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At least 19 recordsLinked to original sources
PubMed2000

Naltrexone maintenance treatment for opioid dependence.

BACKGROUND: Despite widespread use of naltrexone maintenance in many countries for more than ten years now (e.g., USA since 1984, UK since 1988) a sound documentation of the research on this drug is still missing. OBJECTIVES: To evaluate the effects of naltrexone maintenance treatment in preventing relapse in opioid addicts after detoxification. SEARCH STRATEGY: We searched MEDLINE, EMBASE, CCTR and handsearched the "Bolletino per le Farmacodipendenze e l'Alcolismo"; contact was sought with pharmaceutical producers of naltrexone, with authors and other CRGs; references of obtained studies. Trials were reliably identified and data extracted. Date of most recent searches: June 1998. SELECTION CRITERIA: All studies controlled for naltrexone; treatment of heroin addicts after detoxification with naltrexone. Studies were classified into three categories (high, moderate or low risk of bias) according to their methodological quality. DATA COLLECTION AND ANALYSIS: Reviewers evaluated data independently and analysed outcome measures taking into consideration adherence to and success of the study intervention. Data was extracted and analysed stratifying for the three categories of study quality. Where possible, meta-analysis was performed. MAIN RESULTS: Eleven studies were included in this review, and not all of them were randomised. Meta-analysis could be done to a low degree only, because the studies and their outcomes were very heterogeneous. The result of this quantitative analysis was statistically poor, and so was the methodological quality of the included studies. REVIEWER'S CONCLUSIONS: The available trials do not allow a final evaluation of naltrexone maintenance treatment yet. A trend in favour of treatment with naltrexone was observed for certain target groups, as described in the literature before. A well-done clinical trial is needed in order to get better evidence as soon as possible.

Humans↗
PubMed2004

Blood naltrexone and 6-beta-naltrexol levels following naltrexone implant: comparing two naltrexone implants.

The aim of this study was to profile and compare blood naltrexone and 6-beta-naltrexol levels with time following treatment with two sustained-release naltrexone preparations produced by GoMedical Industries, Australia at a community heroin treatment clinic in Perth, Western Australia. A sample of 10 patients who each received a 1.7 g naltrexone implant were compared to 24 patients who each received a 3.4 g naltrexone implant as treatment for heroin dependence. Blood naltrexone levels following treatment with the 1.7 g naltrexone implant remained above 2 and 1 ng/ml for approximately 90 and 136 days, respectively. Use of the 3.4 g naltrexone implant extended the period of coverage to approximately 297 (1 ng/ml) or 188 (2 ng/ml) days. Blood 6-beta-naltrexol levels remained above 10 ng/ml for approximately 18 and 83 days, respectively, following use of the 1.7 g and 3.4 g naltrexone implants. The current study data indicate that blood naltrexone and 6-beta-naltrexol levels following treatment with either the 1.7 g or 3.4 g naltrexone implant are greater than those reported in other published data on other sustained-release naltrexone preparations. Furthermore, duration of blood naltrexone and 6-beta-naltrexol levels achieved following use of the 3.4 g implant were superior to those achieved with the 1.7 g naltrexone implant, with naltrexone blood levels maintained above 2 ng/ml for a period of approximately 6.3 months compared to 3 months, respectively. The implications of this in managing the heroin-dependent patient, especially those who find it difficult to shift away from dependent use patterns, are discussed.

Adult↗
PubMed1975

Metabolic reduction of naltrexone. I. Synthesis, separation and characterization of naloxone and naltrexone reduction products and qualitative assay of urine and bile following administration of naltrexone, alpha-naltrexol, or beta-naltrexol.

