Reducing hospital presentations for opioid overdose in patients treated with sustained release naltrexone implants. Maintenance treatment with depot opioid antagonists in subcutaneous implants: an alternative in the treatment of opioid dependence. Naltrexone implants -- duration, tolerability and clinical usefulness. A pilot study. [Naltrexone implants--a pilot project]. Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial. A pilot evaluation of the safety and tolerability of repeat dose administration of long-acting injectable naltrexone (Vivitrex) in patients with alcohol dependence. Naltrexone implants can completely prevent early (1-month) relapse after opiate detoxification: a pilot study of two cohorts totalling 101 patients with a note on naltrexone blood levels. Single- and multiple-dose pharmacokinetics of long-acting injectable naltrexone. Sustained-release naltrexone for alcoholism treatment: a preliminary study.
Non-fatal overdoses represent a significant morbidity for regular heroin users. Naltrexone is an opioid antagonist capable of blocking the effects of heroin, thereby preventing accidental overdose. However, treatment with oral naltrexone is often associated with non-compliance. An alternative is the use of a sustained release preparation of naltrexone. The aim of this study was to assess the change in number of opioid and other drug overdoses in a large cohort of heroin dependent persons (n=361; 218 males) before and after treatment with a sustained release naltrexone implant. A sub-group of this cohort (n=146; 83 males) had previously received treatment with oral naltrexone, which also allowed a comparison of overdoses pre- and post-oral and also post-implant treatments.
                We used a pre-post design, with data prospectively collected via the West Australian Health Services Research Linked Database, and the Emergency Department Information System. Participants were treated under the Australian Therapeutic Goods Administration's special access guidelines.
                Most (336, 93%) of the cohort was in one or both databases. We identified 21 opioid overdoses involving 20 persons in the 6 months pre-treatment that required emergency department presentation or hospital admission: none were observed in the 6 months post-treatment. This is consistent with the existing pharmacokinetic data on this implant, which indicates maintenance of blood naltrexone levels at or above 2 ng/ml for approximately 6 months. A reduced number of opioid overdoses were also observed 7-12 months post-implant. The study found a significant increase in sedative "overdoses", some of which occurred in the 10 days following implant treatment and were likely associated with opioid withdrawal and/or implant treatment. For those previously treated with oral naltrexone, more opioid overdoses occurred in both the 6-months prior to and after oral compared to the 6-months post-implant treatment.
                The findings support the clinical efficacy of this sustained release naltrexone implant in preventing opioid overdose. However, given the high prevalence of poly-substance use among dependent heroin users, programs offering this type of treatment should also focus on preventing, detecting and managing poly-substance use. A report is presented of treatment of 156 patients (male 98%) with opioid dependence (ICD-10 criteria) using a maintenance programme with depot opioid antagonists (naltrexone) as subcutaneous implants, started after an outpatient rapid antagonization regimen. The retention index in the treatment was from 80% in the sixth month, and 65% after one year. The patients were followed-up for 1 year after discharge. For 6 months after discharge 55.4% were still returning for follow-up visits and 20.8% after 1 year, all of them remaining abstinent to opioids. It is concluded that the programme is safe for the patients and shows a better retention index than programmes using oral antagonists, with an improved compliance (negative urine analysis) compared to the latter. Naltrexone blocks opioid effects effectively, but poor compliance limits the clinical usefulness in the treatment of opioid dependence. Long-acting implanted formulations might increase the clinical feasibility. Several implants have been produced, but few clinical reports have been published. This paper describes an open trial with an Australian implant. This implant is claimed to have duration of up to six months with double implants and acceptable levels of side effects. This was explored in the present pilot study with 13 opioid-dependent patients. By single implant of 1.8 g naltrexone the duration judged by naltrexone plasma levels above 1 ng/ml naltrexone was between 2 and 4 months. Double implants maintained such plasma levels for 5-6.5 months. Clinically, the implants appeared promising. Side effects were minimal. During the period with adequate plasma levels of naltrexone, use of opioids was absent and use of other psychoactive drugs reduced. At 1-year follow-up, the patients rated the implants highly positively. An increasing number of Norwegian heroin addicts have had naltrexone implants abroad without proper documentation. The authors established a joint project to study duration and safety.
