1. Does Transdermal Nicotine-Induced Withdrawal Suppression Depend on Smokers’ Gender? Sarah E. Evans, Ph.D. Seminars in Addiction Psychiatry October 6, 2005

2. NIH: - R01 DA11082 - T32 DA 07027 Research staff: - Cynthia Sams, R.N., Melodie Anderson, R.N. - Robert James Collins, Kasha White, Jenny Gray, Tom Campbell, Amy Opilla and Tamika Gilreath - Lynn Anderson, Melissa Blank, Alison Breland and Annie Kleykamp Michael Weaver, M.D. Randy James, Ph.D. Thomas Eissenberg, Ph.D. Acknowledgments.

3. Smoking kills >400,000 Americans/year. Quitting smoking reduces risk of tobacco-related death and disease. Several medications, including nicotine replacement (e.g., transdermal nicotine or TN) help smokers quit. Medication (including TN) efficacy thought to be based on suppression of nicotine/tobacco withdrawal during abstinence. Even with medication, lower quit rates for women are observed. Lower quit rates for women may reflect less medication-induced withdrawal suppression. Introductory topics include: Clinical evidence for nicotine reinforcement and withdrawal, NRT’s efficacy and withdrawal suppression, gender differences in response to NRT. Overview.

4. Clinical evidence for reinforcement and withdrawal. Nicotine is a reinforcer in humans - Robust self-administration of pure nicotine and tobacco- delivered nicotine. After discontinuation of chronic tobacco-delivered nicotine: - Signs such as reduced heart rate, increased caloric intake and weight, change in EEG frequency - Behavioral performance decrements such as decreased concentration, impaired attention - Symptoms such as urge to smoke, impatient, irritability, difficulty concentrating Withdrawal syndrome can reduce the likelihood of a quit attempt and decrease chances of long-term cessation.

5. Pharmacologically Pure Nicotine is Efficacious. Nicotine replacement therapy (NRT): Gum, transdermal, lozenge, inhaler, and nasal spray - Approximately doubles long-term cessation rates - Thought to work, at least in part, via withdrawal suppression (i.e., reduced urge to smoke, impatient, irritability, difficulty concentrating). NRT-induced withdrawal suppression has been demonstrated with every formulation.

6. Transdermal nicotine suppresses withdrawal effects: Decreased heart rate Changes in brain activity Weight gain Decreased performance Urge to smoke, impatient, irritability, difficulty concentrating

7. Gender differences in response to nicotine & NRT. Gender differences in response to NRT: laboratory evaluations - pain sensitivity - self-administration Gender differences in response to NRT: clinical trials - Many trials report lower cessation rates for women (Bjornson et al., 1995; Wetter et al., 1995;TNSG, 1991) - No trials have shown lower cessation rates for men. Gender differences NRT-induced withdrawal suppression? - Greater impatience, hunger for women (Hatsukami et al., 1995). - Craving suppressed for men only (Killen et al., 1990). - Better sleep efficiency for men (Wetter et al., 1999).

8. Detecting gender differences: design issues. Power (N = 34, Wetter et al., 1999). Dose (no placebo dose, Hatsukami et al., 1995; single dose, Wetter et al., 1999; Killen et al., 1990). Outcome measures (symptom checklists instead of standardized measures, Hatsukami et al., 1995).

9. Purpose. To determine if TN-induced withdrawal suppression is influenced by smokers’ gender in a large sample of men and women, across a variety of TN doses, and using standardized measures of tobacco/nicotine withdrawal.

10. Method. Within subject (crossover) design; N = 128. Four, double-blind, Latin square-ordered, 6.5-hour sessions. The sessions corresponded to four TN doses (0, 7, 21, 42 mg). 8+ hours pre-session abstinence, verified by CO < 10ppm. Plasma nicotine, heart rate, and subjective withdrawal assessed regularly in each session. Women participants scheduled only during days 2 – 16 of their menstrual cycle.

11. Inclusion: - Smokers of any “king size” or “100s” cigarettes. - Between 18-55 years of age. - Afternoon expired air carbon monoxide (CO) >15 ppm. - Reported smoking > 15 cigs/day for past 2 years. Exclusion: - Pregnant or breast feeding. - History of chronic psychiatric or health problems. - Score > 17 on BDI (abstinence exacerbates depression) Inclusion/exclusion criteria.

