A systematic review of the effectiveness of naltrexone in the maintenance treatment of opioid and alcohol dependence

doi:10.1016/j.euroneuro.2005.11.001

European Neuropsychopharmacology

Volume 16, Issue 5, July 2006, Pages 311-323

https://doi.org/10.1016/j.euroneuro.2005.11.001 Get rights and content

Abstract

This systematic review summarises evidence of the effectiveness of naltrexone (NTX) and the added value of psychosocial treatment in the maintenance treatment of opioid and alcohol dependence.

Studies were selected through a literature search conducted in March 2004. Seven opioid and seventeen alcohol studies were identified. When possible, meta-(regression) analyses were performed. There is lack of evidence about the effectiveness of NTX in the maintenance treatment of opioid dependence. There is evidence for the effectiveness and applicability of NTX in the management of alcohol dependence. The opioid studies combined NTX with a variety of psychosocial interventions, which plagued the evaluation of their value. Concomitant psychosocial interventions used in the alcohol studies were mainly cognitive behavioural, which seems to be more effective than NTX combined with supportive therapy. Available data do not allow firm conclusions regarding the added effect of psychosocial interventions. However, the data suggest that a combination of naltrexone with cognitive behavioural relapse prevention therapy is beneficial in alcohol dependent patients.

Introduction

Naltrexone (NTX), an opioid antagonist, blocks intrinsic properties of psychoactive substances that act on the μ, κ, and δ opioid receptor sites by competitive occupation. It is ascertained that alcohol acts on the opioid receptor sites. By blocking these sites, NTX prevents the reinforcing effects of alcohol consumption (O'Brien et al., 1996). The metabolic pattern of NTX predominantly involves the reduction of NTX into 6-β-hydroxy naltrexone (6-β-naltrexol; Wall et al., 1981). The long acting properties of NTX are mainly due to this metabolite, which has an elimination half-life (T_1/2) of approximately 13 h compared to the parent drug with a T_1/2 value of 4 h. The dose-related antagonism on both subjective and objective responses has been subject to some research, although these findings are based on small samples (Resnick et al., 1974, Verebey, 1981). NTX and 6-β-naltrexol are dose proportional (linear increase) in terms of AUC and C_max over the range of 50 to 200 mg. A bio-equivalence was demonstrated after 100-mg single doses (Meyer et al., 1984). Despite the excellent pharmacological (blocking) properties, in practice NTX treatment is often hampered by dropout, non-compliance and consequently relapses into opioid or alcohol abuse (Rothenberg et al., 2002, Tucker et al., 2004).

However, evidence is scant regarding the question whether and which type of psychosocial intervention should be combined with NTX treatment in order to optimise its effectiveness.

First and foremost, the current study was conducted to unfold and update the effectiveness of NTX. To summarise the available (recent) evidence on the effectiveness of NTX, in the maintenance treatment of alcohol and opioid dependence, a systematic (meta-analytic) review was conducted with the following aims:

1.
to study the effects of NTX compared to placebo in the maintenance treatment of opioid and alcohol dependence;
2.
to study whether combining NTX with psychosocial treatment is more effective than treatment with NTX alone.

Section snippets

Criteria for considering studies for this review

Randomised (placebo) controlled trials (RCTs) and controlled clinical trials (CCTs) with NTX maintenance treatment were included. When group allocation in a trial was determined randomly, the study could be labelled as an RCT. If the randomisation procedure was unclear, but considered as randomised (e.g. double-blind study), the trial was assumed to be a CCT.

RCTs and CCTs had to include participants with alcohol or opiate abuse or dependence (DSM-III-R or DSM-IV) between 18 and 75 years of age.

Study selection: NTX in opioid studies

After consulting Pubmed, EMBASE, PsychINFO and CCTR 119, 275, 149 and 65 publications, including duplicates, were identified respectively. Only seven placebo-controlled trials on maintenance treatment of opioid dependence met the selection criteria and were included in the review (Brahen et al., 1977, Guo et al., 2001, Hollister, 1978, Lerner et al., 1992, Mello et al., 1981, San et al., 1991, Shufman et al., 1994).

Study selection: NTX in alcohol studies

The search via Pubmed, EMBASE, PsychINFO and CCTR yielded 136, 461, 101 and 165

Discussion

We conducted a review on the effectiveness of NTX in the maintenance treatment of opioid and alcohol dependence. Where possible, studies were statistically pooled using the random effects model. This model takes into account the within-study sampling error and between-studies variation.

