Sex Differences in Nicotine Use

© Alcohol Medical Scholars Program

Reagan R. Wetherill, Ph.D.

Department of Psychiatry, University of Pennsylvania Perelman School of Medicine


I. Introduction

            A. Case Presentation: CC (SLIDE 2)

                        1. Demographics and substance use history

                                    a. 48yo, Caucasian female

                                    b. M.A.-Psychology, Realtor

                                    c. 20 cigarettes/day for 15 years

                                    d. Fagerstrom Test for Nicotine Dependence: 6 (moderate dependence)

                                    e. No other substance use

                        2. Psychiatric Hx (SLIDE 3)

                                    a. Hx of smoking cessation treatments

                                                1’. Buproprion (5 years ago, unsuccessful)

                                                2’. Nicotine Replacement Therapy (gum and patch, unsuccessful)

                                    b. No other significant clinical symptoms

c. Reason for seeking treatment à pneumonia twice, health concerns

            B. Smoking: Leading Cause of Death[1] (SLIDE 4)

                        1. ~500,000 deaths each year in US

                        2. >16 million have smoking-related diseases

                        3. Women ↑↑ severe health consequences

            C. Quitting Smoking is Challenging (SLIDE 5)

                        1. Withdrawal (symptoms the opposite of the initial effects of nicotine)

                        2.Triggers (reminders of smoking like a friend you often smoked with)

                        3.Ambivalence (I love to smoke but --------)

            E. This Lecture Will Cover: (SLIDE 6, 7)

                       1. Definitions

                       2. Course of NUD

           3. Key factors underlying sex differences in NUD

                       4. Treatment options & response

II. Definitions

            A. Cigarettes and cigarette smoke[2] (SLIDE 8)

                        1. Complex mixture of chemicals (carcinogens)

                               a. Fungicides and pesticides

                               b. Cadmium (lung/prostate cancer)

                               c. Benzene (leukemia)

                               d. Formaldehyde (lung cancer)

                        2. Nicotine (stimulant)

B. Brain effects of nicotine[3] (SLIDE 9)

                        1. → Neurotransmitters and hormone release

                        2. Alters cognitive and mood states

                                    a. ↑ Attention, learning and memory

            b. ↑ Pleasure

                                    c. Improve mood

                                    d. ↓ Appetite

C. Diagnostic and Statistical Manual of Mental Disorders (DSM-5) NUD[4] (SLIDE 10)

1. NUD defined as: 2+ problems within same 12 months

2. From among 11 symptoms:

            a. Larger amounts for longer than intended

            b. Persistent desire/Unsuccessful efforts to ↓ or control use

            c. Large amount of time acquiring/using tobacco

            d. Craving (i.e., strong desire/urge) for tobacco

            e. Failure to fulfill life obligations (e.g., missing work)

            f. Giving up important activities (e.g., exercise)

            g. Use in hazardous situations

            h. Continued use despite social/interpersonal problems

            i. Continued use despite physical/psychological problems

            j. Tolerance (e.g., needing to use ↑ to get same effect)

            k. Withdrawal symptoms after stopping (as defined next)

D. Nicotine Withdrawal (opposite of acute drug effects)[5] (SLIDE 11)

1. Physical symptoms (to name a few)

a. Weight gain (~10 lbs)

            b. Headaches

            c. Tingling in hands and feet

            d. Sweating

2. Cognitive/Emotional symptoms (SLIDE 12)

            a. Craving

b. ↑ Irritability

            c. ↑ Anxiety & depression symptoms

            d. ↓ Concentration

E. Sex versus gender (SLIDE 13)

            1. Sex → biological sex

            2. Gender → socially constructed

F. Ovarian hormones *cartoon of idealized cycle (SLIDE 14)

            1. Menstrual cycle

                    a. Idealized cycle → 28 days (varies 21-35 days)

                    b. Differing definitions of phases and phase length

                        1’. Early Follicular or Menstruation 

                        2’. Late Follicular

                        3’. Ovulation

                        4’. Early Luteal

                        5’. Late Luteal

            2. Estrogen (SLIDE 15)

                    a. Responsible for female physical features and reproduction

                    b. 3 types of estrogen, estradiol (E) is the most common and focus here

                    c. E levels are lowest during menstruation

                    d. E increases during follicular phase and peaks just prior to ovulation

                    e. E decreases then has a second peak and decreases during late luteal phase

            3. Progesterone (P) (SLIDE 16)

                    a. Stimulates and regulates several functions

                    b. Maintains pregnancy

                    c. P levels are low during the follicular phase

                    d. P levels increase during luteal phase then dramatically decrease just prior to menstruation

G. Hypothalamic-pituitary adrenal (HPA) axis[3] (SLIDE 17)

            1. Central control and regulatory system of hormones including:

        a. Digestion

                    b. Immune system

                    c. Mood and Emotions

                    d. Energy

            2. Helps person adapt and respond to environment (SLIDE 18)

            3. Cortisol → mobilizes resources for energy

                    a. Sex differences in cortisol levels and stress response

                    b. ♀ report stress as reason for relapse

III. Course of NUD and Sex Differences  (SLIDE 19)

A.    Age of first use[6] (SLIDE 20)

1.      Females → 16.7 years

2.      Males → 15.6 years

            B. Escalation of use and progression to NUD (SLIDE 21)

                        1. Symptoms of NUD within days-weeks of occasional use

                                a. Urge/Desire to smoke upon waking

                                b. Smoking to help stay alert/concentrate

                                c. Urge/Desire to smoke when exposed to cues

                        2. Women escalate use and progress to NUD faster[7]

                                a. Onset of dependence symptoms for women → 21 days

                                b. Onset of dependence symptoms for men → 183 days

            C. Withdrawal and relapse (SLIDE 22)

                        1. Withdrawal symptoms after monitored overnight abstinence[8]

                                    a. ♀ report more severe symptoms of negative mood

                                        1’. 6.5 pt ↑ in tension-anxiety

                                        2’. → 2.9 pt ↑ in tension-anxiety

b. ♀ report greater relief from withdrawal symptoms after smoking

                                        1’. 1.4 pt ↓ in psychological symptoms

                                        2’. → 0.5 pt ↓ in psychological symptoms

                        2. Lapse vs relapse for ♀[9] (SLIDE 23)

                                    a. 21% greater risk of a lapse (e.g., back to smoking for 2 or 3 days)

