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`Author Manuscript
`Arch Gen Psychiatry. Author manuscript; available in PMC 2014 October 17.
`Published in final edited form as:
`Arch Gen Psychiatry. 2006 February ; 63(2): 210–218. doi:10.1001/archpsyc.63.2.210.
`
`Injectable, sustained-release naltrexone for the treatment of
`opioid dependence: a randomized, placebo-controlled trial
`
`Sandra D. Comer, PhD, Maria A. Sullivan, MD, PhD, Elmer Yu, MD, Jami L. Rothenberg,
`PhD, Herbert D. Kleber, MD, Kyle Kampman, MD, Charles Dackis, MD, Charles P. O'Brien,
`MD, C. Nora Chiang, PhD, and Richard L. Hawks, PhD
`Division on Substance Abuse, New York State Psychiatric Institute and the Department of
`Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY (Drs
`Comer, Sullivan, Rothenberg, Kleber); University of Pennsylvania and Philadelphia VA Medical
`Center (Drs Yu, Kampman, Dackis, O'Brien); National Institute on Drug Abuse, Bethesda, MD
`(Drs Chiang, Hawks)
`
`Abstract
`
`Context—Naltrexone is a medication available in oral form that can completely block the effects
`produced by opioid agonists, such as heroin. However, poor medication compliance with
`naltrexone has been a major obstacle to the effective treatment of opioid dependence.
`
`Objective—To evaluate the safety and efficacy of a sustained-release depot formulation of
`naltrexone in treating opioid dependence.
`
`Design, Setting, and Participants—Randomized, double-blind, placebo-controlled, 8-week
`multi-center trial of male and female heroin-dependent patients who participated in the study
`between September 2000 and November 2003. Participants were stratified by years of heroin use
`(≥5, <4.9) and gender, and then randomized to receive one of three doses: placebo, 192 mg, or 384
`mg depot naltrexone. Doses were administered at the beginning of Week 1 and then again four
`weeks later at the beginning of Week 5. All participants received twice-weekly relapse prevention
`therapy, provided observed urine samples, and completed other assessments at each visit.
`
`Main Outcome Measures—Primary outcome measures were retention in treatment and
`percentage of opioid-negative urine samples.
`
`Results—A total of 60 patients were randomized at two centers. Retention in treatment was dose
`related with 39%, 60%, and 68% of the patients in the placebo, naltrexone 192 mg, and naltrexone
`384 mg groups, respectively, remaining in treatment at the end of the two-month treatment period.
`Analysis of the time to dropout revealed a significant main effect of dose with mean time to
`dropout of 27, 36, and 48 days, respectively, for the placebo, naltrexone 192 mg, and naltrexone
`384 mg groups. The percentage of urine samples negative for opioids varied significantly as a
`function of dose, as did the percentage of urine samples negative for methadone, cocaine,
`benzodiazepines, and amphetamine. The percentage of urine samples negative for cannabinoids
`was not significantly different across groups. When the data were recalculated without the
`
`Corresponding Author: Sandra D. Comer, PhD, The New York State Psychiatric Institute & College of Physicians & Surgeons of
`Columbia University, 1051 Riverside Dr., Unit 120, New York, NY 10032 (sdc10@columbia.edu; 212-543-5981 (tel); 212-543-5991
`(FAX)).
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`ALKERMES EXHIBIT 2041
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
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`assumption that missing urine samples were positive, however, a main effect of group was not
`found for any of the drugs tested with the exception of cocaine, where the percentage of cocaine-
`negative urines was lower in the placebo group. Adverse events were minimal and generally mild
`in severity. This sustained-release formulation of naltrexone was well tolerated and produced a
`robust and dose-related increase in treatment retention.
`
`Conclusion—The present data provide exciting new evidence for the feasibility, efficacy, and
`tolerability of long-lasting antagonist treatments for opioid dependence.
