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Investigation of Naltrexone for Pathological Gambling

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01057862
Recruitment Status : Completed
First Posted : January 27, 2010
Results First Posted : September 12, 2017
Last Update Posted : October 13, 2017
National Center for Responsible Gaming
Information provided by (Responsible Party):
Yale University

Tracking Information
First Submitted Date  ICMJE January 25, 2010
First Posted Date  ICMJE January 27, 2010
Results First Submitted Date  ICMJE January 11, 2017
Results First Posted Date  ICMJE September 12, 2017
Last Update Posted Date October 13, 2017
Actual Study Start Date  ICMJE February 2009
Actual Primary Completion Date February 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 11, 2017)
Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (YBOCS-PG) [ Time Frame: Weekly/bi-weekly visits ]
The Yale Brown Obsessive Compulsive Scale adapted for Pathological Gambling (PG-YBOCS) was developed to measure the severity and change in severity of pathological gambling symptoms.The PG-YBOCS is a 10-item clinician-administered questionnaire that measures the severity of PG over a specified time interval. Scores of 0 through 4 are assigned to each question according to the severity of the response (0 = least severe response, 4 = most severe response). The first five questions assess urges and thoughts associated with pathological gambling, whereas the last five questions assess the behavioral component of the disorder. Each set of questions is totaled separately as well as together for a total score. The total score can range from 0 (low) to 40 (most severe) with higher numbers representing a more severe form of pathological gambling.
Original Primary Outcome Measures  ICMJE
 (submitted: January 26, 2010)
Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (YBOCS-PG) [ Time Frame: Weekly/bi-weekly visits ]
Change History Complete list of historical versions of study NCT01057862 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 11, 2017)
Gambling Symptom Assessment Scale (G-SAS) [ Time Frame: Weekly/bi-weekly visits ]
The G-SAS is a 12-item self-rated scale designed to assess gambling symptom severity and change during treatment. Each item on the 12-item scale has a score ranging from 0 - 4. All items ask for an average symptom based on the past 7 days. Total score ranges from 0 - 48: extreme = 41 - 48, severe = 31 - 40, moderate = 21 - 30, mild = 8 - 20.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 26, 2010)
Gambling Symptom Assessment Scale (G-SAS) [ Time Frame: Weekly/bi-weekly visits ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Investigation of Naltrexone for Pathological Gambling
Official Title  ICMJE Double-Blind Placebo-Controlled Investigation of Naltrexone for Pathological Gambling
Brief Summary The investigators plan to investigate the safety, tolerability, and efficacy of the opioid antagonist naltrexone in Pathological Gambling. We hypothesize that naltrexone will be superior to placebo in reducing gambling urges and behavior, when combined with adjuvant non-pharmacological treatment as usual.
Detailed Description

Pathological gambling (PG) is a significant public health problem that can cause significant devastation for the individuals affected and their families. Those afflicted may experience unemployment, considerable debt, marital problems, family dysfunction, legal troubles, incarceration, and mental health issues including suicidality. Prevalence estimates vary but most estimates put it at between 1% and 2%, with annual costs of over $5 billion in the United States alone. Thus, PG is costly not only for the affected individuals and their families, but also for society in general.

The current treatment as usual for PG is limited to various types of counseling, psychotherapy (e.g. cognitive behavioral therapy), and self-help groups such as Gamblers Anonymous. However, such treatment modalities have not been shown to be particularly effective. High rates or relapse are common and treatment attrition is often a concern.

Currently, no drugs are approved by the U.S. Food and Drug Administration for the treatment of PG. Pharmacological treatment studies are still in their infancy but show considerable promise. Several placebo-controlled, randomized clinical trials have been conducted, but results have been limited by small sample sizes, short durations, exclusion of individuals with co-occurring disorders, and heterogeneity in treatment response measures and diagnostic criteria used for inclusion.

Selective serotonin reuptake inhibitors (SSRIs) have shown mixed results in PG. Some studies have suggested a benefit of active drug over placebo while other studies have not. Mood stabilizers have not been extensively studied but some reports suggest that certain patients, such as those with co-morbid bipolar spectrum disorders, may benefit from this type of medication. Atypical antipsychotics have also been tried with limited success and may be more appropriate for patients with co-occurring psychotic disorders.

Opioid antagonists such as naltrexone and nalmefene, possibly through their modulation of the mesolimbic dopamine system, have demonstrated preliminary efficacy superior to placebo in treating PG. As with substance use disorders (SUD), it has been suggested that opioid antagonists may exert their therapeutic benefit by helping to reduce the appetitive urges or cravings present in symptomatology of addiction.

From the neurochemical perspective, the pharmacological action of opioid antagonists is to block the effects of endogenous endorphins on mu-opioid receptors and may inhibit dopamine release in the nucleus accumbens. The mu-opioid system is generally thought to be involved in the mediation of hedonic, rewarding and reinforcing behaviors. The mu-opioid and mesolimbic pathways have been implicated in PG. For example, problem gamblers have been shown to have elevated levels of the endogenous opioid β-endorphin during gambling (Shinohara et al 1999).