                Methodology to measure naltrexone in plasma was developed. 10 patients had 21 implants. Plasma samples were collected before, one and three hours after implantation, daily for one week, then weekly. Patient satisfaction, side effects and unwanted medical events were recorded.
                Patients had a protective level of naltrexone for 35-80 days. Side effects were few. Two patients had abstinence reactions caused by insufficient detoxification. Two patients had their repeat implants removed because of tissue reactions. One patient developed hepatitis C infection in the second week after implantation. One had transient increase in transaminases after heavy multi-drug use. The others were without signs of hepatic toxicity.
                Use of implants secures a prolonged period of naltrexone protection. Implants are mostly well tolerated, but tissue reactions to repeat implants could be a problem. Evaluation of the patients should be thorough and the treatment integrated in a competent follow up. Oral naltrexone can completely antagonize the effects produced by opioid agonists. However, poor compliance with naltrexone has been a major obstacle to the effective treatment of opioid dependence.
                To evaluate the safety and efficacy of a sustained-release depot formulation of naltrexone in treating opioid dependence.
                Randomized, double-blind, placebo-controlled, 8-week trial conducted at 2 medical centers.
                Sixty heroin-dependent adults.
                Participants were stratified by sex and years of heroin use (> or = 5 vs < 5) and then were randomized to receive placebo or 192 or 384 mg of depot naltrexone. Doses were administered at the beginning of weeks 1 and 5. All participants received twice-weekly relapse prevention therapy, provided observed urine samples, and completed other assessments at each visit.
                Retention in treatment and percentage of opioid-negative urine samples.
                Retention in treatment was dose related, with 39%, 60%, and 68% of patients in the placebo, 192 mg of naltrexone, and 384 mg of naltrexone groups, respectively, remaining in treatment at the end of 2 months. Time to dropout had a significant main effect of dose, with mean time to dropout of 27, 36, and 48 days for the placebo, 192 mg of naltrexone, and 384 mg of naltrexone groups, respectively. The percentage of urine samples negative for opioids, methadone, cocaine, benzodiazepines, and amphetamine varied significantly as a function of dose. When the data were recalculated without the assumption that missing urine samples were positive, a main effect of group was not found for any drugs tested except cocaine, where the percentage of cocaine-negative urine samples was lower in the placebo group. Adverse events were minimal and generally mild. This formulation of naltrexone was well tolerated and produced a robust, dose-related increase in treatment retention.
                These data provide new evidence of the feasibility, efficacy, and tolerability of long-lasting antagonist treatments for opioid dependence. : Oral naltrexone is currently used as part of a treatment regimen for alcohol-dependent patients, but its clinical utility is hampered by poor patient adherence. A long-acting injectable naltrexone formulation (Vivitrex) was designed to facilitate patient adherence by providing an extended duration of therapeutic naltrexone over 1 month, thereby eliminating the need for daily dosing.
                : A multicenter, randomized, double-blind, placebo-controlled pilot study was conducted to evaluate the safety and tolerability of intramuscular repeat dose administration of this extended-release naltrexone formulation in DSM-IV alcohol-dependent patients. Thirty patients were randomized to treatment with injectable naltrexone (400 mg; n = 25) or a matching placebo injection (n = 5) and were dosed once every 28 days over 4 months. Psychosocial treatment was offered to patients in both treatment groups. Outcome measures related to drinking activity and trough plasma concentrations of naltrexone and its primary metabolite, 6-beta-naltrexol, were evaluated.
                : Injectable naltrexone was generally safe and well tolerated. Reported adverse events were mild to moderate and resolved without intervention; only two patients discontinued due to adverse events. The most common adverse events (nausea and headache) occurred at a similar rate for patients in both treatment groups. Pharmacokinetic analysis confirmed that therapeutic levels of naltrexone were delivered throughout the four 1-month treatment cycles.