Reduction of naltrexone and naloxone with sodium borohydride gave a mixture (85:15) of the 6alpha- and 6beta-hydroxy epimers, alpha- and beta-naltrexol and alpha- and beta-naloxol, respectively. Each pair of epimers was separated by preparative thin-layer chromatography and the physical and spectral properties of each compound were determined. Previous assignments for the configuration of the epimers were verified. A semi-quantitative electron capture gas-liquid chromatographic method was devised for distinguishing either alpha- or beta-naltrexol in the presence of the other and in the presence of large amounts (at least 10-fold greater) of naltrexone. The method was used to determine the approximate weight ratio of beta-naltrexol to naltrexone present in enzymatically hydrolyzed urine samples. It was found that substantially greater quantities of beta-naltrexol and/or its conjugates were excreted in the urine of man, monkey, guinea pig and rabbit after administration of naltrexone, whereas very small quantities were excreted by the mouse, rat and dog. In contrast, just trace amounts of the 6alpha-hydroxy epimer, alpha-naltrexol, were detected in the urine of only 2 of the 7 species that had received naltrexone, i.e., monkey and guinea pig. After administration of 3H-15,16-naltrexone, 1 mg/kg, i.v. to the guinea pig, 25% of the radioactivity found following thin-layer chromatography of the extract of acid-hydrolyzed urine corresponded to beta-naltrexol. In gall bladder bile from the guinea pig, only conjugates of naltrexone and beta-naltrexol were found 2 hours after administration of naltrexone. Following administration of beta-naltrexol, 1 mg/kg, i.v. to guinea pigs only beta-naltrexol and/or its conjugates were detected in urine or bile. However, urine collected after administration of alpha-naltrexol, 1 mg/kg, i.v. to guinea pigs contained alpha-naltrexol and its conjugates, as well as a yet unidentified metabolite.

Animals↗
PubMed1976

Comparison of two naltrexone treatment programs: naltrexone alone versus naltrexone plus behavior therapy.

During a period of one year naltrexone was given to twenty-nine subjects. Fifteen of these subjects concurrently participated in a comprehensive behavior therapy program. The subjects in this naltrexone/behavior therapy group were maintanine on naltrexone for nearly twice as long as naltrexone group clients who received no therapy. If the chances for readdiction are reduced by increased time on naltrexone, then the data states the naltrexone should be dispensed as part of a broader therapeutic strategy. Follow-up data, which will be collected during the next year will test the validity of this hypothesis.

Adult↗
PubMed2003

Discrimination of a single dose of morphine followed by naltrexone: substitution of other agonists for morphine and other antagonists for naltrexone in a rat model of acute dependence.

Rats were trained to discriminate 4-h pretreatment with 10 mg/kg morphine and 15-min pretreatment with 0.3 mg/kg naltrexone (morphine-->naltrexone) from pretreatment with saline and 0.3 mg/kg naltrexone (saline-->naltrexone). The discrimination seems to derive from interoceptive stimuli from antagonist-precipitated withdrawal from acute morphine dependence. The purpose of this study was to extend pharmacological characterization of the discrimination by testing opioid agonists other than morphine and antagonists other than naltrexone. Of seven mu-opioid agonists tested in place of morphine, only two (heroin and levorphanol) substituted completely for it; trials completed on the morphine-->naltrexone-appropriate lever increased as a function of agonist and naltrexone dose. Agonists with intrinsic efficacy higher (etorphine, fentanyl, and methadone) or lower (buprenorphine and meperidine) than that of morphine substituted only partially. However, when naltrexone was administered during continuous infusion of fentanyl or methadone via s.c. osmotic pump, rats responded as if they had received morphine-->naltrexone; discriminative responding correlated with global withdrawal scores. Rats responded primarily on the saline-->naltrexone-appropriate lever when naltrexone was administered after pretreatment with dextrorphan, the dextrorotatory isomer of levorphanol, or kappa-opioid agonists (5-alpha,7-alpha,8-beta)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl]-benzeneacetamide (U69,593) and spiradoline. Antagonists with no intrinsic efficacy at mu-opioid receptors (naloxone and diprenorphine) substituted completely for naltrexone, whereas those with some efficacy (nalorphine and levallorphan) substituted partially. Thus, morphine-->naltrexone-like stimulus control of behavior by drugs administered acutely requires pretreatment with certain mu-opioid agonists and a pure antagonist, is independent of agonist efficacy, and is stereoselective. Interoceptive stimuli from naltrexone-precipitated opioid withdrawal are more similar across morphine-like agonists during chronic dependence than they are during acute dependence.

Acute Disease↗
PubMed2003

Blood morphine levels in naltrexone-exposed compared to non-naltrexone-exposed fatal heroin overdoses.

