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BMJ Clin Evid. 2011; 2011: 1015.
Published online 2011 September 20.
PMCID: PMC3275107

Opioid dependence

K Thyarappa Praveen,# Fergus Law, Senior Clinical Lecturer in Psychopharmacology,# Jacinta O'Shea,# and Jan Melichar, Consultant Psychiatrist in Substance Abuse#

Abstract

Introduction

Dependence on opioids is a multifactorial condition involving genetic and psychosocial factors. There are three stages to treating opioid dependence. Stabilisation is usually by opioid substitution treatments, and aims to ensure that the drug use becomes independent of mental state (such as craving and mood) and independent of circumstances (such as finance and physical location). The next stage is to withdraw (detox) from opioids. The final stage is relapse prevention. This treatment process contributes to recovery of the individual, which also includes improved overall health and wellbeing, as well as engagement in society.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for stabilisation (maintenance) in people with opioid dependence? What are the effects of drug treatments for withdrawal in people with opioid dependence? What are the effects of drug treatments for relapse prevention in people with opioid dependence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 26 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review, we present information relating to the effectiveness and safety of the following interventions: buprenorphine; clonidine; lofexidine; methadone; naltrexone; and ultra-rapid withdrawal regimens.

Key Points

Dependence on opioids is a multifactorial condition involving genetic and psychosocial factors.

There are three stages to treating opioid dependence.

  • Stabilisation is usually by opioid substitution treatments, and aims to ensure that the drug use becomes independent of mental state (such as craving and mood) and independent of circumstances (such as finance and physical location).
  • The next stage is to withdraw (detox) from opioids.
  • The final stage is relapse prevention.

Methadone and buprenorphine help to stabilise opioid use, as they decrease heroin use and help to retain people in treatment programmes.

Methadone, buprenorphine, and alpha2-adrenoceptor agonists (lofexidine, clonidine) can all help people to withdraw from dependence on illicit opioids.

  • Lofexidine and clonidine may be less effective than methadone and buprenorphine in withdrawal, although evidence is weak.
  • Ultra-rapid withdrawal can help in detoxification, although there are important safety risks in keeping people heavily sedated or under general anaesthesia for a day, or under general anaesthesia for a few hours, and outcomes are no better.

Naltrexone can help to prevent relapse of heroin use if combined with psychosocial treatment.

About this condition

Definition

Opioids (opiates) are highly addictive, and opioid dependence is a chronic relapsing disorder. Heroin is the most commonly abused opioid; others include morphine, buprenorphine, codeine, and methadone. Dependence is a cluster of physiological, behavioural, and cognitive phenomena in which the use of a substance takes on a much higher priority for a given individual than other behaviours that once had a greater value. Diagnosis: Diagnosis of dependence syndrome is usually made from a combination of history and examination including urinalysis to corroborate the history, looking for the presence of opioid metabolites (e.g., morphine) in the urine. A definite diagnosis of dependence should usually be made only if three or more of the following have been present together at some stage during the previous year: 1) a strong desire or compulsion to take opioids; 2) difficulties in controlling substance-taking behaviour in terms of its onset, termination, and levels of use; 3) a physiological withdrawal state; 4) evidence of tolerance; 5) progressive neglect of alternative pleasures or interests because of opioid use; and 6) persisting with substance use despite clear evidence of overtly harmful consequences. Physical examination can also provide evidence of acute intoxication, withdrawal, and chronic or physical consequences of drug administration, such as abscesses, malnutrition, poor dentition, and DVT. When commencing treatment, urinalysis should confirm the use of opioids, and some practitioners require a number of samples be taken several days apart to confirm ongoing use. However, regular urinalysis might not be necessary with continuing treatment because studies report that, in situations where there is no coercion, self-reports of drug users are sufficiently reliable and valid to provide descriptions of drug use, drug-related problems, and the natural history of drug use. Random sampling is, however, still useful. Population: All patients reported in this review were 16 years and older.

