Clinical trial NCT00270231: Effects of Naltrexone on Nicotine Reinforcement
Official title: Pharmacogenetic Investigation of Naltrexone
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tobacco Dependence
Keywords: within-subjects, crossover, laboratory study
Naltrexone vs. Placebo
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: National Institute on Drug Abuse (NIDA)
First posted: 2005-12-26
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER

Brief 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.

Detailed 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Number of Nicotine Cigarette Choices Taken During the Cigarette Choice Procedure.
timeFrame: 2 hours
Secondary outcomes:
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Tobacco Use Research Center
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Caryn Lerman, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
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. doi: 10.1038/sj.mp.4002002. No abstract available.
citation: 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. doi: 10.1007/s00213-006-0504-2. Epub 2006 Sep 8.