The aim of this study was to investigate the association between prior exposure to naltrexone and increased risk of fatal heroin overdose using a review of toxicology reports for heroin-related fatalities between July 1997 to August 1999 for two groups: those treated with oral naltrexone and those who were not treated. Additional information for the oral naltrexone group was obtained from clinic files. Naltrexone-treated deaths were identified from the patient database at the Australian Medical Procedures Research Foundation (AMPRF), Perth, Western Australia (WA) through the Western Australian Department of Health, Data Linkage Project. Non-treated cases were identified from the database at the Forensic Science Laboratory, State Chemistry Centre (WA). We identified and investigated blood morphine concentrations following 21 fatal heroin overdoses with prior exposure to naltrexone and in 71 non-naltrexone-exposed cases over the same time period. The proportion of deaths where heroin use was a major contributing factor was little different in the non-naltrexone compared to the naltrexone-exposed group. Furthermore, in 'acute opiate toxicity' deaths, blood morphine levels were lower in non-naltrexone-exposed compared with naltrexone-exposed cases. Although there was a higher number of deaths designated as rapid (i.e. occurring within 20 minutes) in the naltrexone-exposed (89%) compared with the non-exposed group (72%) this was not statistically significant. Other drug use in relation to heroin-related fatalities is discussed. Findings do not support the hypothesis that prior exposure to naltrexone increases sensitivity to heroin toxicity.

Adult↗
PubMed1985

Effects of quaternary naltrexone and chlordiazepoxide in squirrel monkeys with enhanced sensitivity to the behavioral effects of naltrexone.

Dose-effect curves were determined for the effects of the opioid antagonist, naltrexone, on lever-pressing responses of squirrel monkeys maintained under a 30-response fixed-ratio schedule of food presentation. Cumulative doses of naltrexone up to 3 mg/kg i.m. had little or no effect on fixed-ratio responding, whereas higher doses reduced responding in all monkeys. After initial determinations of the dose-effect curve for naltrexone, repeated daily injections of high doses of naltrexone resulted in enhanced sensitivity to its behavioral effects. The cumulative dose-effect curve for naltrexone determined after termination of daily injections was shifted more than 3-fold to the left. In these same monkeys, the dose-effect curve for naltrexone methobromide, a quaternary derivative of naltrexone with limited access to the central nervous system, was similar to the initial dose-effect curve for naltrexone. Chlordiazepoxide given 1 hr before the experimental session shifted the naltrexone dose-effect curve back toward its initial position before the regimen of daily injections, but had no systematic effect on the dose-effect curve for quaternary naltrexone. Enhanced sensitivity to the behavioral effects of naltrexone in these experiments appears to depend on a central component of action and is attenuated by chlordiazepoxide.

Animals↗
PubMed2004

Determination of naltrexone and 6-beta-naltrexol in human plasma following implantation of naltrexone pellets using gas chromatography-mass spectrometry.

An alternative to detoxification by oral therapy with the narcotic antagonist naltrexone is the subcutaneous implantation of naltrexone pellets. From detoxified patients with naltrexone implants (1g) 26 blood samples were collected up to 73 days after implantation. The assay for naltrexone and 6-beta-naltrexol in plasma was developed using automated mixed-mode solid-phase extraction, catalysed trimethylsilylation and gas chromatography-mass spectrometry in single ion monitoring mode with naloxone as internal standard. The analytical method was very sensitive with limits of detection of 0.1 ng/ml and was linear up to 60 ng/ml for naltrexone and 200 ng/ml for naltrexol. Intra-day precision for naltrexone and naltrexol were 24.3 and 22.9%, respectively, at the LLOQ (accuracy 1.4 and 0.4%, respectively) and less than 10% (2.0, 6.0 and 20.0 ng/ml, n = 6 each) above. Inter-day precision was 7.9% (accuracy -0.6%) for naltrexone and 10.9% (accuracy 1.6%) for naltrexol (20 ng/ml, n = 10). Extraction recoveries were 83% for both analytes (10 ng/ml, n = 6). The concentrations of naltrexone and naltrexol in the plasma samples were in the range of 0.7-13.7 and 0.9-17.0 ng/ml, respectively. The simple analytical procedure described provided good sensitivity for the assay of naltrexone and naltrexol in plasma after naltrexone pellet implantation.

