National Congress on Tobacco or Health October 25, 2007 Andrea King, Ph.D. University of Chicago, Dept. Psychiatry A Translational Approach to Nicotine, Smoking and Weight A Translational Approach to Nicotine, Smoking and Weight Naltrexone, smoking cessation, and cessation-related weight gain

Outline Background –Women, weight, and smoking cessation –Role of endogenous opioid system Preliminary trial with naltrexone (King et al., 2006): –Quit rates –Sex differences –Weight gain, weight concerns Future directions

Smoking & Gender Prevalence of adult smoking: (CDC, 2006) Men: 23% Women: 19% Women may have lower quit rates than men, particularly with traditional treatments (NRT) Why a “gender gap”? For women, greater.. –Withdrawal symptoms –Depression –Lack of social support –Smoking for exteroceptive factors –Concerns about weight gain

Smoking & Weight In general, smokers weigh about 7-11 lbs less than nonsmokers; when they quit, the avg. weight gain is 6-13 lb (1 yr), most weight gain occurs early Why? Nicotine appetite suppressant, increases metabolic rate, and cigarettes take the place of food In cessation, appetite increases, metabolism decreases and/or behavioral changes (i.e. eating for smoking) Weight concerns deter some to attempt cessation, or continue in a cessation attempt These issues may be more salient and more common in women than men

Women and smoking: tobacco advertisement

Pharmacotherapy Targets Pharmacotherapies (FDA approved) can double quit rates. Most do not affect weight gain, or only delay it, except perhaps nicotine gum The endogenous opioid system is connected to brain reward pathways, and may in part mediate nicotine reinforcement Evidence: Nicotine increases endorphin-like chemicals, - Opioid antagonists block nicotine effects Naltrexone: –Orally administered, safe, well-tolerated –Primarily mu-receptor opioid antagonist –FDA-approved in treatment for other addictions (Opioid, Alcohol Dependence)

Naltrexone reduces smoking desire 0 (pill) 2 hr rest cig 1 1 hr rest single cigarette King & Meyer (2000) Pharm Biol Behav 66: VAS rating: Desire to Smoke N=22

Naltrexone in smoking: mixed results Laboratory paradigms  Naltrexone: decrease urges, # cigs smoked, # puffs, pleasure ratings, response to smoking cue  But some studies show negative results Clinical studies Promising results (Covey, O’Malley) No effects of naltrexone (Wong) –Small sample sizes, short-term outcome, different methods and sample characteristics

Opioid system and eating “Eating is one of life’s great pleasures” (USDA, 1995) Endogenous opioids may underlie preference for sweet and high fat foods Lab studies: naltrexone decrease appetite, and food pleasure (obese men) & reduce sweet and high fat preferences (binge-eating women) Sweets and high fat foods are often consumed in greater quantities during smoking cessation If naltrexone alters reinforcement, food preferences or binge eating episodes, it may reduce weight gain during cessation

Clinical Trial of Naltrexone in Smoking Cessation N=110 adult smokers (56 women) enrolled in Chicago area Naltrexone (50 mg) vs. placebo for two months. All received nicotine patch* and individual therapy first one month. Quit rates: 1 and 2 months (end of treatment), and 6 month follow-up Quit status verified by expired air CO (<10 ppm) *[used with patch because high drop out in one trial and some evidence of withdrawal-like symptoms] King et al. (2006) Nicotine & Tobacco Research

Participants: eligibility Regular smoker (15+ cigs/day) for 2+ years Desire to quit (score 6+ on ladder) No past adverse reaction to nicotine patch or naltrexone No major medical, psychiatric disorders Alcohol or drug recovery at least 1 year + Willing to attend study visits, follow-up, and be randomized

Demographics Placebo (n=58) Naltrexone (n=52) Age (years) Education (years) Race (% Caucasian) 35 (60%)37 (71%) BMI (kg/m 2 )

Smoking and Drinking Characteristics Placebo (n=58) Naltrexone (n=52) Cigarettes / Day Smoke Duration (yrs) Fagerström (FTND) * Other smokers in household 17 (30%) 19 (37%)

Quit Rate Success

Weight Change from Baseline *** med, p<.001

**=p<0.005*=p<0.01 Weight Concerns ***=p<0.001 Body Dissatisfaction Cognitive Restraint Smoking-Specific Weight Concerns Desire for Thinness

* * * * Dose ranging study: O’Malley et al., 2006, Arch Int Med Naltrexone weight gain lowest in 25 mg and 50 mg groups

Withdrawal (negative affect) GEE: Sex, p<.05, Time p=.08, Med p=.10 Sad mood, irritability, concentration difficulty

Smoking Urges GEE: Sex, Time, Med, ps<.05; Sex x Med p=.07,

Conclusions Naltrexone may show promise for smoking cessation for some smokers, but more data is needed Sex differences in response needs to be replicated in a priori study Mechanisms of sex differences lower response in the nicotine patch only condition relief of withdrawal, or craving higher drug levels hormonal factors salience of less weight gain

Future Directions

Chicago STOP Smoking Research Project Enroll N=324 smokers Naltrexone vs. placebo for 3 months All receive nicotine patch and individual therapy Quit rates assessed through 12- month follow-up Weight taken at each visit Detailed weekly reports: appetite, food consumption, and eating hedonics O’Malley (Yale University): examining 25 mg naltrexone in weight-concerned smokers

Clinical Addictions Research Laboratory (CARL) Staff

Acknowledgements Harriet de Wit, Ph.D. Patrick McNamara, B.S. Raymond Niaura, Ph.D. Megan Conrad, B.S. Dorothy Hatsukami, Ph.D. Roslynn Riley, B.S. Stephanie O’Malley, Ph.D.Mihai Raicu, M.S. Henry Kranzler, M.D.Rachel Torello, M.A. Michelle Wasserman, Ph.D.Lisa Sanchéz-Johnsen, Stephanie Canada, M.A. Ph.D. K08-AA00276, R01-DA016834, and NCI P30-CA Patches provided by GlaxoSmithKline Consumer Healthcare Naltrexone/placebo acquired by Mallinckrodt, Inc.