Treating Nicotine Dependence in Patients with Addictive Disorders Eric Heiligenstein, M.D. Director of Psychiatry University Health Services University of Wisconsin-Madison

Evidence of effective strategies for addressing the disproportionate rate of tobacco use among smokers with co- occurring addictive disorders is lacking The 2008 update of the US Clinical Practice Guidelines for treating tobacco dependence was informed by more than 8700 tobacco control studies

Fewer than 2 dozen randomized controlled trials have focused on smokers with addictive disorders Smokers with mental illness or substance use disorders are among the most likely to be excluded from clinical trials because they are viewed as too complicated

That said, we cannot continue to overlook the epidemic of tobacco dependence that has plagued persons with substance use disorders The following recommendations are based on the best available evidence and national expert consensus panels

Treatment Principles for Nicotine Dependence in MHA All smokers trying to quit should be encouraged to use both counseling and medication 1 –Counseling and medication in combination are more effective than either alone Dose level and duration of drug treatment individualized Many will need –Higher doses of medication –Longer duration of treatment –Combination treatments 1. PHS Clinical Practice Guideline, 2008

Clinical Solutions: Treating Nicotine Dependence in MHA Traditional cessation treatments may be inadequate –Flexibility in setting quit date –Reduced smoking to reach abstinence –Practice quit attempts –Combination and tailored treatments (behavioral & medical) Peters & Hughes, 2009; McFall et al, 2010

Determining Readiness to Proceed Motivation –“Interested” is sufficient –Don’t rule out initiating some type of intervention if not motivated to quit now Stability –Need to be psychiatrically stable-do not need to be in full remission –No major medication changes –No major life changes –No active intoxication/withdrawal; consumer/client in recovery process

Nicotine-Drug Interactions Smoking induces CYP1A2 isoenzyme –Approximately doubles clearance of Antipsychotics: fluphenazine, haloperidol, olanzapine, clozapine, chlorpromazine Antidepressants: amitriptyline, nortriptyline, imipramine, clomipramine, doxepin, fluvoxamine Cessation may produce rapid, significant increase in blood levels Need to monitor for increased side effects

First-line Pharmacotherapies Nicotine patch Nicotine gum Nicotine lozenge Nicotine inhaler Nicotine nasal spray Buproprion SR Varenicline

Reasons for Using NRT It helps the person feel more comfortable (treats nicotine withdrawal syndrome). It is very safe: the person is getting “clean” nicotine instead of “dirty” nicotine with 4000 plus chemicals. 11

NRT Combinations Provide an increase in long-term quit rates (42%) Limited safety concerns Which combinations? – Patch + patch – Patch + oral product – Oral product + oral product

Pre-Quit Use of NRT (Patch) Starting patch 2 weeks before quitting increases the odds of quitting about 4 fold Weakens link between smoking and pleasure Need to switch to low-nicotine cigarettes

NRT Summary NRT increases the odds of quitting about 2 fold Long-term and high-dose NRT (patch) may not produce added benefit beyond regular dose (14-25 mg) and duration (6- 14 weeks) 14

Bupropion SR Atypical antidepressant that acts as a norepinephrine and dopamine reuptake inhibitor Is a nicotinic antagonist that prevents cravings and withdrawal symptoms

Bupropion SR Dose response efficacy in treating smokers Attenuates weight gain Can be prescribed to diverse populations of smokers with expected comparable results Hays JT & Ebbert JO. Mayo Clin Proc 78:1020, 2003

Bupropion SR Summary Bupropion SR increases the odds of quitting about 2 fold Insufficient evidence that adding Bupropion SR to NRT provides an additional long-term benefit Extended therapy with Bupropion SR to prevent relapse after initial cessation has not find evidence of a significant long-term benefit Trials comparing Bupropion SR to Varenicline showed a lower odds of quitting with Bupropion SR Concerns that Bupropion SR may increase suicide risk are currently unproven

Varenicline Varenicline is a partial agonist activating the α4β2 nAChR subtypes to prevent cravings and withdrawal symptoms It also acts as a partial antagonist by occupying receptor sites and blocking nicotine binding leading to a reduction in the satisfaction gained by smoking

Varenicline Summary Varenicline at standard dose increased the chances of successful long-term smoking cessation between two- and threefold Lower dose regimens also conferred benefits for cessation, while reducing the incidence of adverse events More patients quit successfully with Varenicline than with Bupropion Limited evidence suggests that Varenicline may have a role to play in relapse prevention Possible links with serious adverse events, including depressed mood, agitation and suicidal thoughts, have been reported but are so far not substantiated

Behavioral Toxicity and Pharmacotherapy for Nicotine Dependence Bupropion SR and Varenicline have slight risk for suicide or attempts (1.12 OR; 1.17 OR), and suicidal ideation (1.20 OR; 1.43.OR) Untreated nicotine withdrawal can cause adverse behavioral changes, including suicidal ideation All patients should be informed of this potential when treatment is discussed Half of all smokers who don’t stop by middle age will die from a tobacco-related disease Gunnell, et al, 2009

Smoking and Substance Use Disorders The research on the association between smoking and substance use outcomes is limited by a lack of longer follow-ups Most studies have not exceed 18 months and none examined prospectively the impact of smoking on long-term outcomes

Treating Nicotine Dependence in SUD Smoking cessation attempts or concurrent smoking cessation and substance use treatment does not interfere with recovery from substance use disorders Stopping smoking during the first year after substance use treatment predicted better long-term substance use outcomes through 9 years after intake Burling et al, 1996; Cooney et al, 2009; Tsoh et al, 2010

Treating Nicotine Dependence in SUD Standard combinations of behavioral and pharmacological treatment (e.g., weekly counseling plus NRT) have produced disappointing results in alcoholic smokers Bupropion SR not effective in one trial Combination NRT, Naltrexone, Topiramate, and Varenicline hold promise Kalman et al, 2006; Hays et al, 2009; Cooney et al, 2009; Ebbert et al 2009; Johnson et al, 2005; O’Malley et al, 2006

Unique Tobacco Treatment Needs Determine need for involvement from primary care/other health care providers Determine need for more intensive behavioral therapy Address psychotropic medication issues Tailor treatment plan based on –Current symptoms/recovery –Functional status –Current psychotropic medications – Previous quit history –Stage of readiness –Level of impairment/functional status