`
`Introduction
`
`Heroin abuse and, more recently, prescription opioid abuse are significant and growing
`public health problems in the U.S., as measured by a variety of indicators1–4. Treatment
`strategies for opioid dependence commonly include agonist maintenance therapies, such as
`methadone, buprenorphine, and the buprenorphine/naloxone combination. While all of these
`medications are effective in reducing illicit opioid use5–8, problems associated with their use
`such as social resistance to the idea of “replacing one drug of abuse with another,”
`difficulties in tapering patients off the medication due to long-lasting withdrawal effects, and
`illicit diversion of the maintenance medications make the search for alternative forms of
`pharmacotherapy important.
`
`Orally delivered naltrexone is approved by the Food and Drug Administration for the
`treatment of both opioid and alcohol dependence. It acts as a competitive antagonist at
`opioid receptors and is highly effective in both preventing and reversing the effects
`produced by mu opioid agonists. Despite its strong theoretical potential for treating opioid
`dependence, clinical experience with naltrexone has been disappointing because of high
`dropout rates during treatment and poor compliance with medication ingestion9–12. The
`development of sustained-release depot formulations of naltrexone has renewed interest in
`this medication for treating opioid dependence. Depot naltrexone has also been used recently
`in the treatment of alcohol dependence13–14. A recent inpatient study conducted in our
`laboratory demonstrated that an injectable depot formulation of naltrexone was safe, well
`tolerated, and effective in reducing the subjective, cognitive, and physiological effects of
`intravenously delivered heroin for 3–5 weeks, depending on dose15. The present study was
`designed to examine the safety and efficacy of depot naltrexone in a clinical setting for
`patients who were seeking treatment for opioid dependence.
`
`Methods
`
`Study Participants
`
`Participants were heroin dependent men and women (18–59 years of age), as defined by the
`Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), who were
`voluntarily seeking treatment for their dependence. The target enrollment was 60 patients,
`stratified by years of heroin use (≥5, <4.9) and gender. Participants were randomized in
`blocks of 6 into one of three parallel cohorts. Patients were in good health based on medical
`history, physical examination, vital signs measurements, and 12-lead electrocardiogram, and
`laboratory tests within appropriate normal ranges (hematology, blood chemistry, urinalysis).
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`Patients were excluded from the study if they were dependent on methadone or on drugs
`other than heroin, nicotine, or caffeine (based on DSM-IV criteria), pregnant or lactating,
`unwilling to use a satisfactory method of birth control, currently diagnosed with major
`DSM-IV Axis I psychopathology (e.g., mood disorder with functional impairment,
`schizophrenia) that might have interfered with study participation, considered to have a
`significant risk of suicide or had made one or more attempts in the past year, had acute
`hepatitis or liver damage as evidenced by SGOT or SGPT greater than three times the upper
`end of the laboratory normal range, had a history of allergy, adverse reaction or sensitivity to
`the study medication, regularly used psychoactive drugs including anxiolytics and
`antidepressants, currently received any other investigational drug, or had any medical
`condition that might have interfered with study participation or significantly increased the
`medical risks of study participation. Participants were recruited through advertising in local
`newspapers and through word-of-mouth. Written informed consent was obtained from all
`participants through a multi-step process in which study procedures were explained by
`several staff members. This study was approved by the Institutional Review Boards of the
`New York State Psychiatric Institute and the University of Pennsylvania, Philadelphia.
`
`Study Design
`
`The study was designed as a multi-center randomized, double-blind, placebo-controlled,
`parallel-group, 8-week clinical trial. Patients received an initial inpatient detoxification,
`followed by oral naltrexone for 3 consecutive days in order to ensure that they were willing
`and able to tolerate the effects of depot naltrexone. Patients were then randomized to receive
`placebo, 192 mg, or 384 mg depot naltrexone (Depotrex®, Biotek Inc., Woburn, MA). Four
`weeks later, patients received a second dose of the study medication. The same dose was
`administered on both occasions.
