Opioid dependence is a substantial problem associated with significant morbidity and
mortality. Extended-release naltrexone has been found effective at reducing opioid use and
maintaining abstinence, but its use has been limited by the difficulties encountered with
treatment initiation, which involves detoxification from opioids and oral naltrexone
titration. Improving the likelihood of a successful transition to naltrexone is therefore an
important public health goal.
N-methyl-D-aspartate receptor (NMDA) antagonism has been found to alleviate the signs and
symptoms of withdrawal from opioids, as well as to address adaptations associated with
chronic opioid use, such as opioid-induced hyperalgesia (increased pain sensitivity). These
benefits may persist for at least 72 hours after a single dose. NMDA antagonism may therefore
facilitate a rapid transition to naltrexone by reducing discomfort, improving motivation, and
ameliorating adaptations associated with drug dependence, such as craving and arousal.
The purpose of this trial is to assess the feasibility of NMDA antagonist-assisted naltrexone
initiation in opioid dependent individuals. After administration of extended-release
naltrexone, participants will be followed for 4 weeks, and transitioned to appropriate care
subsequently (oral naltrexone, extended-release naltrexone).
1. Active opioid dependence, with at least one positive utox result; no history of opioid
overdose; and not currently using methadone or buprenorphine
2. Physically healthy
3. No adverse reactions to study medications
4. 21-60 years of age
5. Capacity to consent and comply with study procedures
6. Seeking treatment
1. Meets DSM IV criteria for current major depression, bipolar disorder, schizophrenia,
any psychotic illness, including substance-induced psychosis, and current
substance-induced mood disorder with HAMD > 12.
2. Physiological dependence on another substance requiring medical management, such as
alcohol or benzodiazepines, excluding caffeine, nicotine, and cannabis
3. Pregnant or interested in becoming pregnant
4. Delirium, Dementia, Amnesia, Cognitive Disorders, or dissociative disorders
5. Current suicide risk or a history of suicide attempt within the past 2 years
6. On psychotropic or other medication whose effect could be disrupted by participation
in the study
7. Recent history of significant violence (past 2 years).
8. Heart disease as indicated by history, abnormal ECG, previous cardiac surgery.
9. Unstable physical disorders which might make participation hazardous such as end-stage
AIDS, hypertension (>140/90), anemia, active hepatitis or other liver disease
(transaminase levels < 2 X the upper limit of normal will be considered acceptable),
or untreated diabetes
10. Previous history of CI-581 abuse, and/or a history of adverse reaction/experience wtih
prior exposure to CI-581 or benzodiazepines
11. BMI > 35, or a history of unmanaged obstructive sleep apnea
12. First degree relative with a psychotic disorder (bipolar disorder with psychotic
features, schizophrenia, schizoaffective disorder, or psychosis NOS)
13. History of opioid overdose over the past 2 years requiring medical intervention
14. Currently using methadone or buprenorphine