Varenicline for Smoking Cessation in Heavy Drinking Smokers

Smoking rates are elevated among drinkers compared to non-drinkers (Marks et al., 1997).
Moreover, there is some evidence that both smokers who drink alcohol are less successful
quitting smoking (Leeman, Huffman, & O'Malley, 2007). Thus, identifying interventions that
are effective in reducing both smoking and heavy drinking in this population is warranted.
Varenicline, a medication recently approved by the FDA, results in smoking cessation rates
as high as 50%, significantly better than bupropion or placebo. There is preliminary
experimental evidence from both animal and human laboratory research that varenicline
reduces alcohol seeking and consumption (McKee, 2008; Steensland et al., 2007).

The typical dose schedule for varenicline involves a 1 week pretreatment phase prior to
quitting smoking (Gonzales et al., 2006; Jorenby et al., 2006; Nides et al., 2006). However,
greater quit rates have been observed 1 month after using varenicline compared to 1 week.
Therefore, it is possible that extended pretreatment with varenicline may also yield better
cessation outcomes than the standard 1 week lead in period. This may be particularly true if
pretreatment also reduces alcohol consumption prior to the quit attempt.

Thirty regular smokers who drink alcohol heavily will receive open-label varenicline for 5
weeks according to the recommended titration schedule up to 1mg varenicline twice daily,
with treatment starting 1 week before the smoking quit date. Prior to this treatment phase,
subjects will be randomized to receive pretreatment with either placebo or varenicline
(titration up to 1mg) for 3 weeks.

The primary aims of the study are to examine: (a) the efficacy of extended varenicline
pretreatment for smoking cessation, (b) the safety and tolerability of varenicline in heavy
drinking smokers, and (c) the efficacy of varenicline for reducing alcohol consumption in
human participants. Effect size estimates for prolonged smoking abstinence and heavy
drinking will be generated for a NIH grant application.

Inclusion Criteria:

1. Between the ages of 18 and 75.

2. Smoking 5 or more cigarettes per occasion at least 3 times per week.

3. Fewer than 3 months of smoking abstinence in the past year.

4. Motivated to stop smoking.

5. Report exceeding maximum weekly drinking limits every week in the past 4 weeks and
exceeding maximum daily drinking limits on at least 1 occasion in the past 4 weeks.
Weekly heavy drinking is defined as 8 or more drinks for women and 15 or more drinks
for men. Daily heavy drinking is defined as 4 or more drinks for women and 5 or more
drinks for men on an occasion.

Exclusion Criteria:

1. Exhibit current, clinically significant physical disease or abnormality on the basis
of medical history, physical examination, or routine laboratory evaluation

2. Any unexplained elevations in liver enzymes (i.e., transaminases, bilirubin)

3. Clinically significant cardiovascular disease

4. Uncontrolled hypertension

5. Hepatic or renal impairment

6. Severe chronic obstructive pulmonary disease

7. Diabetes mellitus requiring insulin or oral hypoglycemic medications.

8. Baseline systolic blood pressure higher than 150 mm Hg or diastolic blood pressure
higher than 95 mm Hg

9. History of cancer (except treated basal cell or squamous cell carcinoma of the skin).

10. History of clinically significant allergic reactions.

11. Exhibit serious psychiatric illness (i.e., schizophrenia, bipolar disorder, severe
major depression, panic disorder, borderline personality disorder, organic mood or
mental disorders, or substantial suicide or violence risk) by history or
psychological examination)

12. Have a current diagnosis of DSM-IV drug dependence other than nicotine or alcohol.

13. Have a current DSM-IV diagnosis of alcohol dependence that is clinically severe
defined by a) a history of seizures, delirium, or hallucinations during alcohol
withdrawal, b) a Clinical Institute Withdrawal Assessment scale (Sullivan et al.,
1989) score of > 8, c) report drinking to avoid withdrawal symptoms, or d) have had
prior treatment of withdrawal.

14. Use of another investigational drug within 30 days.

15. Intention to donate blood or blood products during the treatment phase of the study.

16. Use of tobacco products other than cigarettes or use of marijuana.

17. Use of nicotine replacement therapy, clonidine, varenicline, bupropion, or
nortriptyline within the month prior to enrollment or intention to use medication
that might interfere with study medication.

18. Body Mass Index (calculated as weight in kilograms divided by the square of height in
meters) less than 15 or greater than 38 or weight less than 45 kg.

19. Females of childbearing potential who are pregnant, nursing, or not practicing
effective contraception (oral, injectable, or implantable contraceptives,
intrauterine device, or barrier method with spermacide).