annual Meeting, Symposium 5B, Chicago Ill, March 3, 2016 Authors Conclusions Neuropsychiatric Safety The EAGLES trial provides evidence that varenicline and bupropion do not pose a neuropsychiatric safety risk
These drugs can be used safely by smokers without a history of psychiatric disorders and by smokers with stable psychiatric disease Efficacy Varenicline, bupropion, and NRT transdermal patches are more effective than placebo in aiding smoking cessation in patients with and without a history of psychiatric disorder Varenicline is more effective than bupropion and NRT in psychiatric and non-psychiatric cohorts 1. Benowitz N, et al. Symposium 5B, 2.West, R et al. Symposium 5C Presented at Society for Research on Nicotine and Tobacco Annual Meeting,, Chicago Ill, March 3, 2016. Efficacy of Varenicline + NRT Patch v Varenicline alone n=435, multicentre, RCT 12 weeks Rx + 12 weeks f/u CAR Wk 9-12: 55.4% v 40.9% (0R 1.85)
Conclusion: Var/NRT more effective than Var alone. No difference in adverse events (except skin rash) Koegelenberg CF et al. Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial. JAMA. 2014 Jul;312(2):155-61. Electronic Nicotine Delivery Systems (ENDS) Electronic Nicotine Delivery Systems (ENDS) E-cigarettes Are not currently marketed as cessation products at all Are not regulated or approved for sale in Canada Have not been fully evaluated for their efficacy as smoking cessation therapies Have not been fully evaluated for their safety Formaldehyde-releasing molecules can be formed2
1. Sweanor D. Disease Interrupted: Tobacco Reduction and Cessation. Els et al. (Ed.); 2014; 2. Jensen RP, et al. N Engl J Med 2015;372:392-4; Electronic Nicotine Delivery Systems (ENDS) The USPSTF concludes that the current evidence is insufficient to recommend ENDS for tobacco cessation in adults recommends that clinicians direct patients who smoke tobacco to other cessation interventions with established effectiveness and safety estimates show e-cigarettes are 95% less harmful than normal cigarettes, and when supported by a smoking cessation service, help most smokers to quit tobacco altogether. Siu, AL, . Behavioral and Pharmacotherapy Interventions for Tobacco Smoking Cessation in Adults, Including Pregnant Women: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2015 McNeil A et al. E-cigarettes: an evidence update. Public Health England. August 2015 .
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