does transdermal nicotine-induced withdrawal suppression depend on smokers’ gender? sarah e....
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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