Drug Implants↗
PubMed1987

Comparison of naltrexone and quaternary naltrexone after systemic and intracerebroventricular administration in pigeons.

The behavioral effects of naltrexone and quaternary naltrexone were evaluated in two groups of pigeons. One group responded under a fixed-ratio schedule of food reinforcement and was trained to discriminate between 3.2 mg/kg morphine (i.m.) and saline. Drug-appropriate responding occurred in a dose-related manner to morphine, given intramuscularly and intraventricularly. When administered intraventricularly morphine was 50 times more potent as a discriminative stimulus and 50-100 times more potent at suppressing responding. Naltrexone, given intraventricularly and intramuscularly, attenuated the discriminative stimulus effects of morphine. Quaternary naltrexone was more potent at suppressing responding when administered intraventricularly but it failed to attenuate the discriminative stimulus effects of morphine. A second group of pigeons, responding under a variable-interval schedule of food reinforcement, was treated with 100.0 mg/kg/day of morphine. Naltrexone and quaternary naltrexone suppressed responding by both routes of administration. Naltrexone was approximately equipotent when given intramuscularly or intraventricularly, and the doses that suppressed responding were 50-500 times smaller than doses required to suppress responding in untreated pigeons. Although quaternary naltrexone was 1800 times more potent when given intraventricularly, the doses necessary to suppress responding by each route were the same as doses required in untreated pigeons. These results extend the conditions under which a quaternary derivative of naltrexone failed to display antagonist activity in the pigeon. The utility of this compound for characterizing central and peripheral mechanisms of action has not been established in different species and testing conditions and, therefore, appears to be appropriate only under conditions in which it is evaluated after systemic, as well as central, administration.

Animals↗
PubMed1997

The safety profile of naltrexone in the treatment of alcoholism. Results from a multicenter usage study. The Naltrexone Usage Study Group.

BACKGROUND: Naltrexone hydrochloride is the first medication approved in the United States for the treatment of alcohol dependence in almost 50 years. This study was designed to collect safety data in a setting that reflected the expected clinical use of naltrexone. METHODS: This was a 12-week, nonrandomized, open-label usage study conducted in 40 alcoholism treatment centers throughout the United States, including free-standing alcoholism treatment programs, university clinics, Veterans Administration hospitals, and office-based primary care practices. Eligible patients were assigned, at the investigators' discretion, to a naltrexone treatment group or to a reference group that did not receive study medication. At study entry, patients must have been abstinent from alcohol for 1 to 6 weeks and enrolled in a psychosocial treatment program for alcoholism. Patients often underrepresented in controlled clinical trials, including women and patients with comorbid medical and psychiatric illness, were eligible. Patients with polysubstance abuse or infection with the human immunodeficiency virus were not excluded. RESULTS: Of 865 patients enrolled, 570 received naltrexone and 295 were in a reference group. The most common new-onset adverse clinical events in the naltrexone group were nausea (9.8%) and headache (6.6%). Naltrexone was discontinued in 15.0% of patients because of adverse events, most frequently nausea. The results of liver function tests in the naltrexone group were similar to those in the reference group. No death occurred during the study. CONCLUSIONS: This is the largest study to date describing the safety of naltrexone in a heterogeneous population of persons with alcoholism. No new safety concerns were identified.

Adolescent↗
PubMed2004

Achieving long-term continuous blood naltrexone and 6-beta-naltrexol coverage following sequential naltrexone implants.

The aim of this study was to assess blood free naltrexone and 6-beta-naltrexol levels with time following treatment with sequential sustained-release naltrexone preparations. Data were collected from blood samples analysed independently for naltrexone and 6-beta-naltrexol and from clinical record review at a community heroin treatment clinic in Perth, Western Australia. Five patients received sequential 3.4 g (3.49+/-0.01 g and 3.36+/-0.05 g, respectively) naltrexone implants. The second implant was received on average within 131.2+/-15.67 days of the first implant. The mean length of follow-up was 307.2+/-18.28 days of the first implant. Blood naltrexone levels have the potential to remain above 2 and 1 ng/ml for a total of 390 and 524 days, respectively, and blood 6-beta-naltrexol was maintained above 10 ng/ml for a total of 222 days following insertion of these implants. No patient relapsed to dependent heroin use during the implant coverage period while blood naltrexone concentrations were above 2 ng/ml. Results indicate that blood naltrexone and 6-beta-naltrexol levels can be maintained above therapeutic levels for prolonged periods following use of sequential 3.4 g naltrexone implants. These extended periods of coverage will offer significant benefits for managing the heroin-dependent patient.