`
`Following each dose administration, patients attended the clinic twice per week to receive
`manualized relapse prevention therapy and to complete various questionnaires designed to
`assess drug craving, opioid withdrawal symptoms, and global functioning. At each visit,
`potential adverse events were assessed and patients provided urine samples for analysis of
`opioids, cocaine, benzodiazepines, cannabinoids, methadone, and amphetamine. Urine
`sample collections were observed by research staff and subsequently analyzed by Northwest
`Toxicologies, Inc. (Salt Lake City, UT). Blood samples for liver function tests and for
`analysis of naltrexone and 6-beta-naltrexol levels were collected weekly. Depression was
`assessed twice monthly and patients met with a psychiatrist at least once per month. At the
`last study visit, hematology and blood chemistry profiles, liver function tests, urinalyses,
`electrocardiograms, and physical examinations were performed.
`
`Depot Naltrexone
`
`A long-lasting, injectable formulation of naltrexone (Depotrex® was manufactured by
`BIOTEK, Inc. (Woburn, MA) and provided by the National Institute on Drug Abuse
`(Rockville, MD). Naltrexone microcapsules and placebo microspheres were packaged in
`sterile single-dose vials. After reconstituting in suspending medium, 2.4 ml of the
`suspension was injected. Each single-dose vial of the active formulation contained drug
`equivalent to 192 mg naltrexone base. This formulation per vial was designed to release
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`approximately 5 mg naltrexone per day. The placebo formulation contained the equivalent
`weight in polymer microspheres. Injections were administered subcutaneously into the
`buttocks (one 2.4 ml injection per buttock), using an 18 gauge needle. All participants
`received two injections to maintain the dosing blind. For the placebo dose, participants
`received two placebo injections, for the low dose, participants received one placebo and one
`naltrexone injection (192 mg naltrexone base), and for the high dose, participants received
`two naltrexone injections (394 mg naltrexone base).
`
`Data Analysis
`
`Analyses of the efficacy measures were conducted on the intent-to-treat population. Primary
`dependent measures were average number of weeks in treatment and the percentage of
`negative urine toxicology samples for opioids during the 8-week treatment period. The
`number of negative samples taken in the 8-week treatment period was used to calculate the
`percent for each patient. The denominator was the maximum number of possible samples for
`a completed patient, with the assumption that the missing visits and missing test results were
`positive16. The data were also recalculated without those assumptions. The difference in the
`percent of negative urine results between each naltrexone group and the placebo and the
`difference between the two naltrexone groups was analyzed with a two-way analysis of
`variance model (ANOVA) including the treatment and center factors. The three pairwise
`comparisons and the 95% confidence intervals for the differences between treatments were
`performed using Tukey's method, controlling for the experiment-wise error rate at 0.05.
`Residuals of the ANOVA were analyzed to verify whether the normality assumption was
`violated. Levene's test was used to determine whether the assumption of homogeneity of
`variance was violated. If either assumption was violated, then the rank transformation or
`nonparametric procedure was applied instead. Consistency of the evaluation between the
`centers was examined with the ANOVA model with the added treatment-by-center
`interaction term, should there be no signs of violation of the assumptions of ANOVA.
`Consistency of the evaluation across age, race, and gender for the primary efficacy measure
`was evaluated with the ANOVA or ANCOVA model.
`
`Secondary dependent measures included the following: time to dropout, percentages of
`negative urine samples for cocaine, benzodiazepines, cannabinoids, amphetamine, and
`methadone, heroin craving scores, clinical global impression scale scores for severity of
`opiate and cocaine use rated by clinicians (CGIC) and patients (CGIS), and Hamilton
`Depression Index (HAM-D) total scores. The distributions of time to dropout in the three
`treatment groups were compared to determine significance of the difference in retention
`between treatments. The number of days from randomization to dropout or completion of
`the study was summarized by treatment. Kaplan-Meier's method was used to estimate the
`distribution of the time to dropout, where completion of the study was handled as censored
`observations. The distribution of the time to dropout in each pair of treatment groups was
`compared using the log-rank test. The percentages of negative urine toxicology outcomes
`were examined with an analysis of variance (ANOVA) model. How much or how little the
`patient felt that he or she wanted and needed heroin since the last visit was rated on a visual
`analog scale. The craving scores at the post-baseline visits were analyzed with the model for
`repeated measures to assess significance of the treatment by time interaction and the
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`treatment effect. The severity of opiate and cocaine use was rated on the CGIS and CGIC
`using an 8-point scale with 1 being no pathology, 7 extreme pathology and 8 not assessed.
