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

Does Transdermal Nicotine-Induced Withdrawal Suppression Depend on Smokers’ Gender?

Sarah E. Evans, Ph.D.

Seminars in Addiction PsychiatryOctober 6, 2005

• 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.

• 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.

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.

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.

Transdermal nicotine suppresses withdrawal effects:

• Decreased heart rate

• Changes in brain activity

• Weight gain

• Decreased performance

• Urge to smoke, impatient, irritability, difficulty concentrating

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).

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).

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.

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.

• 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.

• 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.

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

Subjective measure: QSU.

My desire to smoke seems overwhelming Strongly

disagreeStrongly agree

Smoking a cigarette wouldnot be pleasant Strongly

disagreeStrongly agree

I need a cigarette nowStronglydisagree

Strongly agree

Subjective measure: Direct Effects VAS.

Nauseous

Not at all Extremely

Dizzy

Not at all Extremely

Lightheaded

Not at all Extremely

Session procedure.

Plasma Nicotine

Subjective

Time in hours

0 1 2 3 4 5 6

PatchAdministration

(0, 7, 21 or 42 mg)

S SSSSSS

B B BB B BB

Characteristic Men (N= 75) Women (N= 53)

Non-white (%) 49 51

Mean age [SD] 35.4 [10.2] 32.3 [10.4]

Mean cigarettes per/day 24.1 [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 (%) 25 25

1Max score = 11

Participant characteristics.

Clear dose-related effects on plasma nicotine.

Women

0

10

20

30

40

50

60

Time in minutes, relative to patch administration

ng/m

l

0 30 90 150 210 270 330

422170

Men

Time in minutes, relative to patch administration 0 30 90 150 210 270 330

Plasma Nicotine

Women

0

10

20

30

40

50

60

Time in minutes, relative to patch administration

ng/m

l

0 30 90 150 210 270 330

422170

422170

Men

Time in minutes, relative to patch administration 0 30 90 150 210 270 330

Plasma Nicotine

Dose-related effects, gender differences on heart rate.

Men

Women

Heart rate

60

65

70

75

80

0 7 21 42Transdermal nicotine dose (mg)

bpm

* *

‡

‡

+ +Men

Women

Men

Women

Heart rate

60

65

70

75

80

0 7 21 42Transdermal nicotine dose (mg)

bpm

* *

‡

‡

+ +

Active patch suppressed Craving and Urges.

Urges to Smoke VAS

0 60 120 180 240 300 360

Craving VAS

0

20

40

60

100

0 60 120 180 240 300 360Time in minutes, relative to patch administration

Sco

re

422170

Time in minutes, relative to patch administration

Urges to Smoke VAS

0 60 120 180 240 300 360

Craving VAS

0

20

40

60

100

0 60 120 180 240 300 360Time in minutes, relative to patch administration

Sco

re

422170

Time in minutes, relative to patch administration

** *

*

Active patch suppressed Craving and Urges.

Urges to Smoke VAS

Men

Women

*

Craving VAS

0

20

40

60

100

Sco

re *

0 7 21 42Transdermal nicotine dose (mg)

0 7 21 42Transdermal nicotine dose (mg)

DSM-IV items suppressed, not dose-related.

Irritability/Frustration/Anger VAS

0

10

20

30

40

100

0 7 21 42Transdermal nicotine dose (mg)

Men

Women

Some patch doses produced aversive effects.

Nauseous VAS

0

5

10

15

20

25

100

Sco

re

*

*

+

Dizzy VAS

Men

Women

*

*

+

7 21 42Transdermal nicotine dose (mg)

0 7 21 42Transdermal nicotine dose (mg)

0

Few gender effects.

QSU Factor 1

0

10

20

30

40

50

60

70

80

90

Transdermal nicotine dose (mg)

Sco

re

7 21 420

+

‡*

QSU Factor 1

0

10

20

30

40

50

60

70

Transdermal nicotine dose (mg)

Sco

re

+

‡*

Men

Women

Men

Women

Men

WomenLightheaded VAS

0

5

10

15

20

25

100

0 7 21 42Transdermal nicotine dose (mg)

Sco

re

*

‡+

*

Lightheaded VAS

0

5

10

15

20

25

0 7 21 42

Sco

re

*

‡+

*

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.

Future research interests.

• Clear dose-related effects for plasma nicotine and heart rate.

• Assessing smoking characteristics of MA users

• CReSSMicro