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A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Efficacy in the Management of Opioid Dependence

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Naltrexone is a long acting competitive antagonist at opioid receptors which blocks the subjective and objective responses produced by intravenous opioid challenge. It is suitable for oral administration, and has been studied as an adjunct for use in opioid addiction management programmes.

In non-comparative clinical trials involving detoxified patients, oral naltrexone reduced heroin craving and between 23 and 62% of patients remained in treatment after 3 to 4 weeks. However, in two studies 32 to 58% of patients who continued in treatment were opioid-free between 6 and 12 months after stopping naltrexone. As might be expected studies involving highly motivated patients have shown this type of patient group to achieve greater treatment success rates during naltrexone therapy, and remain opioid-free longer than other groups of apprently less motivated patients. In addition, when naltrexone is combined with family support, psychotherapy and counselling, patients are more likely to remain opioid-free. Naltrexone produces a low incidence of side effects, with gastrointestinal effects being the most commonly reported symptoms. Thus, despite the overall high attrition rates from trials, in selected patient groups and in combination with appropriate support mechanisms and psychotherapy, naltrexone represents a useful adjunct for the maintenance of abstinence in the detoxified opioid addict.

Pharmacodynamic Properties

Naltrexone produces negligible opioid agonist properties, with no analgesic activity in the mouse and limited or no activity in rat writhing tests. In human studies there have been only isolated reports of agonist effects such as pupillary miosis, dysphoria and unpleasant sensations following naltrexone administration.

In the rhesus monkey, intravenous naltrexone suppressed morphine self-administration and in the drug-dependent animal precipitated opioid withdrawal with a potency at least 12 times that of nalorphine and 2.5 times that of naloxone or cyclazocine. In post-addict volunteers, oral naltrexone 100mg produced 90% blockade of subjective and objective responses, including euphoria and reinforcement produced by intravenous heroin challenge at 24 hours, with the naltrexone antagonism of subsequent heroin challenges decreasing over 72 hours.

In morphine-dependent subjects naltrexone was approximately 17 times more potent than nalorphine and twice as potent as naloxone, respectively, in precipitating an abstinence syndrome. Following daily oral administration, naltrexone 50mg attenuated the development of abstinence and dependence with a potency similar to that produced by cyclazocine 4mg orally in subjects dependent on 240mg of morphine per day.

In opioid-dependent or detoxified patients and healthy volunteers, oral administration of naltrexone 25 to 100mg daily produced significant increases in plasma concentrations of β-endorphin, cortisol and luteinising hormone, equivocal changes in prolactin and testosterone concentrations, non-significant increases in adrenocorticotrophic hormone and no effect on follicle-stimulating hormone concentrations. Naltrexone is a competitive antagonist at opioid receptor sites. Following long term naltrexone administration to animals, marked increases in the numbers of putative brain opioid receptors, but not the σ subclass, were detected but these observations have not been reported in humans. In morphine-dependent animals, naltrexone produced supersensitivity to morphine in the locus coeruleus which is the central nervous system site believed to be involved in the genesis of opioid dependence.

Pharmacokinetic Properties

Oral administration of naltrexone results in rapid absorption with peak plasma concentrations of 19 to 44 μg/L being reached within 1 hour. Oral bioavailability was reported to range between 5 and 60%. Linear increases in the area under the plasma concentration-time curve (AUC) were observed for naltrexone and β-naltrexol (a metabolite of naltrexone) following oral administration of naltrexone 50, 100 and 200mg. There was no evidence of accumulation of naltrexone after multiple dosing in healthy subjects Naltrexone is 20% bound to plasma proteins and has an apparent volume of distribution of 16.1 L/kg after single doses and 14.2 L/kg after repeated administration.

Metabolism of naltrexone is predominantly through reduction to 6β-naltrexol, which in common with other minor metabolites undergoes extensive glucuronide conjugation in the liver. Up to an estimated 60% of an oral dose reaches the systemic circulation, with 24-hour urinary recovery reported as conjugated naltrexone 18% and conjugated β-naltrexol 21%. The elimination half-life of orally administered naltrexone derived from urinary excretion data varied from 1.1 to 10.3 hours; the differences could be due to variations in enterohepatic recycling between subjects.

The plasma concentration and elimination half-life of naltrexone, and to a lesser extent that of the main metabolite β-naltrexol, correlate with the degree of opioid antagonism as evidenced by the objective and subjective withdrawal signs produced following intravenous heroin administration.