References (115)

N.H. Azrin et al.
Evaluation of an instructional program for improving medication compliance for chronically mentally ill outpatients
Behav. Res. Ther.
(1998)
K.M. Carroll
Integrating psychotherapy and pharmacotherapy to improve drug abuse outcomes
Addict. Behav.
(1997)
J.W. Cornish et al.
Naltrexone pharmacotherapy for opioid dependent federal probationers
J. Subst. Abuse Treat.
(1997)
J. Cramer et al.
Medication compliance feedback and monitoring in a clinical trial: predictors and outcomes
Value Health
(2003)
D.A. Fiellin et al.
New therapies for alcohol problems: application to primary care
Am. J. Med.
(2000)
R.A. Greenstein et al.
Predictors of favorable outcome following naltrexone treatment
Drug Alcohol Depend.
(1983)
H.R. Kranzler et al.
Naltrexone vs. nefazodone for treatment of alcohol dependence: a placebo-controlled trial
Neuropsychopharmacology
(2000)
E.M. Krupitsky et al.
Naltrexone for heroin dependence treatment in St. Petersburg, Russia
Subst. Abuse Treat.
(2004)
C. McGregor et al.
A comparison of antagonist-precipitated withdrawal under anesthesia to standard inpatient withdrawal as a precursor to maintenance naltrexone treatment in heroin users: outcomes at 6 and 12 months
Drug Alcohol Depend.
(2002)
C.P. O'Brien et al.
Naltrexone in the treatment of alcoholism: a clinical review
Alcohol
(1996)

D. Oslin et al.

Naltrexone as an adjunctive treatment for older patients with alcohol dependence

Am. J. Geriatr. Psychiatry

(1997)

D.W. Oslin et al.

Alcoholism treatment adherence: older age predicts better adherence and drinking outcomes

Am. J. Geriatr. Psychiatry

(2002)

L.M. Oswald et al.

Catechol-O-methyltransferase polymorphism alters hypothalamic-pituitary-adrenal axis responses to naloxone: a preliminary report

Biol. Psychiatry

(2004)

M.X. Patel et al.

Medication adherence: predictive factors and enhancement strategies

Psychiatry

(2004)

K.L. Preston et al.

Improvement in naltrexone treatment compliance with contingency management

Drug Alcohol Depend.

(1999)

R.B. Resnick et al.

Narcotic antagonists in the treatment of opioid dependence: review and commentary

Compr. Psychiatry.

(1979)

J.L. Rothenberg et al.

Behavioral naltrexone therapy: an integrated treatment for opiate dependence

J. Subst. Abuse Treat.

(2002)

E.N. Shufman et al.

The effectiveness of naltrexone in preventing reabuse of heroin after detoxification

Biol. Psychiatry

(1994)

J. Ahmadi et al.

A double blind placebo-controlled study of naltrexone in the treatment of alcohol dependence

German J. Psychiatry

(2002)

R.F. Anton

New methodologies for pharmacological treatment trials for alcohol dependence

Alcohol., Clin. Exp. Res.

(1996)

R.F. Anton et al.

Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics, results of a placebo-controlled trial

Am. J. Psychiatry

(1999)

R.F. Anton et al.

Posttreatment results of combining naltrexone with cognitive-behavior therapy for the treatment of alcoholism

J. Clin. Psychopharmacol.

(2001)

D.E. Arnold-Reed et al.

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

Addict. Biol.

(2003)

J. Balldin et al.

A 6-month controlled naltrexone study, combined effect with cognitive behavioral therapy in outpatient treatment of alcohol dependence

Alcohol., Clin. Exp. Res.

(2003)

C. Bouza et al.

Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review

Addiction

(2004)

L.S. Brahen et al.

Naltrexone and cyclazocine

Arch. Gen. Psychiatry

(1977)

C. Brewer et al.

Naltrexone: report of lack of hepatotoxicity in acute viral hepatitis, with a review of the literature

Addict. Biol.

(2004)

E. Callahan et al.

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

NIDA Res. Monogr.

(1976)

J.E. Carreno et al.

Maintenance treatment with depot opioid antagonists in subcutaneous implants: an alternative in the treatment of opioid dependence

Addict. Biol.

(2003)

K.M. Carroll et al.

Targeting behavioral therapies to enhance naltrexone treatment of opioid dependence: efficacy of contingency management and significant other involvement

Arch. Gen. Psychiatry

(2001)

K.M. Carroll et al.

Contingency management to enhance naltrexone treatment of opioid dependence: a randomized clinical trial of reinforcement magnitude

Exp. Clin. Psychopharmacol.

(2002)

J. Chick et al.

A multicentre randomized double-blind placebo controlled trial of naltrexone in the treatment of alcohol dependence or abuse

Alcohol Alcohol.

(2000)

J. Cramer

Medication use by the elderly: enhancing patient compliance in the elderly Role of packaging aids and monitoring

Drugs Aging

(1998)

J. Cramer et al.

Enhancing medication compliance for people with serious mental illness

J. Nervous Mental Dis.

(1999)

E. Digiusto et al.

Serious adverse events in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD)

Addiction

(2004)

M.R. DiMatteo et al.

Achieving Patient Compliance: The Psychology of Medical Practitioner's Role

(1982)

C. Dyer

Addict died after rapid opiate detoxification

BMJ

(1998)

W. Fals-Stewart et al.

Behavioral family counseling and naltrexone for male opioid-dependent patients

J. Consult. Clin. Psychol.

(2003)

B.A. Flannery et al.

