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.

Investigation of Naltrexone for Pathological Gambling

Pathological Gambling

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.

Naltrexone

Placebo

Double-Blind Placebo-Controlled Investigation of Naltrexone for Pathological Gambling

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.

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.

Investigation of Naltrexone for Pathological Gambling

About this trial

Study ID

Status

Type

Phase

Placebo

Accepting

Not accepting

Trial Timing

What is this trial about?

What are the participation requirements?

Locations

Location

Status