`Patients with no assessment were not included for analysis. The treatment effects on CGIS
`and CGIC for opiates and cocaine were analyzed with an ANOVA model. If the distribution
`of CGIS and CGIC concentrated on a few rating scores, then the data were analyzed with the
`Cochran-Mantel-Haenszel method, stratified by center. The total score of the HAM-D was
`analyzed with an ANOVA model.
`
`Safety of the treatment was evaluated based on reports of adverse events (AE's), vital signs,
`liver function tests, clinical lab tests and electrocardiograms. Only the treatment-emergent
`adverse events were analyzed. Treatment-emergent adverse events were defined as adverse
`events that occurred after start of study medication or previously occurring adverse events
`that worsened after start of study medication. The incidence of treatment-emergent adverse
`events was summarized by treatment, body system and severity. The incidence of the
`treatment-emergent adverse events that were considered possibly, probably or definitely
`related to the study medication was summarized similarly. Adverse events that resulted in
`discontinuation were tabulated by treatment group and listed individually. The overall
`incidence of treatment-emergent adverse events in each naltrexone group was compared
`with that of the placebo group using the Fisher's exact test.
`
`Clinical monitoring was performed under the direction of the National Institute on Drug
`Abuse. The primary clinical monitoring was performed by Biopharmaceutical Research
`Consultants, Inc. (BRCI, Dexter, MI). BRCI conducted periodic audits during and after the
`study on all case report forms and corresponding source documents for each participant. The
`BRCI monitors assured that submitted data were accurate and in agreement with source
`documentation, verified that investigational agents were properly stored and accounted for,
`verified that patients' consent for study participation had been properly obtained and
`documented, confirmed that research participants entered into the study met inclusion and
`exclusion criteria, and assured that all essential documentation required by good clinical
`practices guidelines were appropriately filed.
`
`Demographics A total of 60 patients were randomized at 2 centers. Patients were between 19
`and 59 years old, 77% of whom were male. The White and Black races were equivalent at
`37% and 35%, respectively, and were the majority. The distributions of gender, age, and
`race were not significantly different in the three groups (Table 1). Lifetime drug use was
`quite similar across all groups, as was drug use in the past 30 days (Table 1). There were no
`significant differences between study sites for any of the demographic measures or for any
`of the dependent measures described below.
`
`Plasma levels of study medication Plasma levels of naltrexone (Figure 1, left panel) and 6-
`beta-naltrexol (Figure 1, right panel) are shown as a function of study week and treatment
`group. After administration of 192 mg depot naltrexone, average naltrexone plasma levels
`ranged between 0.4 and 1.9 ng/ml. After administration of 384 mg depot naltrexone, average
`naltrexone plasma levels ranged between 1.3 and 3.2 ng/ml. Across the 8-week study,
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`Results
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`plasma naltrexone levels tended to be fairly constant, with perhaps a slight decline during
`the fourth week after drug administration. Plasma levels of 6-beta-naltrexol, the primary
`pharmacologically active metabolite of naltrexone, tended to be higher than naltrexone and
`more variable across time and between subjects.
`
`Retention in treatment and time to dropout The percentage of patients retained in treatment
`(Figure 2) is presented as a function of study week and treatment group. During the first
`visit, all randomized subjects were present. By Week 8-Visit 16, 7 patients out of 18
`randomized in the placebo group (39%), 12 patients out of 20 randomized in the 192 mg
`naltrexone group (60%), and 12 patients out of 22 randomized in the 384 mg naltrexone
`group (68%) remained in treatment. The distribution of time from randomization to dropout
`or completion in the three treatment groups was compared to determine the significance of
`the difference in retention between groups (Table 2). The number of days to dropout was
`lowest in the placebo group (27 days; 3.8 weeks), followed by the naltrexone 192 mg group
`(36 days; 5.1 weeks), and the naltrexone 384 mg group (48 days; 6.8 weeks). The main
`effect of group was significant at P<0.002. Pairwise comparisons between groups revealed a
`significant difference in days to dropout between the placebo and 384 mg naltrexone groups
`(P<0.0001) and between the two active dose groups (P<0.05).