Naltrexone, a pure opioid antagonist, is an FDA-approved medication with two labeled indications. Firstly, for the blockade of the effects of exogenously administered opioids. And secondly, for the treatment of alcohol dependence. However, it's labeling is clear that it has not been shown to provide any therapeutic benefit except as part of an appropriate plan of management for addiction. Naltrexone has been investigated in PG in part due to its proposed ability to modulate the mesolimbic dopamine pathway. In preliminary studies, it has shown efficacy superior to placebo. As with clinical trials of alcohol dependence, it appears that naltrexone targets craving and urge states. In fact, naltrexone has shown to be particularly effective in individuals with stronger urges to gamble at treatment onset.

A double-blind, placebo-controlled twelve-week investigation of naltrexone in 83 subjects (of which 45 were used for analysis) has been described(Kim et al 2001). Doses were initiated at 25 mg/day and titrated to a maximum dosage of 250 mg/day, with an average final dose of 187.50 mg/day (SD=96.45). Naltrexone was superior to placebo and was associated with statistically significant improvement in various measures of gambling severity, both self-reported and clinician-administered. A post hoc analysis showed that naltrexone was more effective in gamblers who reported more severe urges.

More recently, an eighteen-week double-blind, placebo-controlled study of naltrexone for PG was reported(Grant et al 2008). Following a single-blinded one-week placebo lead-in, seventy-seven PG subjects were randomized to daily doses of 50mg, 100mg, or 150mg naltrexone. Unlike the previous shorter naltrexone study, this group included subjects with a range of co-occurring disorders. Outcomes did not significantly differ among the three dosages. The three active arms of the study were combined and compared to placebo. Analyses showed that naltrexone was more effective than placebo in decreasing PG severity, gambling urges, gambling behavior, and psychological functioning.

Nalmefene hydrochloride is a similar-acting opioid antagonist. Contrary to naltrexone, nalmefene is not associated with possible liver toxicity. A sixteen-week multicenter, randomized, dose-ranging, double-blind, placebo-controlled investigation was conducted at 15 outpatient treatment centers in the U.S., including at Yale(Grant et al 2006). Two hundred and seven male and female subjects were randomized to either 25mg, 50 mg, 100mg per day or to an equivalent placebo. All three active arms began with a one-week course of 25mg per day. This study did not include individuals with co-occurring disorders. Subjects assigned to the active arms showed statistically significant reductions in gambling severity. The 50mg and 100mg doses resulted in intolerable side effects. It appears that the lower 25mg dose was the most efficacious. In fact, the 25mg dose was unique in terms of demonstrating superiority to placebo based on overall response to treatment as measures by the Clinical Global Impression (CGI) improvement scale.

Based on previous encouraging results both at Yale and elsewhere, this study will attempt to replicate and extend the safety, tolerability, and efficacy findings of opioid antagonists in the management of PG. In addition, this study will provide much needed information regarding pharmacotherapy in conjunction with treatment as usual for PG.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Pathological Gambling
Intervention  ICMJE
  • Drug: Naltrexone
    Targeted dosage of 50mg PO daily
    Other Name: Naltrexone hydrochloride
  • Other: Placebo
    Sugar pills daily PO
Study Arms  ICMJE
  • Experimental: Naltrexone
    Intervention: Drug: Naltrexone
  • Placebo Comparator: Placebo
    Intervention: Other: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 11, 2017)
Original Estimated Enrollment  ICMJE
 (submitted: January 26, 2010)
Actual Study Completion Date  ICMJE January 2017
Actual Primary Completion Date February 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Men or women over age 18
  2. Current DSM-IV PG Diagnosis as determined by a score of ≥ 5A criteria and B criterion present on the SCI-PG and a score ≥ 5 on the SOGS
  3. Gambling behavior within 2 weeks prior to enrollment
  4. For women, stable use of a medically accepted form of contraception and negative results on urine pregnancy test at study onset
  5. Currently entering, enrolled, or interested in treatment for PG

Exclusion Criteria:

  1. Gambling that does not meet DSM-IV criteria for PG
  2. Unstable medical illness or clinically significant abnormalities on laboratory tests, EKG, or physical examination at screen
  3. Past or current acute hepatitis or liver failure
  4. History of renal impairment
  5. Current or recent (within one week) treatment with an opioid agonist/opioid analgesic or current opioid withdrawal
  6. Opiate agonist maintenance therapy (e.g. methadone)
  7. Known sensitivity to opioid antagonists
  8. Current pregnancy or lactation, or inadequate contraception in women of childbearing potential
  9. A need for medication with unfavorable interactions with naltrexone
  10. Clinically significant suicidality
  11. Lifetime history of dementia, schizophrenia, or any psychotic disorder determined by SCID
  12. Clinically significant cognitive impairment
  13. Previous treatment with naltrexone or nalmefene
  14. Treatment with investigational medication or depot neuroleptics within 3 months
  15. Lack of proficiency in written and spoken English
  16. Unable to travel to study sites for appointments
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01057862
Other Study ID Numbers  ICMJE 0901004667
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Yale University
Study Sponsor  ICMJE Yale University
Collaborators  ICMJE National Center for Responsible Gaming
Investigators  ICMJE
Principal Investigator: Marc N Potenza, M.D., Ph.D. Yale University
PRS Account Yale University
Verification Date August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP