Study Notes on Opiate Antagonists and Pathological Gambling

Authors: Jon E. Grant, J.D., M.D., M.P.H.; Suck Won Kim, M.D.; Eric Hollander, M.D.; Marc N. Potenza, M.D., Ph.D.
Affiliations: University of Minnesota School of Medicine, Mount Sinai School of Medicine, Yale University School of Medicine
Abstract: Describes the study aimed at identifying predictors of treatment outcomes for individuals with pathological gambling (PG) receiving opiate antagonists.

Opiate antagonists have demonstrated potential in treating PG. However, responses to these medications vary among individuals. No prior studies have systematically examined predictors influencing treatment outcomes in PG.
Emphasizes the need for understanding clinical variables to develop treatment algorithms for PG.

To identify clinical variables associated with treatment responses among PG subjects receiving opiate antagonists.

Sample Size: 284 subjects with DSM-IV PG (137 women, 48.2%) were treated in two double-blind placebo-controlled trials, one involving 16 weeks of nalmefene and another with 18 weeks of naltrexone.
Assessment Tool: Gambling severity was assessed with the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS). A positive response was defined as a ≥ 35% reduction in the PG-YBOCS score for at least one month by the study endpoint.
Variables Analyzed: Included depression, anxiety, and psychosocial functioning utilizing stepwise logistic regression analyses to identify factors linked to treatment response.

Key Finding: A positive family history of alcoholism was the strongest predictor of positive responses to an opiate antagonist (p = 0.006).
Additional Findings:
- In subjects on higher doses of opiate antagonists, the intensity of gambling urges (measured by the PG-YBOCS urge subscale) was positively associated with treatment response on a trend level (p = 0.036).
- For placebo responses, younger age correlated with positive treatment outcomes (p = 0.012).

The findings suggest a familial influence on treatment response, highlighting the need for future research to explore specific genetic factors affecting responsiveness to opiate antagonists.

opiate antagonists; impulsivity; impulse control disorders; addiction; pharmacotherapy; placebo

Established Efficacy: Three placebo-controlled studies have validated the efficacy of opiate antagonists for treating PG.
Mechanism of Action: Likely involves opioidergic modulation of mesolimbic dopamine pathways leading to decreased gambling urges, as shown in studies examining their effects in other addictions (e.g., alcohol, heroin).
Response Rates: 10% to 30% of treated PG patients show no significant improvement with opiate antagonists, necessitating the identification of predictive factors for treatment success.

Study Basis: Data came from two double-blind placebo-controlled trials involving nalmefene (n=207) and naltrexone (n=77).
Inclusion Criteria:
- DSM-IV criteria for PG
- Minimum score of ≥5 on the South Oaks Gambling Screen (SOGS)
Exclusion Criteria:
- Infrequent gambling, unstable medical conditions, current psychotic or substance use disorders, among others.

Psychiatric Comorbidity: Assessed using the Structured Clinical Interview for DSM-IV (SCID).
Clinical Information: Collected through a semi-structured questionnaire administered by blind raters.
Primary Outcome Measure: PG-YBOCS, which assesses gambling symptoms over the last week.
Secondary Measures: Included the Sheehan Disability Scale (SDS), Hamilton Anxiety Rating Scale (HAM-A), and Hamilton Depression Rating Scale (HAM-D).

Definition of Treatment Response: A 35% or more reduction in PG-YBOCS total score for at least one month; this correlates with clinically significant changes in PG.
Statistical Methods: Cox regression models conducted to analyze response predictors, incorporating variables such as age, gender, and family history of alcoholism, with adjusted alpha levels for multiple comparisons set at p < 0.01.

Demography: The average age was 45.9 years (±11.4) with a range of 19-72; demographics were consistent across treatment and placebo groups.
Prevalence of Co-occurring Disorders: 23.9% of subjects had mood disorders, with no associations found between co-occurring disorders and treatment response.

Key Findings:
- Family history of alcoholism (HR = 1.74, p = 0.006) was significantly correlated with treatment success.
- Baseline urges to gamble had trend association with responders to higher doses, suggesting potential dosage modulation effects in treatment efficacy.

Placebo Analysis: Younger age significantly predicted placebo response (HR = 0.70, p = 0.012); with each 10-year increment, the likelihood of placebo response decreased by 30%.
Discussion of Placebo: Indicates that understanding placebo responses is critical; factors impacting placebo power differ from those affecting medication efficacy.

Clinical Implications: Strong family history and gambling urges can guide treatment approaches for PG; future research should explore the role of genetic factors and other medications.
Possible endophenotypic links between PG and alcohol dependence highlight the potential for behavioral addiction categorization, lending importance to both clinical practice and research.

The research received funding from various grants and awards, ensuring compliance with relevant ethical standards.