Naltrexone and Varenicline: Weight Gain and Tolerability in Cigarette Smokers

Varenicline, a medication recently approved by the FDA, results in smoking cessation rates as
high as 50%, significantly better than bupropion or placebo. However, varenicline does not
reduce post-cessation weight gain, so weight concerns may keep some smokers from taking
advantage of this effective therapy.

A potential solution would be to combine varenicline with an agent that reduces weight gain.
In this regard, several studies have shown that naltrexone reduces weight gain (O'Malley et
al., 2006; Toll et al., 2007).

This effect appears to be dose dependent, favoring lower doses (i.e., 25 mg daily). Thus, the
proposed study seeks to conduct a pilot clinical trial of low dose naltrexone (25 mg daily)
compared to placebo for minimizing weight gain in combination with varenicline for smoking
cessation. Forty individuals who smoke at least 10 cigarettes per day will receive open-label
varenicline for 12 weeks according to the recommended titration schedule up to 1 mg
varenicline twice daily. Subjects will be randomized to receive either placebo or 25 mg
naltrexone daily, with treatment starting at the quit date (after 1 week on varenicline to
minimize nausea, a side effect of both varenicline and naltrexone) and continuing for 11
weeks. Subjects will take 12.5 mg naltrexone daily for the first week and 25 mg naltrexone
daily for the next 10 weeks of treatment. In an effort to uncover mechanisms for naltrexone's
weight suppressant effects, an experiment will be conducted using food odors and food
consumption to examine naltrexone's effects on palatability, incentive value, and
alliesthesia.

This experiment will be conducted pretreatment and after 2 weeks on naltrexone. The primary
aim of this pilot study is to examine weight gain in participants who complete the clinical
trial treatment. Weight gain for those who are continuously abstinent for the last 4 weeks of
treatment and rates of adverse events will be secondary outcomes. The effects of naltrexone
on odor/food palatability, incentive value, and alliesthesia will be exploratory outcomes.
Effect size estimates for weight gain will be generated for a NIH grant application.

Inclusion Criteria:

1. Between the ages of 18 and 75

2. Smoking 10 or more cigarettes per day

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

4. Motivated to stop smoking

Exclusion Criteria:

1. Current use of opiates, and/or a urine toxicology screen positive for opiates

2. Chronic pain conditions necessitating opioid treatment (naltrexone, an opioid
antagonist will make these medications ineffective)

3. Evidence of significant hepatocellular injury as evidence by AST or ALT >3 x normal or
elevated bilirubin

4. History of cirrhosis

5. Any serious or unstable disease within 6 months

6. Seizure risk

7. Diabetes mellitus requiring insulin or oral hypoglycemic medications

8. Hepatic or renal impairment

9. Use of a monoamine oxidase inhibitor in the prior 14 days

10. Clinically significant cardiovascular disease within 6 months

11. Uncontrolled hypertension

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

13. Severe chronic obstructive pulmonary disease

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

15. History of clinically significant allergic reactions

16. Major depressive disorder within the past year requiring treatment

17. History of or current panic disorder, psychosis, bipolar disorder, or eating disorders

18. Alcohol or drug abuse/dependency within the past year

19. Use of another investigational drug within 30 days

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

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

22. 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

23. 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.

24. 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)