                                    b. 29% greater risk of relapse  (e.g., return to meeting NUD criteria)

            D.  Women ↑ severe health consequences[10] (SLIDE 24)

                        1. Risks to children before and after birth

                                    a. Smoking during pregnancy causes serious problems:

                                       1’. ↑ Risk of miscarriage

                                       2’. Problems with the placenta (premature separation from womb)

                                       3’. Premature birth

                                       4’. Low birth weight

                                       5’. Risk factor of Sudden Infant Death Syndrome (SIDS)

                                       6’. ↑ Risk of birth defects (e.g., cleft lip or palate)

                        2. Lung cancer: 2x more likely than male smokers (SLIDE 25)

                        3. Coronary heart disease: 25% greater relative risk than male smokers

4. COPD (e.g., emphysema): 2-3x more likely to be hospitalized and die of than male smokers

IV. Key Factors Underlying Sex Differences in NUDs (SLIDE 26)

A. Nicotine action (very complex but briefly discuss)[3] (SLIDE 27)

1. ♀ more sensitive to nicotine effects (ovarian hormones)

                        2. ♀ dopamine (DA) system varies with ovarian hormone levels

                                    a. Progesterone → modulates signaling of nicotinic receptor

                                    b. Estrogen → increases DA release

B. Once NUD is Established[11, 12] (SLIDE 28)

1. ♂ use → maintaining nicotine levels

            a. Able to identify difference in nicotine levels

            b. Increased number of nicotine receptors in reward-regions

2. ♀ use → non-nicotine factors (e.g., smoking cues)

            a. Experience withdrawal relief from smoking denicotinized cigarette

            b. Smoke less when taste and smell cues are blocked

            C. Ovarian Hormones in ♀ (SLIDE 29) (Use figure to illustrate text)

                        1. Late follicular phase à E > P

                                    a. Enhanced responses to cues

                                    b. Smoke more

                        2. Mid-Luteal Phase à P > E

                                    a. Diminished response to cues

                                    b. Lower self-reported craving

            D. Smoking cessation (SLIDE 30)

                        1. Quit rates → decline less pronounced in

                        2. ♀ Less successful

V. Treatment Options for NUD & Response (SLIDE 31)

            A. Overview (SLIDE 32)

                        1. Psychotherapy (cognitive behavioral therapy, relapse prevention)

                        2. FDA-approved medications

B. Psychotherapy

1. Cognitive behavioral therapy (CBT) (SLIDE 33)

                        a. Basic idea: thoughts → feelings and behaviors

b. Teach pts to identify & correct problematic thoughts and behaviors

                        c. Explore positive & negative consequences of actions

                        d. Learn to identify craving quickly to avoid smoking

                                    d. Relapse prevention

                        2.  Relapse Prevention (SLIDE 34)

                                    a. Identify & avoid high-risk situations

                                    b. ↑ Effective non-smoking coping skills (e.g., handling stress)

                                    c. ↑ Pt’s belief that he/she can change

                                    d. Keep smoking “lapses” short; before problems ↑

            C. FDA-approved medications (SLIDE 35)

                        1. Nicotine replacement or NRT (5 types)

                                    a. Nicotine w/o all of the negative effects of smoking (e.g., smoke)

                                    b. Taper amount of nicotine until discontinue

                                    c. NRT better than placebo

                                    d. 70-80% who use NRT relapse w/i 6 mos

                                    e. → poor response

                                    f. Patient CC à not effective

                        2. Bupropion or BUP (Wellbutrin, Zyban) (SLIDE 36)

                                    a. Reduces craving

                                    b. Reduces withdrawal symptoms

                                    c. → similar efficacy to NRT and varenicline

                                    d. → poor response

                                    e. Patient CC → not effective

3. Varenicline or VAR (Chantix) (SLIDE 37)

                                    a. Reduces craving

                                    b. Decreases rewarding/pleasure effects of nicotine

                                    c. No sex differences in Rx response

                                    d. Patient CC → Reduced smoking from 20 to 0 in 9 weeks

                        4. Sex differences in Rx response (SLIDE 38)

                                    a. Head-to-head comparisons of meds in

                                        1’. VAR superior to NRT and BUP

                                        2’. ♀ on VAR 41% more likely to be abstinent at 6-mo f-u

                                    b. Head-to-head comparisons of meds in

                                        1’. No statistically significant differences

                                        2’. ♂ on VAR 16% more likely to be abstinent at 6-mo f-u 

  VII. Conclusions and Future Directions for Sex Differences Research

A.    Conclusions (SLIDE 39)

1. Sex differences in all phases of NUD

                        2. Women have increased vulnerability to and more severe

                                    a. Health-related consequences

                                    b. Lapses and relapses

                        3.Varenicline most effective medication for all smokers

                        4. Several areas for needed inquiry

B. Future directions (SLIDE 40)

1. Appropriate consideration of sex in analyses

2. ↑ collection of hormone levels

                        3. ↑ number of females in research studies

                        4. Evaluate sex differences in psychosocial Rx response

                        5. Consider hormonal milieu when planning Rx




















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