Adult↗
PubMed1985

Pharmacokinetics of morphine and its surrogates V: Naltrexone and naltrexone conjugate pharmacokinetics in the dog as a function of dose.

Sensitive reversed-phase HPLC assays with electrochemical detection, developed to quantify naltrexone, 6 beta-naltrexol, and their conjugates in biological fluids, provided assay sensitivities of 2-14 ng/mL in plasma, urine, and bile. Plasma, urine, and bile were monitored in dogs after bolus administrations of 0.5 and 5.0 mg/kg iv naltrexone hydrochloride. Plasma-time data showed two sequential half-lives of 5 +/- 1 (SEM) and 47 +/- 5 min. Pharmacokinetics were dose-independent; total and renal clearances were 1043 +/- 98 mL/min and 72 +/- 11 mL/min, respectively, with a similar renal clearance (85 +/- 12) for the conjugate. The percentages of the dose excreted in the urine as naltrexone and its conjugate were 7 +/- 1% and 58 +/- 3%, respectively, with the remainder being excreted in the bile as conjugates. As much as 36% was collected as conjugate in the total bile of the bile-cannulated dog. There was no biliary secretion of unchanged naltrexone. The conjugate was apparently enterohepatically recirculated. 6 beta-Naltrexol is not a metabolite of naltrexone in dogs. Within the limits of analytical detection (2 ng/mL) neither 6 beta-naltrexol nor its conjugates appeared in any monitored biological fluids when such fluids were assayed quickly after sampling.

Animals↗
PubMed1977

Quantitative determination of naltrexone and naltrexone prodrugs by electron-capture gas-liquid chromatography.

An electron-capture gas chromatographic method has been applied to the determination of eleven ester and ether derivatives of naltrexone believed to act as prodrugs. Standard analytical curves are presented for all prodrugs and quantitation is shown to be possible from 10 ng to 1.5 microgram of each compound. Ester derivatives of naltrexone are hydrolyzed to naltrexone prior to analysis as the perfluoroalkyl esters. Analysis of synthetic mixtures of these with naltrexone demonstrated that quantitation by difference measurements is possible with naltrexone-derivative ratios from 4:1 to 1:10. Ether derivatives are analyzed without hydrolysis. This method is applicable to biological fluids as well as aqueous solutions.

Chromatography, Gas↗
PubMed1988

Naltrexone-3-salicylate (a prodrug of naltrexone): synthesis and pharmacokinetics in dogs.

Naltrexone-3-salicylate (3), a prodrug of naltrexone (1), was prepared by a simple procedure from naltrexone-3-acetylsalicylate (2). The plasma (dog and human) hydrolysis half-life of 3 was found to be approximately 30 min. Compound 2 was previously shown to hydrolyze in dog and human plasma with a fast deacetylation step to 3, followed by slower hydrolysis of 3 to 1 (t1/2, approximately 30 min). Oral naltrexone bioavailability was greatly improved (approximately 30-fold) after oral administration of 3 to dogs, similar to the improvement observed after oral administration of 2. The half-life of naltrexone in dogs after oral administration of 3 was similar to that observed after oral administration of 2 (approximately 1 hr).

Animals↗
PubMed1995

Naltrexone in the treatment of alcoholism: predicting response to naltrexone.

The pooled results of 99 subjects from our Veterans Affairs population show that naltrexone-treated subjects had a greater reduction in alcohol craving, number of drinking days, and alcoholic relapse rates when compared with placebo-treated subjects. Based on our findings and results from other double-blind trials of naltrexone, we conclude that naltrexone is a safe and useful adjunct in the rehabilitation of alcohol-dependent patients. Increased baseline levels of psychological distress and craving as well as higher levels of somatic distress, anxiety, phobic anxiety, and obsessive-compulsive symptoms predicted an increased number of drinking days during the study. Significant interactions between naltrexone treatment, initial craving, and somatic distress suggest that naltrexone may be useful for subjects who present with high levels of craving and somatic symptoms.

