Effects of Naltrexone on Nicotine Reinforcement

Tobacco Dependence Clinical Trial

Official title:

Pharmacogenetic Investigation of Naltrexone

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00270231
• Other study ID #: 800810
• Secondary ID: R01DA017555
• Status: Completed
• Phase: Phase 2
• First received: December 23, 2005
• Last updated: November 12, 2013
• Start date: March 2004
• Est. completion date: October 2005

Study information

• Verified date: November 2013
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Despite preclinical evidence supporting the role of the endogenous opioid system in the reinforcing effects of nicotine, the efficacy of the opioid antagonist naltrexone (NTX) as a tobacco dependence treatment remains unresolved. Research is needed to identify those smokers for whom NTX will have the strongest beneficial effects on smoking behavior.

The research bridges existing knowledge of genetic, pharmacologic, and behavioral responses to nicotine, and translates this knowledge to treatment for tobacco dependence. The immediate goal was to test whether genetic variation in the mu-opioid receptor gene predicts the effects of naltrexone (NTX) on nicotine reinforcement.

Description:

The study was a within-subject double-blind study of the effects of naltrexone versus placebo on the reinforcing value of nicotine, using a validated cigarette choice paradigm. A key question was whether smokers differ in their responses based on the mu opioid receptor gene (OPRM1) Asn40Asp (A118G) variant.

Following informed consent, 64 smokers were enrolled in the study. Of these, 60 completed two 4-day study phases interspersed with a 5-7 day washout phase. Baseline statistics are provided for the 64 smokers who enrolled.

Each 4-day study phase included a 3-day drug run-up and monitoring phase, then on the 4th day participants came to our Biobehavioral Lab (BBL) where they took their final 50mg of study medication and completed a cigarette choice paradigm. Following a washout phase, the 4-day sequence will be repeated with the alternative study medication. The order of study medication was randomized and counterbalanced between subjects.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 64
• Est. completion date: October 2005
• Est. primary completion date: October 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Participants must be greater than or equal to 18 years

2. Based on the medical history, physical and laboratory examination, female subjects must:

1. Agree in consent to practice effective contraception during study, be status post-bilateral tubal litigation or be post-menopausal.

2. Not be pregnant, nursing, or planning pregnancy

3. Based upon self-report, subjects must smoke greater than or equal to 10 non-menthol cigarettes per day

4. Because the OPRM1 variant is common (25-30%) in persons of European ancestry, but very rare in other ethnic groups (e.g., 2-9% of African Americans) it is not scientifically justified to include members of other ethnic groups. Therefore, only persons of European ancestry will be recruited.

5. Following orientation by the research staff, subjects must sign written informed consent and HIPAA form.

Exclusion Criteria:

1. Current diagnosis of kidney disease or history of renal function impairment (unless they have recent kidney function tests (within last 3 months) and approval of their primary physician to participate in the study.)

2. Women who are pregnant, planning a pregnancy, or lactating

3. Current alcohol use > 25 standard drinks/week (this is because NTX is used to treat alcohol dependence, and effects of NTX on alcohol consumption in alcohol dependent subjects could have indirect effects on cigarette consumption).

4. Current medical problems for which NTX is contraindicated including: active hepatitis (Liver Function Tests 3 times the Upper Limit of Normal).

5. History of opiate dependence (prescription drug or illicit use).

6. History of or current Diagnostic and Statistical Manual of Mental Disorders (Version IV) (DSM IV) substance use disorders (abuse or dependence involving alcohol, cocaine, stimulants, or benzodiazepines)

7. Diagnosis of bulimia and/or anorexia nervosa in the last year

8. Current or past use (with in past 12 months) of any medications containing NTX (e.g., Revia, Trexan), allergy to NTX

9. Concomitant medications (e.g., monoamine oxidase inhibitors or benzodiazepines within past 14 days, antipsychotics, antidepressants, theophylline, systemic steroids, over-the-counter stimulants and anorectics)

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator)

Related Conditions & MeSH terms

• Tobacco Dependence

Intervention

Drug:
• Naltrexone
All participants took naltrexone during one of the two 4-day study medication periods. Both 4-day study medication periods were randomized and counterbalanced between naltrexone and placebo; all study medication periods were separated by a 5-7 day washout period. Dosing of the naltrexone was the same for all participants: Day 1: 12.5mg, Day 2: 25mg, Days 3 and 4: 50mg.
• Placebo
All participants took a placebo (sugar pill) during one of the two 4-day study medication periods. Both 4-day study medication periods were randomized and counterbalanced between naltrexone and placebo. Placebo capsules matched the naltrexone in color, weight and inactive ingredients. The only difference the lack of active naltrexone in each capsule.

Locations

Country	Name	City	State
United States	Tobacco Use Research Center	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
University of Pennsylvania	National Institute on Drug Abuse (NIDA)

Country where clinical trial is conducted

United States, 

References & Publications (2)

Ray R, Jepson C, Patterson F, Strasser A, Rukstalis M, Perkins K, Lynch KG, O'Malley S, Berrettini WH, Lerman C. Association of OPRM1 A118G variant with the relative reinforcing value of nicotine. Psychopharmacology (Berl). 2006 Oct;188(3):355-63. Epub 20 — View Citation

Ray R, Jepson C, Wileyto P, Patterson F, Strasser AA, Rukstalis M, Perkins K, Blendy J, Lerman C. CREB1 haplotypes and the relative reinforcing value of nicotine. Mol Psychiatry. 2007 Jul;12(7):615-7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Nicotine Cigarette Choices Taken During the Cigarette Choice Procedure.	On day 4 of each study medication period, participants completed a cigarette choice procedure where the subject is asked to take 4 puffs from a nicotinized (nicotine-containing) or a denicotinized (no nicotine) cigarette every 30 minutes for 2 hours (maximum of 24 puffs). The outcome variable is the number of nicotine cigarette choices or puffs out of 24 total puffs during these cigarette choice procedures.; Subjects who had the A/A genotype took an average of 18.5 puffs from the nicotine-containing cigarettes. Subjects with the A/G or G/G genotypes took an average of 16.2 puffs from the nicotine-containing cigarettes.	2 hours	No