College of Problems of Drug Dependence, June 14, 2010 Scottsdale, AZ

College of Problems of Drug Dependence,

June 14, 2010 Scottsdale, AZ

Modafinil on Smoking Cessation:

A Clinical Trial

Catherine Martin, G Guenthner, K House, B Beck R Charnigo, T Kelly

Departments of Psychiatry and Behavioral Science

College of Medicine and College of Public Health

University of Kentucky

cmartin@uky.edu

Funded

NIDAR21DA023049P50 DA05312

CephalonStudy Drug and Data

Entry

Scope of the Problem

Smoking is the single most preventable cause of premature death and disease in the U.S. (CDC, 2009)

Modafinil

◘ FDA approved for use in narcolepsy, shift-work sleep disorder and obstructive sleep apnea with excessive sleepiness

◘ Peak plasma concentrations are at 2-3 hours

◘ Half-life is 14-17 hours◘ Usual dose is 200 mg

Modafinil

◘ Mechanism of action is not clear but appears to be related to:▪ GABA and glutamate levels▪ Noradrenergic (including dopaminergic),

serotonergic, histaminergic and adrenergic systems must be intact

▪ Orexin role is controversial ▪ For a review see Kumar 2008

Modafinil as Treatment

◘ Cocaine dependence, Dackis et al., 2005; Andersib et al., 2009

◘ Methamphetamine dependence in a subset of abusers, Heinzerling et al., 2010

◘ Nicotine dependence: with 200 mg saw less decrease in smoking behaviors than controls, Schnoll et al., 2008

Modafinil for smoking cessation: possible mechanism

Impacts on symptoms associated with smoking and possible symptoms of nicotine withdrawal, including:

depression (Price and Taylor, 2005) ADHD (Amiri et al, 2008) weight concerns (Makris et al., 2004); we observed

decreases in VAS hungry in a Phase I clinic trial investigating the combination of modafinil and nicotine (Martin et al., 2006)

Clinical Trial:Inclusion and exclusion

criteriaInclusion: medically stable individuals between 18 and 55 a CO of >10 ppm self-report smoking >10 cigarettes

Exclusion:regular use of drugs of abuse current use of psychiatric medicationspregnancy or unwillingness to use non-steroidal birth control current and regular use of nicotine through routes other than tobacco smoking

Modafinil Dose and Stratification

initially were randomized to 200 mg if < 200 lbs and 300 mg if > 200 pounds

after communication with Dr. Schnoll (via Dr. Childress), subjects were randomized to placebo or 300 mg

stratified by gender and smoking level (low: 10-19 cigarettes/day and high: > 20 cigarettes/day)

for this first analysis, we examined those subjects randomized to 300 mg of modafinil or placebo

Subjects 168 clinical screens 72 received drug 50 maintained on the 8 week active drug

phase•34 females (8 African American; 26 white)•16 males (1 African American; 15 white)

8 randomized to 200 mg 42 randomized to placebo or 300 mg

Baseline

Drug

Week 1: Day 1 (Quit Day); Day 2; Day 7Week 2Week 3Week 4Week 5Week 6Week 7Week 8

Follow-up

Week 9Week 20

Eight-week intervention and follow-up

AssessmentsCigarette Smoking Medical Monitoring•Timeline Followback •Vital Signs•CO •BMI•Cotinine •Weight

Measures of Drug Effects

•Pregnancy Tests

•Medication Side Effects

•Urine Drug Screens

•CPT •Alcohol BAC•VAS •Beck Depression

Inventory•ARCI •CAARS

Nicotine Withdrawal•Fagerstrom•QSU

Toba

cco

Con

sum

ptio

n

0.0

2.5

5.0

7.5

10.0

12.5

15.0

17.5

20.0

Time

-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

Tobacco Consumption Trajectories

PLOT Placebo Modafinil

TTimeline Followback

Modafinil Side Effects p < .05

Hea

rt R

ate

75.0

77.5

80.0

82.5

85.0

87.5

90.0

92.5

95.0

Time

-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

Heart Rate Trajectories

PLOT Placebo Modafinil

Dia

stol

ic B

lood

Pre

ssur

e

70.0

72.5

75.0

77.5

80.0

82.5

85.0

87.5

90.0

Time

-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

Diastolic Blood Pressure Trajectories

PLOT Placebo Modafinil

Syst

olic

Blo

od P

ress

ure

115.0

117.5

120.0

122.5

125.0

127.5

130.0

132.5

135.0

Time

-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

Systolic Blood Pressure Trajectories

PLOT Placebo Modafinil

Con

cent

ratio

n

3

4

5

6

7

8

9

Time

-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

Concentration Trajectories

PLOT Placebo Modafinil

VAS: Concentrate

Summary of Modafinil and Smoking Cessation

Based on self-report decreased smoking decreased appetite increased concentration

No evidence of increased smoking relative to placebo

Side effects were observed, including increased heart rate and blood pressure increased heart rate was clinically significant one time

Modafinil may have a role to play in smoking cessation, especially in special populations