Adult↗
PubMed1982

Naltrexone-insensitive facilitation and naltrexone-sensitive inhibition of passive avoidance behavior of the ACTH-(4-9) analog (ORG 2766) are located in two different parts of the molecule.

Subcutaneous injection of the ACTH-(4-9) analog (OG 2766) in ng amounts prior to the retention test facilitated, while microgram doses attenuated passive avoidance behavior. The inhibitory effect could easily be overcome by treatment with ACTH-(1-10) either before or after ORG 2766 administration. Thus, inhibition of passive avoidance behavior by ORG 2766 probably was not due to competition with ACTH-like peptides or a functional antagonistic influence on brain structures sensitive to ACTH-like peptides. Intracerebroventricular administration of ACTH-(4-10) in a wide dose range (0.5-10.0 micrograms) and of ORG 2766 in low doses (0.5-1.0 ng) facilitated passive avoidance behavior, whereas 'high' doses of ORG 2766 (5.0 and 10.0 ng) and graded doses of COOH terminal tripeptide of ORG 2766 (Phe-D-Lys-Phe; PDLP; 0.5-10.0 ng) attenuated passive avoidance behavior. The NH2 terminal tetrapeptide of ORG 2766 (H-Met/O2/-Glu-His-Phe) facilitated passive avoidance behavior, whereas the NH2 terminal tripeptide (H-Met/O2/-Glu-His) was ineffective. Naltrexone pretreatment antagonized the attenuating effect of ORG 2766 and PDLP. Following pretreatment with this opiate antagonist both 'low' and 'high' doses of ORG 2766 and the NH2 terminal tetrapeptide of ORG 2766 induced facilitation of passive avoidance behavior, while PDLP was ineffective in the presence of naltrexone. Thus, ORG 2766 exerts a dual effect on passive avoidance behavior. The facilitating effect of ORG 2766 resides in the NH2 terminal part and is unrelated to naltrexone-sensitive brain opiate receptor sites, whereas the inhibiting influence is located in the COOH terminal part of the peptide and depends on naltrexone-sensitive brain opiate receptor sites.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Dyskinesias occur in response to saline and naltrexone alone after priming with combination of dopaminergic agents and naltrexone in the MPTP parkinsonian monkeys.

Storage of motor memory involves the basal ganglia and more precisely the striatum, which receives afferents from all regions of the cerebral cortex. In Parkinsonian (MPTP) monkeys, we observed an increase in the dyskinetic response to dopaminergic agents when combined with opioid antagonists (naloxone or naltrexone) while morphine, attenuated the dyskinetic response. An interesting phenomenon observed after several acute co-administrations of naltrexone with dopaminergic agents was the manifestation of dyskinesias even after the injection of saline or naltrexone alone. However, this phenomenon was not observed when morphine was used in the same conditions. These unexpected observations concerning the acquisition of dyskinesias with saline or naltrexone alone, reported for the first time, might suggest the implication of a learning phenomenon in the induction of levodopa-induced dyskinesias.

Animals↗
PubMed1996

Application of the message-address concept to the docking of naltrexone and selective naltrexone-derived opioid antagonists into opioid receptor models.

A binding site model for the opioid family of G-protein coupled receptors (GPCRs) is proposed based on the message-address concept of ligand recognition. Using ligand docking studies of the universal opioid antagonist, naltrexone, the structural basis for "message' recognition is explored across all three receptor types, mu, delta, and kappa. The binding mode proposed and basis for selectivity are also rationalized using the naltrexone-derived ligands, naltrindole (NTI) and norbinaltorphimine (nor BNI). These ligands are docked to the receptor according to the common naltrexone core or message. The resulting orientation places key "address' elements in close proximity to amino acid residues critical to selectivity among receptors types. Selectivity is explained by sequence differences in the mu, delta, and kappa receptors at these recognition points. Support for the model is derived from site directed mutagenesis studies and ligand binding data for the opioid receptors and other related GPCRs.

Amino Acid Sequence↗