Investigation of Naltrexone for Pathological Gambling

Conditions

Pathological Gambling

Trial Phase

Phase 2

Trial Purpose and Description

Trial Purpose

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.


Trial 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 ß-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.

Participation Guidelines

Age:
18 Years and older
Gender:
Both

Eligibility Criteria


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
Sponsor:
National Center for Responsible Gaming
Yale University
Dates:
February 2009
Last Updated:
January 29, 2013
Study HIC#:
0901004667

Clinicaltrials.gov ID: NCT01057862