`
`Urine drug toxicology The mean percentage of urine samples negative for opioids across the
`study was lowest for the placebo group (25.3%) and highest for the 384 mg naltrexone
`group (61.9%; Table 3, Figure 3). The main effect of group was significant (P<0.03).
`Pairwise comparisons between groups revealed a significant difference between the placebo
`and 192 mg naltrexone groups (P<0.04) and the placebo and 384 mg naltrexone groups
`(P<0.001). However, when the data were recalculated without the assumption that missing
`visits and missing samples were positive, the mean percentage of urines negative for opioids
`increased to 74.2% in the placebo group, 73.5% in the 192 mg naltrexone group, and 79.4%
`in the 384 mg naltrexone group and there were no significant differences between groups.
`
`Similar trends in the average percentage of negative urines as a function of group (Figure 3)
`were obtained for cocaine (P<0.003), benzodiazepines (P<0.02), amphetamine (P<0.03), and
`methadone (P<0.05) when the missing values were calculated as positive for the drug of
`interest. The difference among the three groups for cannabinoids was not significant
`(P<0.08). The percentage of missing urines (Table 3) was inversely related to the percentage
`of negative urines with the highest percentage of missing urines for the placebo group
`(64.4%), followed by the 192 mg naltrexone group (42.7%) and the 384 mg naltrexone
`group (29.4%).
`
`Across time, the percentage of urines negative for cocaine was significantly lower in the
`placebo group than in the naltrexone 192 mg at Week 1-Visit 2 (30% vs 90.9%; P<0.003),
`Week 2-Visit 4 (62.5% vs 93.8%; P<0.03), Week 5-Visit 10 (33.3% vs 100%; P<0.03) and
`Week 7-Visit 14 (0% vs 100%; P<0.01). The percentage of urines negative for cocaine was
`significantly lower in the placebo group than in the naltrexone 384 mg group at Week 1-
`Visit 2 (30% vs 88.9%; P<0.002), Week 3-Visit 6 (71.4% vs 100%; P<0.04) and Week 7-
`Visit 14 (0% vs 84.6%; P<0.04). The percentages of urines negative for benzodiazepines
`and methadone were significantly lower in the placebo group than in the naltrexone 384 mg
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`group at Week 7-Visit 13 (66.7% vs 100%; P<0.02 for both drugs). There were no
`significant differences in the percentages of negative urines among groups for cannabinoids
`or amphetamine.
`
`When the data were recalculated without the assumption that missing values were positive,
`there were no significant differences between groups for any of the drugs. For cocaine, the
`average percentage of negative urine samples was lower, but not significantly so, in the
`placebo group (65.7%), compared to the naltrexone 192 mg (86.0%) and naltrexone 384 mg
`groups (83.9%). The average percentage of urines negative for cannabinoids ranged between
`60.7% and 63.5% across the three groups, and the average percentage of negative urines
`ranged between 87.8% and 100% for benzodiazepines, amphetamine, and methadone.
`
`Heroin craving At baseline, heroin craving was high for all three groups: mean ratings of
`“wanting heroin” and “needing heroin” ranged between 54 mm and 64 mm on a 100 mm
`line. After receiving the study medication, the lowest heroin craving scores were reported by
`the naltrexone 192 mg group for the majority of visits (range: 1–28 mm). No statistically
`significant differences (p=0.217) were found for ratings of “wanting heroin” among the
`treatment groups during the study. However, patients who received active depot naltrexone
`reported “needing heroin” less than those who received placebo (p=0.002). The pairwise
`comparisons for ratings of “needing heroin” showed that there were significant differences
`between placebo and naltrexone 192 mg (p<.001), and between placebo and naltrexone 384
`mg (p<.001), but insignificant differences between naltrexone 192 mg and naltrexone 384
`mg (p=0.195).