Incidence/ Prevalence

Opioid use/intravenous drug use rose substantially in the 1990s. New notifications to the Addicts Index (a register held by the UK Home Office) by physicians of people dependent on opioids increased over 30-fold, from approximately 600 in 1966 to >18,000 in 1996, and nearly tripled during the 1990s. The UK drug strategy reported 100,000 to 200,000 problem drug users in the mid-1990s. A pilot study of national estimation methods suggested that there were 143,000 to 266,000 problem drug users, with about 75,000 to 150,000 opioid users in England and Wales in 1996. More recently, the number of people becoming dependent on opioids in 2000 ranged from 13,000 (0.06/100 adults aged 15–44 years) to >26,000 (0.13/100 adults aged 15–44 years). A reduction in the supply of heroin in Australia has also led to a halving in the prevalence of opioid abuse and dependence between the late 1990s and the present. In 2008/9; a report from the National Drug Evidence centre estimated 262,428 problematic opiate users in England, suggesting a rate of 7.69 per 1000 population aged 15 to 64 years.

Aetiology/ Risk factors

Opioid dependence is a multifactorial condition involving genetic and psychosocial factors. Studies in twins report that both the genetic and shared environmental effects on risk for use and misuse are usually entirely non-specific in their effects. Environmental experiences unique to the person largely determine whether predisposed individuals will use or misuse opioids.

Prognosis

Addictive disorders are chronic relapsing conditions with no known "cure". Naturalistic studies have demonstrated that over a 5-year period, approximately half of individuals recover from the dependence.

Aims of intervention

The main aims of intervention can be broadly divided into three main stages: 1) stabilisation (maintenance) treatment of opioid dependence; 2) treatments for withdrawal (detoxification) from opioids; and 3) relapse prevention. Stabilisation (maintenance) treatment aims to ensure that the drug use becomes independent of mental state (such as craving and mood) and circumstances (such as finance and physical location). Substitution treatment assists in this, but is not always necessary before undertaking treatments for withdrawal. Stabilisation is appropriate when the person with opioid addiction is unprepared for a life of abstinence, and where successful withdrawal is unrealistic; it also has the benefit of reducing harm from opioid use (reduces injecting, stabilises drug use and lifestyle, reduces criminal behaviour by avoiding the need to obtain expensive drugs, and reduces mortality). Withdrawal is not a primary goal in itself, and there is much more to detoxification than purely the physical withdrawal. Developing ‘recovery capital’ including personal and life skills, beliefs and desires around recovery, and supports and engagement in family and community are all important. It is much harder to stay off than to get off drugs; therefore, relapse prevention is an important component of opioid dependence treatment and is also considered here, together with withdrawal.

Outcomes

Mortality: from treatment failure. Opioid misuse: self-reported heroin use; relapse rates; proportion of drug-free days; proportion of drug metabolite-free urine samples; rates of injection-risk behaviours. Retention in treatment: retention in the trial; withdrawal rates; treatment completion. Criminality: rates of criminal activity; general criminality, rates of sexual risk-taking behaviours. Adverse effects: mortality from treatment; other adverse effects of treatment. In addition, for the question on treatments for withdrawal: Severity of withdrawal symptoms: severity and incidence of withdrawal symptoms.

Methods

Clinical Evidence search and appraisal March 2011. The following databases were used to identify studies for this systematic review: Medline 1966 to March 2011, Embase 1980 to March 2011, and The Cochrane Database of Systematic Reviews, February 2011 [online] (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs, RCTs, and controlled clinical trials in any language, including open studies and containing >10 individuals of whom >70% were followed up. There was no minimum length of follow-up required to include studies. We included systematic reviews of RCTs, RCTs, and controlled clinical trials where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table
GRADE Evaluation of interventions for Opioid dependence.

Glossary

High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Ultra-rapid opioid detoxification
A relatively new approach for treating opioid dependence is ultra-rapid opioid detoxification, induced with an opioid antagonist while the person is under anaesthesia or heavy sedation. This approach offers the possibility of a rapid and painless withdrawal under anaesthesia, after which the person awakens in a non-opioid-dependent state, thereby, at least in theory, avoiding the discomfort of physical withdrawal. It is designed to limit withdrawal-related discomfort by rendering the person unconscious during withdrawal.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

K Thyarappa Praveen, 2gether Foundation Trust, Gloucester, UK.

