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SEX DIFFERENCES IN NICOTINE USE Reagan Wetherill, Ph.D. Perelman School of Medicine University of Pennsylvania © AMSP 2017 CC: Background • Demographics and substance use Hx: – 48yo, Caucasian female – M.A.-psychology, realtor – 20 cigarettes/day for 15 yrs – Fagerström Test for Nicotine Dependence: 6 – No other substance use © AMSP 2017 2 CC: Psychiatric Hx • Smoking cessation Rx Hx – Bupropion – Nicotine replacement therapy • No other significant clinical symptoms • Reason for Rx pneumonia 2x, health © AMSP 2017 3 Smoking – Leading Cause of Death • ~500,000 deaths/year in U.S. • >16 million w/smoking-related diseases • Women ↑↑ severe health consequences © AMSP 2017 4 Quitting Smoking is Challenging • Withdrawal • Triggers • Ambivalence © AMSP 2017 5 This Lecture Will Cover: • Definitions • Course of nicotine use disorder (NUD) • Factors underlying sex differences in NUD • Treatment options for NUD & response © AMSP 2017 6 This Lecture Will Cover: • Definitions © AMSP 2017 7 Cigarettes and Cigarette Smoke • Complex mix of chemicals – Fungicides and pesticides – Cadmium – Benzene – Formaldehyde • Nicotine → stimulant © AMSP 2017 8 Brain Effects of Nicotine • Neurotransmitters and hormone release • Alters cognitive and mood states – ↑ Attention, learning and memory – ↑ Pleasure – Improves mood – ↓ Appetite © AMSP 2017 9 DSM-5 Nicotine Use Disorder > Amount, longer time smoking Craving ↑ Time obtain/use Use in hazardous situations Failure to fulfill life obligations Tolerance Giving up important activities Withdrawal (WD) Use despite social problems Desire/unable to ↓/control Use despite health problems © AMSP 2017 10 Nicotine Withdrawal • Physical symptoms – Weight gain (~10 lbs) – Headaches – Tingling in hands and feet – Sweating © AMSP 2017 11 Nicotine Withdrawal (2) • Cognitive/emotional symptoms – Craving – ↑ Irritability – ↑ Anxiety & depression symptoms – ↓ Concentration © AMSP 2017 12 Sex Versus Gender • Sex biological sex • Gender socially constructed © AMSP 2017 13 Ovulation Ovarian Hormones Follicular Phase Early 0 Late 7 Luteal Phase 14 Estradiol 21 28 Progesterone © AMSP 2017 14 Estrogen • Female features & reproduction • 3 types of estrogen: estradiol (E) is focus • E levels low during menstruation • E ↑ during follicular phase (FP) • E ↓↑ during luteal phase (LP) then ↓ © AMSP 2017 15 Progesterone (P) • Stimulates and regulates • Maintains pregnancy • P levels low during FP • P ↑ during LP, ↓↓ just before menses © AMSP 2017 16 Hypothalamic-Pituitary-Adrenal Axis • Central control & regulatory system – Digestion – Immune system – Mood and emotions – Energy © AMSP 2017 17 Hypothalamic-Pituitary-Adrenal Axis (2) • Helps adapt and respond • Cortisol mobilizes for energy – Sex differences in cortisol levels/stress response © AMSP 2017 18 This Lecture Will Cover: © AMSP 2017 19 Age of First Use • Females 16.7 yrs • Males 15.6 yrs © AMSP 2017 20 Escalation of Use & Progression to NUD • NUD sxs w/i days-weeks of use – Urge/desire to smoke upon waking – Smoking to help stay alert/concentrate – Urge/desire to smoke when exposed to cues • ♀ Escalate use and progress faster • Onset of dependence for ♀ → 21 days • Onset of dependence for ♂ → 183 days © AMSP 2017 21 Withdrawal (WD) & Relapse • WD sxs after monitored overnight abstinence – ♀ → More severe sxs of negative mood • ♀ → 6.5 pt ↑ in tension-anxiety • ♂ → 2.9 pt ↑ in tension-anxiety – ♀ → Greater relief from