College of Problems of Drug Dependence, June 14, 2010 Scottsdale, AZ

1. Modafinil on Smoking Cessation: A Clinical Trial College of Problems of Drug Dependence, June 14, 2010 Scottsdale, AZ Catherine Martin, G Guenthner, K House, B Beck R Charnigo, T Kelly Departments of Psychiatry and Behavioral Science College of Medicine and College of Public Health University of Kentucky cmartin@uky.edu

2. Funded NIDA R21DA023049 P50 DA05312 Cephalon Study Drug and Data Entry

3. Scope of the Problem Smoking is the single most preventable cause of premature death and disease in the U.S. (CDC, 2009)

4. Modafinil • FDA approved for use in narcolepsy, shift-work sleep disorder and obstructive sleep apnea with excessive sleepiness • Peak plasma concentrations are at 2-3 hours • Half-life is 14-17 hours • Usual dose is 200 mg

5. Modafinil • Mechanism of action is not clear but appears to be related to: •  GABA and  glutamate levels • Noradrenergic (including dopaminergic), serotonergic, histaminergic and adrenergic systems must be intact • Orexin role is controversial • For a review see Kumar 2008

6. Modafinil as Treatment • Cocaine dependence, Dackis et al., 2005; Andersib et al., 2009 • Methamphetamine dependence in a subset of abusers, Heinzerling et al., 2010 • Nicotine dependence: with 200 mg saw less decrease in smoking behaviors than controls, Schnoll et al., 2008

7. Modafinil for smoking cessation: possible mechanism Impacts on symptoms associated with smoking and possible symptoms ofnicotine withdrawal, including: • depression (Price and Taylor, 2005) • ADHD (Amiri et al, 2008) • weight concerns (Makris et al., 2004); we observed decreases in VAS hungry in a Phase I clinic trial investigating the combination of modafinil and nicotine (Martin et al., 2006)

8. Clinical Trial:Inclusion and exclusion criteria Inclusion: • medically stable individuals between 18 and 55 • a CO of >10 ppm • self-report smoking >10 cigarettes Exclusion: • regular use of drugs of abuse • current use of psychiatric medications • pregnancy or unwillingness to use non-steroidal birth control • current and regular use of nicotine through routes other than tobacco smoking

9. Modafinil Dose and Stratification • initially were randomized to 200 mg if < 200 lbs and 300 mg if > 200 pounds • after communication with Dr. Schnoll (via Dr. Childress), subjects were randomized to placebo or 300 mg • stratified by gender and smoking level (low: 10-19 cigarettes/day and high: > 20 cigarettes/day) • for this first analysis, we examined those subjects randomized to 300 mg of modafinil or placebo

10. Subjects • 168 clinical screens • 72 received drug • 50 maintained on the 8 week active drug phase • 34 females (8 African American; 26 white) • 16 males (1 African American; 15 white) • 8 randomized to 200 mg • 42 randomized to placebo or 300 mg

11. Eight-week intervention and follow-up

12. Assessments

13. TTimelineFollowback

14. Modafinil Side Effects p < .05

17. VAS: Concentrate

18. Summary of Modafinil and Smoking Cessation • Based on self-report • decreased smoking • decreased appetite • increased concentration • No evidence of increased smoking relative to placebo • Side effects were observed, including increased heart rate and blood pressure • increased heart rate was clinically significant one time • Modafinil may have a role to play in smoking cessation, especially in special populations