`
`Clinical Global Impression Scale There was no obvious pattern of difference or statistical
`significance between the mean CGI scores across visits among the three treatment groups.
`
`Hamilton Depression Total Score (HAM-D) Throughout the study, depression scores did not
`significantly differ across the three treatment groups. At baseline, mean HAM-D total scores
`for the placebo, 192 mg, and 384 mg groups were 14.8 (N=17), 14.6 (N=19) and 13.3
`(N=20), respectively. By Week 8-Visit 16, mean HAM-D scores for the placebo, 192 mg,
`and 384 mg groups were 4.0 (N=2), 6.7 (N=9) and 3.1 (N=14), respectively.
`
`Adverse Events Overall In the placebo group (N=18), 9 patients (50%) experienced an
`adverse event (AE), 4 patients (22%) experienced a treatment-related AE, and 1 patient (6%)
`discontinued study participation because of an AE. In the naltrexone 192 mg group (N=20),
`13 patients (65%) experienced an AE, 8 patients (40%) experienced a treatment-related AE,
`and 2 patients (11%) discontinued because of an AE. In the naltrexone 384 mg group
`(N=22), 15 patients (68%) experienced an AE, 3 patients (14%) experienced a treatment-
`related AE, and 0 patients discontinued because of an AE. There were no significant
`differences between treatment groups in the number of AE's, treatment-related AE's, or
`discontinuations due to AE's.
`
`Treatment-related Adverse Events The most common treatment-related AE's were found
`among “general disorders and administration site conditions” (e.g., fatigue, injection site
`induration, injection site pain), where 2 AE's (11.1%) were reported in the placebo group, 6
`(30%) were reported in the naltrexone 192 mg group, and 3 (13.4%) were reported in the
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`naltrexone 384 mg group. Five patients who were discontinued from the study included one
`patient from the placebo group who experienced an injection site induration, one patient
`from the naltrexone 192 mg group who experienced an injection site redness, mass and
`induration, one patient in the naltrexone 192 mg group who experienced a headache, and
`two patients from the naltrexone 192 mg group who experienced increases in liver function
`tests (see below). All of the injection site reactions were rated as moderate in severity and
`resolved spontaneously within 2–3 weeks.
`
`Treatment-emergent Adverse Events Two serious adverse events occurred during the study.
`One 50-year old patient developed diabetes mellitus after receiving the second dose of 384
`mg naltrexone. The relationship to the study medication was noted as being “unlikely.”
`Three months after the end of study participation, a patient who received 192 mg naltrexone
`made a suicide attempt, which was deemed unrelated to the study.
`
`Liver function tests AST, ALT, and GGT values were within twice the upper limit of the
`normal range throughout the study, with the exception of one participant who was
`discontinued prior to administration of the second set of injections due to elevated GGT
`values (AST and ALT values were only mildly elevated). This patient was being treated for
`hepatitis C by his primary care physician and it was felt that the most conservative medical
`approach would be to discontinue him from the study. A second patient demonstrated 4–7
`fold increases in ALT, AST, and GGT values over pre-naltrexone values, accompanied by
`other symptoms including jaundice, dark-colored urine and light-colored stools, within one
`week following administration of 192 mg depot naltrexone. This patient, who was hepatitis
`negative during screening, subsequently tested positive for hepatitis C and it was determined
`that the acute increases in LFT values most likely occurred as a result of this new infection.