Fergus Law, University of Bristol Psychopharmacology Unit, University of Bristol, Bristol, UK.

Jacinta O'Shea, Avon and Wessex Deanery, Avon and Wiltshire NHS Mental Health Partnership, Bristol, UK.

Jan Melichar, University of Bristol, Bristol, UK.

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BMJ Clin Evid. 2011; 2011: 1015.
Published online 2011 September 20.

Buprenorphine for stabilisation

Summary

Buprenorphine helps to stabilise opioid use, as it decreases heroin use and helps to retain people in treatment programmes.

Buprenorphine and methadone seem equally effective at stabilising opioid use.

Benefits and harms

Buprenorphine versus placebo:

We found two systematic reviews (search dates 2006 and 2005) comparing buprenorphine versus placebo for maintenance treatment of opioid dependence. The reviews reported on different outcomes and the first systematic review performed a meta-analysis, which we report below. The second review included RCTs and systematic reviews, but did not pool data from the RCTs identified or provide data from the trials. The second review did not perform a meta-analysis, but reported that the systematic reviews it identified found that buprenorphine was more effective at retaining people in treatment, and at reducing opiate use, compared with placebo or no drug treatment.

Mortality

No data from the following reference on this outcome.

Opioid misuse

Compared with placebo High-dose buprenorphine (16 mg) is more effective than placebo at reducing opioid misuse (assessed by urinalysis) at 2 to 52 weeks. However, we don't know whether low-dose buprenorphine (2–5 mg) is more effective than placebo at reducing opioid misuse (assessed by urinalysis) at 2 to 52 weeks (high-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Opioid misuse

Systematic review
487 people
2 RCTs in this analysis
Morphine-positive urine samples 2 to 52 weeks
with low-dose buprenorphine (2–5 mg)
with placebo
Absolute results not reported

SMD +0.10
95% CI –0.80 to +1.01
P = 0.83
Not significant

Systematic review
463 people
2 RCTs in this analysis
Morphine-positive urine samples 2 to 52 weeks
with medium-dose buprenorphine (6–12  mg)
with placebo
Absolute results not reported

SMD –0.28
95% CI –0.47 to –0.10
P = 0.0029
Effect size not calculatedbuprenorphine

Systematic review
620 people
3 RCTs in this analysis
Morphine-positive urine samples 2 to 52 weeks
with high-dose buprenorphine (16 mg)
with placebo
Absolute results not reported

SMD –1.23
95% CI –1.95 to –0.51
P = 0.00081
Effect size not calculatedbuprenorphine

Retention in treatment

Compared with placebo Buprenorphine is more effective than placebo at increasing the proportion of people retained in treatment at 2 to 52 weeks (high-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Retention in treatment

Systematic review
1131 people
5 RCTs in this analysis
Proportion of people retained in treatment 2 to 52 weeks
340/564 (60%) with low-dose buprenorphine (2–4 mg)
224/567 (40%) with placebo

RR 1.50
95% CI 1.19 to 1.88
P = 0.00054
Small effect sizebuprenorphine

Systematic review
887 people
4 RCTs in this analysis
Proportion of people retained in treatment 2 to 52 weeks
281/430 (65%) with medium-dose buprenorphine (6–12 mg)
172/457 (38%) with placebo

RR 1.74
95% CI 1.06 to 2.87
P = 0.030
Small effect sizebuprenorphine

Systematic review
728 people
4 RCTs in this analysis
Proportion of people retained in treatment 2 to 52 weeks
227/362 (63%) with high-dose buprenorphine (16 mg)
150/366 (41%) with placebo

RR 1.74
95% CI 1.02 to 2.96
P = 0.042
Small effect sizebuprenorphine

Criminality

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Frequency of buprenorphine:

We found one RCT.

Mortality

No data from the following reference on this outcome.