Therapeutic Trials

In open and blinded dose-ranging studies oral naltrexone 20 to 200mg daily attenuated the responses to heroin challenge between 24 and 72 hour after naltrexone administration in most patients. Furthermore, it produced a reduction in craving and up to 85% of urine samples were found to be opioid-free.

In non-comparative trials in patients detoxified from opioids, naltrexone 350 mg/week was administered in divided doses. Between 23 and 62% of patients remained in treatment after 3 to 4 weeks; when this group was followed up at 12 months 64% of naltrexone-treated patients were opioid-free compared to 39% in the control group. In 2 non-comparative studies 32 and 58% of patients who continued in treatment were opioid-free between 6 and 12 months after stopping naltrexone, 11 to 33% of urine samples were opioid-positive during naltrexone maintenance, and heroin use and craving was generally reduced, and in some patients eliminated. In non-comparative studies involving particularly motivated patients, such as those at risk of losing employment or liberty, only 18% were readdicted at 6 months after commencing naltrexone. Other non-comparative studies in which naltrexone was used in conjunction with behaviour and family therapy reported improved retention times and success rates, with 52% of these patients continuing in treatment programmes after stopping naltrexone compared with 12.5% of patients receiving naltrexone alone.

Double-blind studies have demonstrated the effectiveness of naltrexone in reducing heroin self-administration and craving compared with placebo. Thus, patients receiving naltrexone injected 2 to 7.5% of available heroin whereas patients on placebo injected 57.5 to 100% of that available, which correlated with the number of urine samples positive for opioids. In a double-blind tolerability study, naltrexone produced 67 drug-related side effects compared with 298 for cyclazocine.

From currently available preliminary clinical data there is no evidence to suggest that naltrexone 5 to 100mg daily improves the symptoms of Alzheimer’s disease, Parkinsonism, Huntington’s disease or schizophrenia. In addition, the effects of naltrexone on food intake and bodyweight are equivocal with further studies required to determine any potential of naltrexone as an anorectic.

Side Effects

Gastrointestinal symptoms, particularly nausea and vomiting, have been the most frequently reported side effects. Other reported effects include headaches, skin rashes, decreased mental acuity, depression, anxiety, and loss of energy. However, such symptoms are also observed in opioid naive subjects and during opioid withdrawal, and thus could be attributed to naltrexone inducing mild abstinence syndrome in certain patients. In obese patients naltrexone in doses up to 300mg produced elevations in serum transaminase enzymes 3 to 19 times greater than baseline values. However, following cessation of naltrexone treatment, values returned to baseline or below.

Dosage and Administration

Administration of naltrexone should not be initiated until the patient has been opioid-free for 7 to 10 days and the naloxone challenge test for opioid withdrawal is negative. If no abstinence signs are observed, following a preliminary dose of naltrexone 25mg, the rest of the daily dose is administered. Maintenance treatment regimen with naltrexone can be flexible where patients may receive naltrexone 50mg on weekdays and 100mg on Saturday or 100mg every other day, or 150mg every third day. Naltrexone is contraindicated in patients with acute hepatitis or liver failure and should not be used in patients receiving opioid analgesics.

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Correspondence to John P. Gonzalez.

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Various sections of the manuscript reviewed by: M. Appelbaum Faculté de Médecine, Xavier Bichat, Université Paris, France; A.A.-B. Badawy, Biomedical Research Laboratory, Whitechurch Hospital, Cardiff, Wales; R. Bullingham, Banbury, England; H.M. Ginzburg, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA; M.S. Gold, Fair Oaks Hospital, Summit, New Jersey, USA; H.D. Kleber, Department of Psychiatry, Yale University, New Haven, Connecticut, USA; M.H. Lader, Institute of Psychiatry, Denmark Hill, London, England; W.R. Martin, Department of Pharmacology, University of Kentucky, Lexington, Kentucky, USA; C.P. O’Brien, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA, N. Seivewright, Mapperley Hospital, Nottingham, England; P.J. Tyrer, Mapperley Hospital, Nottingham, England; J.A. Vale, West Midlands Poison Unit, Dudley Road Hospital, Birmingham, England.

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Gonzalez, J.P., Brogden, R.N. Naltrexone. Drugs 35, 192–213 (1988). https://doi.org/10.2165/00003495-198835030-00002

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  • Morphine
  • Naloxone
  • Heroin
  • Naltrexone
  • Opioid Dependence