`
`Discussion
`
`Although sustained-release preparations of naltrexone have been investigated since the
`1970s17–23, problems with bio-compatibility have prevented their widespread use. The
`present study represents the first prospective, randomized, placebo-controlled clinical trial of
`a sustained-release formulation of naltrexone for the treatment of opioid dependence. The
`data demonstrate that this 30-day, injectable form of naltrexone was safe and effective in
`retaining heroin-dependent patients in treatment. The fact that the percentage of urine
`samples negative for opioids was high (75–80%) regardless of depot naltrexone dose
`suggests that patients who attend clinic visits are more likely to abstain from using opioids
`and other drugs of abuse, with the possible exception of cocaine and cannabinoids. By
`increasing treatment retention, depot naltrexone will allow patients greater contact with
`appropriate supportive counseling to reduce drug use and ease the transition to a life without
`heroin.
`
`Across the time points measured, the average peak naltrexone plasma levels measured
`approximately one week after administration of 192 mg and 384 mg of depot naltrexone
`were 1.9 (± 0.6) and 3.2 (± 0.7) ng/ml, respectively, which were consistent with the levels
`that we reported in our previous study of the same formulation of depot naltrexone15. For
`comparison, a single oral dose of 50 mg naltrexone produces average peak naltrexone
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`plasma concentrations of approximately 9 ng/ml (Cmax) at 1 hr after drug administration
`(Tmax)24. The mean half-life of naltrexone was 3.6 hr, with large individual variability in
`values, which is common with drugs subject to extensive first-pass metabolism24. In
`general, many investigators agree that doses that maintain naltrexone plasma levels of
`approximately 2 ng/ml are sufficient for antagonizing of the effects of high doses of opioid
`agonists.
`
`One potential concern with a long-lasting antagonist is that patients will attempt to override
`the blockade by using large amounts of heroin, thereby placing themselves at increased risk
`of overdose, especially during the period when naltrexone blood levels are decreasing. This
`concern is particularly relevant given the literature in laboratory animals demonstrating an
`up-regulation in µ opioid receptors following discontinuation of chronic treatment with
`opioid antagonists25–33. In normal human participants, however, a study of morphine
`sensitivity before and after naltrexone treatment failed to show any evidence of μ receptor
`up-regulation in the respiratory control system, the most likely site of opioid overdose
`lethality34. There have also been reports of increased opioid overdose in patients following
`discontinuation of oral naltrexone maintenance, compared to discontinuation of agonist
`replacement therapies35–36. The more appropriate comparison, however, would be between
`discontinuation of naltrexone and discontinuation of long-term abstinence because in both
`cases, the former heroin user has remained free of opioids and thus there is significant loss
`of tolerance and greater risk of overdose. In the present study, several participants used
`heroin after receiving the depot injections, but there was no evidence that attempts to
`override the blockade were successful and no accidental or intentional opioid overdoses. In
`fact, a previous study demonstrated that the incidence of opioid overdoses dramatically
`decreased in “high-risk” adolescents treated with an implantable form of naltrexone37.
`Another study by the same group, using a larger sample size, also showed that the incidence
`of opioid overdoses decreased following administration of a naltrexone implant, even
`beyond the period of expected effectiveness of the implant38. It is possible that the gradual
`dissipation of naltrexone from these sustained-release formulations protected these patients
`from experiencing opioid overdose.
`
`Another potential concern with a sustained-release formulation of naltrexone is that the use
`of non-opioid drugs may increase. This phenomenon apparently did not occur in the present
`study because other drug use remained relatively low throughout the study. These data are
`consistent with other studies demonstrating that other drug use declines when patients stop
`using heroin39–40. However, one report concluded that sedative and perhaps other drug
`“overdoses” may increase following administration of a naltrexone implant38. Several of the
`sedative overdoses occurred soon after implant administration, suggesting that the presence
`of residual opioid withdrawal symptoms may have prompted the use of benzodiazepines.
`Because patients who met criteria for current dependence on other drugs of abuse were
`excluded from the present study, it is difficult to conclude confidently that other drug use
`does not increase after treatment with sustained-release naltrexone. Future studies with a
`more heterogeneous drug-abusing population should carefully assess potential changes in
`the amounts and patterns of other drug use.
`
`Arch Gen Psychiatry. Author manuscript; available in PMC 2014 October 17.
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`NIH-PA Author Manuscript
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