12. Physiological effects - Plasma nicotine level assessed each hour. - Heart rate recorded continuously (30 minute bins). Subjective effects assessed each hour: - Hughes-Hatsukami (1986) withdrawal symptom VAS. - Tiffany-Drobes (1991) Questionnaire of Smoking Urges (QSU). - Direct effects visual analog scale (VAS). Outcome measures.

13. Subjective measure: Hughes-Hatsukami VAS. URGES to smoke Not at all Extremely Anxious Not at all Extremely CRAVING a cigarette/nicotine Not at all Extremely

14. Subjective measure: QSU. My desire to smoke seems overwhelming Strongly disagree Strongly agree Smoking a cigarette would not be pleasant Strongly disagree Strongly agree I need a cigarette now Strongly disagree Strongly agree

15. Subjective measure: Direct Effects VAS. Nauseous Not at all Extremely Dizzy Not at all Extremely Lightheaded Not at all Extremely

16. Session procedure. Plasma Nicotine Subjective Time in hours 0 1 2 3 456 Patch Administration (0, 7, 21 or 42 mg) S SSS SS S B BB BBBB

17. CharacteristicMen (N= 75)Women (N= 53) Non-white (%)4951 Mean age [SD]35.4 [10.2]32.3 [10.4] Mean cigarettes per/day24.1 [10.0] 21.3 [5.8] Duration cigarette use 13.0 [9.3] 9.1 [7.4] * Mean Fagerström NTQ [SD] 1 5.8 [2.2]5.1 [2.0] Mean quit attempts [SD]4.0 [7.4]2.6 [2.5] Previous patch use (%) 2525 1 Max score = 11 Participant characteristics.

18. Clear dose-related effects on plasma nicotine.

19. Dose-related effects, gender differences on heart rate.

20. Active patch suppressed Craving and Urges. Urges to Smoke VAS 060120180240300360 Craving VAS 0 20 40 60 100 060120180240300360 Time in minutes, relative to patch administration Score 42 21 7 0 Time in minutes, relative to patch administration Urges to Smoke VAS 060120180240300360 Craving VAS 0 20 40 60 100 060120180240300360 Time in minutes, relative to patch administration Score 42 21 7 0 Time in minutes, relative to patch administration * * * *

21. Active patch suppressed Craving and Urges. Urges to Smoke VAS Men Women * Craving VAS 0 20 40 60 100 Score * 0 72142 Transdermal nicotine dose (mg) 072142 Transdermal nicotine dose (mg)

22. DSM-IV items suppressed, not dose-related. Irritability/Frustration/Anger VAS 0 10 20 30 40 100 0 72142 Transdermal nicotine dose (mg) Men Women

23. Some patch doses produced aversive effects. Nauseous VAS 0 5 10 15 20 25 100 Score * * + Dizzy VAS Men Women * * + 72142 Transdermal nicotine dose (mg) 0 72142 Transdermal nicotine dose (mg) 0

24. Few gender effects. QSU Factor 1 0 10 20 30 40 50 60 70 80 90 Transdermal nicotine dose (mg) Score 7 21 420 + ‡ * QSU Factor 1 0 10 20 30 40 50 60 70 Transdermal nicotine dose (mg) Score + ‡ * Men Women Men Women Men Women Lightheaded VAS 0 5 10 15 20 25 100 0 7 2142 Transdermal nicotine dose (mg) Score * ‡ + * Lightheaded VAS 0 5 10 15 20 25 0 7 2142 Score * ‡ + *

25. Summary Clear dose-related effects for plasma nicotine and heart rate. Clear dose-related suppression for Craving and Urges to Smoke. Many DSM-IV nicotine/tobacco withdrawal symptoms were suppressed by active TN, but this suppression was not dose- related (e.g. Irritability/Frustration/Anger, Anxious, Difficulty Concentrating). Highest TN dose (42 mg) produced reliable, aversive effects such as nausea, lightheadedness and dizziness. Very few outcome measures were influenced by smokers’ gender. Limitations include non-treatment seeking sample and acute, laboratory-based design.

26. Future research interests. Clear dose-related effects for plasma nicotine and heart rate. Assessing smoking characteristics of MA users CReSSMicro