                : The results of this pilot study provide the basis and methods for a larger, more definitive trial to determine the utility of this long-acting injectable naltrexone formulation in the treatment of alcohol-dependent patients. Early relapse is common after opiate withdrawal and deprives addicts of important opportunities to develop new, opiate-free cognitive-behavioural habits. The oral opiate antagonist naltrexone (NTX) significantly reduces relapse only when rigorously supervised and/or probation-linked. Simple but effective NTX implants, containing 1G NTX and giving an average blockade of 6 - 7 weeks, have been available since 1997. We present outcome data for two cohorts. Group 1 were the first 55 consecutive implanted British patients (76% male, 51% unemployed, 64% in social classes III - V). Group 2 were a second consecutive group of 46. Implants were inserted subcutaneously mainly during rapid opiate detoxification under general anaesthesia or sedation. The follow-up rate for group 1 was 100%. At 12 weeks after first implantation, 21% of group 1 patients and 26% of group 2 patients had apparently resumed opiate use. Thirty per cent of patients tested-out the blockade in the first week. None reported any opiate effects at less than 5 weeks after insertion. In other patients, typical blood NTX levels 4 - 5 weeks post-insertion were in the range 3 - 5 ng/ml, which is evidently enough to block 500 mg of pure diamorphine. NTX implants provide considerable protection against early relapse and may increase the likelihood of therapeutically useful periods of abstinence after opiate withdrawal. Troublesome tissue reactions were infrequent. Improvements in implant technology and duration are already occurring. We stress that implants strengthen rather than replace the therapeutic alliance. Oral naltrexone is effective in the treatment of alcohol dependence; however, a major limitation of its clinical utility is poor patient adherence to the daily dosing schedule. A biodegradable, long-acting naltrexone microsphere formulation was developed to achieve continuous naltrexone exposure for 1 month in the treatment of alcohol dependence.
                The single- and multiple-dose safety and pharmacokinetics of a long-acting naltrexone microsphere preparation were evaluated in healthy subjects. One group of subjects (n = 28) received a single dose of oral naltrexone 50 mg followed by a single gluteal intramuscular (IM) injection of long-acting naltrexone 190 or 380 mg or placebo. A different group of subjects (n = 14) received oral naltrexone 50 mg daily for 5 days, followed by IM long-acting naltrexone 380 mg or placebo every 28 days for a total of 4 doses. A 7-day washout period separated oral and IM administrations. Blood samples were collected to determine plasma concentrations of naltrexone and the primary metabolite, 6beta-naltrexol.
                After a single IM injection of long-acting naltrexone 380 mg, naltrexone plasma concentrations were measurable in all subjects for at least 31 days postdose. The pharmacokinetics were proportional to the dose and multiple dose observations were consistent with single dose observations. Mean apparent elimination half-lives for naltrexone and 6beta-naltrexol ranged from 5 to 7 days. Exposure to 6beta-naltrexol was reduced with IM injection compared with that oral administration. No serious adverse events occurred.
                This study demonstrated that the long-acting naltrexone formulation was well tolerated, displayed predictable pharmacokinetics, and resulted in no meaningful drug accumulation upon multiple dosing. Intramuscular administration avoids first-pass metabolism and changes the exposure ratio of 6beta-naltrexol to naltrexone compared with oral administration. By providing continuous exposure to naltrexone for several weeks following IM injection, this long-acting naltrexone formulation may offer therapeutic benefit to those patients who experience difficulty adhering to the daily administration schedule necessitated by oral naltrexone therapy. This 12-week study examined the bioavailability, tolerability, and potential efficacy of an injectable sustained-release preparation (SRP) of naltrexone (NTX). Twenty alcohol-dependent subjects took NTX 50 mg po daily for 2 weeks, followed by a 2-week, no-medication Washout Period, a 4-week Injection Period, and a 4-week Follow-up Period. Fifteen subjects (75%) received a single subcutaneous injection of 206 mg of sustained-release NTX, and five subjects (25%) received a placebo injection. All subjects also received eight weekly coping skills sessions during the Oral NTX, and the Washout and Injection Periods.
                After injection, NTX plasma concentrations exceeded a mean of 1 ng/ml for 21 days. Adverse effects produced by the SRP of NTX were comparable with those resulting from oral NTX therapy. Compared with placebo, the SRP of NTX significantly reduced the frequency of heavy drinking days during the Injection and Follow-up Periods.
                The results of this preliminary study support the potential clinical utility of the SRP of NTX for treatment of alcohol dependence.
There is insufficient evidence to evaluate the effectiveness of sustained-release naltrexone for treatment of opioid dependence.For naltrexone injections, administration site-related adverse effects appear to be frequent, but of moderate intensity and time limited. For a harm-benefit evaluation of naltrexone implants, more data on side effects and adverse events are needed.