WD after smoking • ♀ → 1.4 pt ↓ in psychological sxs • ♂ → 0.5 pt ↓ in psychological sxs © AMSP 2017 22 Lapse vs. Relapse for ♀ • Lapse – 21% greater risk • Relapse – 29% greater risk © AMSP 2017 23 ♀ ↑ Severe Health Problems • Risks to children – Smoking during pregnancy: • ↑ Risk of miscarriage • Placenta problems • Premature birth • Low birth weight • ↑ Risk of birth defects © AMSP 2017 24 ♀ ↑ Severe Health Problems (2) • Lung cancer: 2x more likely than ♂ • Coronary heart disease: 25% > risk than ♂ • Chronic obstructive pulmonary disease: 2-3x more likely hospitalization/death than ♂ © AMSP 2017 25 This Lecture Will Cover: © AMSP 2017 26 Nicotine Action • ♀ More sensitive to nicotine effects • ♀ Dopamine (DA) varies with hormones – P → inhibits the nicotinic receptor – E → ↑ DA release © AMSP 2017 27 Once NUD is Established • ♂ Use → maintain nicotine levels – Able to identify difference in nicotine levels – Increased number of nicotinic receptors • ♀ Use → non-nicotine factors – Experience relief from denicotinized cigarette – Smoke less when taste/smell cues blocked © AMSP 2017 28 Ovarian Hormones in ♀ < Smoking/crav ng Ovulation > Smoking/cravi ng Follicular Phase Early 0 Late 7 Luteal Phase 14 Estradiol 21 28 Progesterone © AMSP 2017 29 Smoking Cessation • Quit rates → decline less pronounced in ♀ • ♀ Less successful © AMSP 2017 30 This Lecture Will Cover: © AMSP 2017 31 Overview of Treatment Options • Psychotherapy • FDA-approved medications – Nicotine Replacement Therapy – Bupropion (Wellbutrin, Zyban) – Varenicline (Chantix) © AMSP 2017 32 Cognitive Behavioral Therapy (CBT) • Basic idea: thoughts → feelings & behaviors • Teach pt. to identify & correct thoughts • Explore +/- consequences • Identify craving quickly to avoid smoking • Relapse prevention © AMSP 2017 33 Relapse Prevention • Identify & avoid high-risk situations • ↑ Effective non-smoking coping skills • Pt’s belief that he/she can change • Keep smoking “lapses” short © AMSP 2017 34 FDA-Approved Medications • Nicotine Replacement or NRT – Nicotine w/o negative effects of smoking – Taper amount of nicotine until discontinue – NRT better than placebo – 70-80% who use NRT relapse w/i 6 mos – ♀ Show poor response – Patient CC not effective © AMSP 2017 35 FDA-Approved Medications (2) • Bupropion (BUP; Wellbutrin, Zyban) – Reduces craving – Reduces withdrawal symptoms – ♂ Show similar efficacy to NRT and varenicline – ♀ Show poor response – Patient CC not effective © AMSP 2017 36 FDA-Approved Medications (3) • Varenicline (VAR; Chantix) – Reduces craving – Decreases rewarding/pleasure effects of nicotine – No sex differences – Patient CC ↓ smoking from 20 to 0 in 9 weeks © AMSP 2017 37 Sex Differences in Rx Response • Head-to-head comparisons of meds in ♀ – VAR superior to NRT and BUP – ♀ on VAR 41% more likely abstinent at 6-mo f-u • Head-to-head comparisons of meds in ♂ – No statistically significant differences – ♂ on VAR 16% more likely abstinent at 6-mo f-u © AMSP 2017 38 Conclusions • Sex differences in all phases of NUD • ♀ have > vulnerability to and more severe: – Health-related consequences – Lapses and relapses • VAR most effective Rx for all smokers • Several areas for needed inquiry © AMSP 2017 39 Future Directions • Consideration of biological sex in analyses • ↑ Collection of hormone levels in research • ↑ Number of women in studies • Evaluate sex differences in psychosocial Rx • Consider hormonal milieu when planning Rx © AMSP 2017 40