Alcohol craving predicts drinking during treatment: an analysis of three assessment instruments

J. Stud. Alcohol

(2003)

J. Foster et al.

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

Addict. Biol.

(2003)

J.U.C. Garbutt et al.

Pharmacological treatment of alcohol dependence

JAMA

(1999)

J.C. Garbutt et al.

Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial

JAMA

(2005)

M. Gastpar et al.

Lack of efficacy of naltrexone in the prevention of alcohol relapse: results from a German multicenter study

J. Clin. Psychopharmacol.

(2002)

T.T. Gorski et al.

Staying Sober: Guide to Relapse Prevention

(1986)

J. Guardia et al.

A double-blind placebo-controlled study of naltrexone in the treatment of alcohol-dependence disorder: results from a multicenter clinical trial

Alcohol., Clin. Exp. Res.

(2002)

S. Guo et al.

Effectiveness of naltrexone hydrochloride for preventing relapse among opiate-dependent patients after detoxification

Hong Kong J. Psychiatry

(2001)

P. Heinälä et al.

Targeted use of naltrexone without prior detoxification in the treatment of alcohol dependence: a factorial double-blind placebo controlled trial

J. Clin. Psychopharmacol.

(2001)

S.T. Higgins et al.

Clinical implications of reinforcement as a determinant of substance use disorders

Annu. Rev. Psychol.

(2004)

L.E. Hollister

Clinical evaluation of naltrexone treatment of opiate-dependent individuals Report of the national research council committee on clinical evaluation of narcotic antagonists

Arch. Gen. Psychiatry

(1978)

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A systematic review of the effectiveness of naltrexone in the maintenance treatment of opioid and alcohol dependence

Abstract

Introduction

Section snippets

Criteria for considering studies for this review

Study selection: NTX in opioid studies

Study selection: NTX in alcohol studies

Discussion

Behav. Res. Ther.

Addict. Behav.

J. Subst. Abuse Treat.

Value Health

Am. J. Med.

Drug Alcohol Depend.

Neuropsychopharmacology

Subst. Abuse Treat.

Drug Alcohol Depend.

Alcohol

Am. J. Geriatr. Psychiatry

Am. J. Geriatr. Psychiatry

Biol. Psychiatry

Psychiatry

Drug Alcohol Depend.

Compr. Psychiatry.

J. Subst. Abuse Treat.

Biol. Psychiatry

A double blind placebo-controlled study of naltrexone in the treatment of alcohol dependence

German J. Psychiatry

New methodologies for pharmacological treatment trials for alcohol dependence

Alcohol., Clin. Exp. Res.

Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics, results of a placebo-controlled trial

Am. J. Psychiatry

Posttreatment results of combining naltrexone with cognitive-behavior therapy for the treatment of alcoholism

J. Clin. Psychopharmacol.

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

Addict. Biol.

A 6-month controlled naltrexone study, combined effect with cognitive behavioral therapy in outpatient treatment of alcohol dependence

Alcohol., Clin. Exp. Res.

Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review

Addiction

Naltrexone and cyclazocine

Arch. Gen. Psychiatry

Naltrexone: report of lack of hepatotoxicity in acute viral hepatitis, with a review of the literature

Addict. Biol.

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

NIDA Res. Monogr.

Maintenance treatment with depot opioid antagonists in subcutaneous implants: an alternative in the treatment of opioid dependence

Addict. Biol.

Targeting behavioral therapies to enhance naltrexone treatment of opioid dependence: efficacy of contingency management and significant other involvement

Arch. Gen. Psychiatry

Contingency management to enhance naltrexone treatment of opioid dependence: a randomized clinical trial of reinforcement magnitude

Exp. Clin. Psychopharmacol.

A multicentre randomized double-blind placebo controlled trial of naltrexone in the treatment of alcohol dependence or abuse

Alcohol Alcohol.

Medication use by the elderly: enhancing patient compliance in the elderly Role of packaging aids and monitoring

Drugs Aging

Enhancing medication compliance for people with serious mental illness

J. Nervous Mental Dis.

Serious adverse events in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD)

Addiction

Achieving Patient Compliance: The Psychology of Medical Practitioner's Role

Addict died after rapid opiate detoxification

BMJ

Behavioral family counseling and naltrexone for male opioid-dependent patients

J. Consult. Clin. Psychol.

Alcohol craving predicts drinking during treatment: an analysis of three assessment instruments

J. Stud. Alcohol

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

Addict. Biol.

Pharmacological treatment of alcohol dependence

JAMA

Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial

JAMA

Lack of efficacy of naltrexone in the prevention of alcohol relapse: results from a German multicenter study

J. Clin. Psychopharmacol.

Staying Sober: Guide to Relapse Prevention

A double-blind placebo-controlled study of naltrexone in the treatment of alcohol-dependence disorder: results from a multicenter clinical trial

Alcohol., Clin. Exp. Res.

Effectiveness of naltrexone hydrochloride for preventing relapse among opiate-dependent patients after detoxification

Hong Kong J. Psychiatry