Naltrexone and Varenicline: Weight Gain and Tolerability in Cigarette Smokers

Naltrexone and Varenicline: Weight Gain and Tolerability in Smokers

The purpose of this study is to determine whether the combination of naltrexone (Depade) and varenicline (Chantix) minimizes post-smoking cessation weight gain and how well the combination is tolerated.

Study Overview

• Status: Completed
• Conditions: Smoking; Nicotine Dependence
• Intervention / Treatment: Drug: Naltrexone; Drug: Varenicline

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Yale University School of Medicine Substance Abuse Treatment Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1; Arm 1 (Experimental) = Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day	Drug: Naltrexone; Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day; Drug: Varenicline; Arm 1 (Experimental) = Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day; Arm 2 (Placebo Comparator) = Varenicline (Chantix) 1 mg oral tablet twice per day + placebo naltrexone 25 mg oral capsule once per day; Other Names: Chantix
PLACEBO_COMPARATOR: 2; Arm 2 (Placebo Comparator) = Varenicline (Chantix) 1 mg oral tablet twice per day + placebo naltrexone 25 mg oral capsule once per day	Drug: Varenicline; Arm 1 (Experimental) = Varenicline (Chantix) 1 mg oral tablet twice per day + naltrexone 25 mg oral capsule once per day; Arm 2 (Placebo Comparator) = Varenicline (Chantix) 1 mg oral tablet twice per day + placebo naltrexone 25 mg oral capsule once per day; Other Names: Chantix

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Weight Gain in Treatment Completers	baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight Gain in Participants Who Are Continuously Abstinent for the Last 4 Weeks of Treatment		4 weeks
Tolerability of the Combination of 25 mg Naltrexone and 2 mg Varenicline	Tolerability was measured by tracking adverse events. These data are reported in detail in the adverse events section. Presented are an unduplicated count of participants that experienced at least 1 adverse event.	11 weeks

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute on Drug Abuse (NIDA); National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Investigators: Principal Investigator: Benjamin A. Toll, PhD, Yale University

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (ACTUAL): June 1, 2009
• Study Completion (ACTUAL): June 1, 2009

Study Registration Dates

• First Submitted: July 13, 2007
• First Submitted That Met QC Criteria: July 16, 2007
• First Posted (ESTIMATE): July 17, 2007

Study Record Updates

• Last Update Posted (ACTUAL): January 17, 2018
• Last Update Submitted That Met QC Criteria: January 12, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Smoking; Tobacco; Naltrexone; Weight; Varenicline
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Body Weight; Body Weight Changes; Tobacco Use Disorder; Weight Gain; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Cholinergic Agents; Sensory System Agents; Narcotic Antagonists; Nicotinic Agonists; Cholinergic Agonists; Alcohol Deterrents; Naltrexone; Varenicline
• Other Study ID Numbers: 0704002538; P50AA015632 (U.S. NIH Grant/Contract); NIH Grant P50-AA15632; NIH Grant K12-DA00167