Opioid misuse

Different dose frequencies compared with each other We don't know whether buprenorphine taken three times weekly is more effective than buprenorphine taken daily at reducing the proportion of people with opioid-positive urine tests (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Opioid misuse

RCT
92 people Proportion of people with opioid-positive urine tests
57% with daily buprenorphine (16 mg/70 kg)
58% with 3 times-weekly buprenorphine (34 mg/70 kg twice weekly plus 44 mg/70 kg once weekly)
Absolute numbers not reported

P = 0.84
Not significant

Retention in treatment

Different dose frequencies compared with each other We don't know whether buprenorphine taken three times weekly is more effective than buprenorphine taken daily at increasing the average length of time retained in treatment (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Retention in treatment

RCT
92 people Average length of time of retention in treatment
11.2 weeks with daily buprenorphine (16 mg/70 kg)
11.0 weeks with 3 times-weekly buprenorphine (34 mg/70 kg twice weekly plus 44 mg/70 kg once weekly)

P = 0.64
Not significant

Criminality

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
92 people Adverse effects
with daily buprenorphine (16 mg/70 kg)
with 3 times-weekly buprenorphine (34 mg/70 kg twice weekly plus 44 mg/70 kg once weekly)
Not significant

Dose of buprenorphine:

We found one systematic review (search date 2005), which searched for systematic reviews and RCTs from 2001 to 2005, and identified 9 systematic reviews comparing different doses of buprenorphine versus each other. The review did not perform a meta-analysis, but reported that the systematic reviews found that higher doses of buprenorphine were more effective than lower doses at increasing the proportion of people retained in treatment.

Buprenorphine versus methadone:

See option on buprenorphine versus methadone for stabilisation.

Further information on studies

In this review the placebo group consisted of buprenorphine doses of either 0 mg or 1 mg.

Comment

One cohort study found that people were retained in treatment for significantly longer with buprenorphine (16 mg/day) than with placebo (106 people; mean days of participation: 42 days with buprenorphine v 14 days with placebo; P <0.001). It also found that self-reported heroin use decreased significantly more with buprenorphine than with placebo at 12 weeks (measured on a 0–10 visual analogue scale, where 0 = drug-free, 10 = daily heavy drug use: –3.21 with buprenorphine v +0.52 with placebo; P <0.001). Quality of life and life satisfaction also significantly improved with buprenorphine compared with placebo (quality of life: P <0.01; life satisfaction: P <0.05). The cohort study found that significantly fewer people had exanthema with buprenorphine than with placebo (P <0.05). It also reported that "no serious adverse effects were observed".

We found one RCT that compared buprenorphine implant (80 mg per implant) versus placebo. The study reported that the buprenorphine implant group had significantly more urine samples that were negative for illicit opioids during weeks 1 to 16 compared with the placebo group (P = 0.04). In this study, 71/108 (66%) people who received buprenorphine implants completed the study compared with 17/55 (31%) who received placebo implants (P <0.001). There was no statistically significant difference in treatment-emergent adverse events between the two groups. Minor implant site reactions were the most common adverse event.

Clinical guide:

NICE recommends flexible dosing regimens of methadone and buprenorphine as part of a programme of supportive care. They advise that administration of the drug should be on a daily basis under supervision for at least the first 3 months, and when compliance is assured, daily administration can be relaxed. The UK ‘Orange Guidelines’ from the Department of Health state that the clinical need for supervision should be reviewed regularly, and may be relaxed following assessment of the patient's compliance and individual circumstances, and may be as little as 2 weeks in highly compliant patients. The decision about which drug to use for maintenance therapy should be made on a case-by-case basis and, if both drugs are considered equally suitable, they recommend methadone as first choice. However, some people might have a preference for one drug over the other, which can influence compliance and retention in treatment. For people at the lower range of dependence who are planning on becoming abstinent, buprenorphine can provide greater flexibility and enable earlier detoxification compared with methadone. It is an additional treatment option for people dependent on heroin, especially those who do not wish to start or continue with methadone, or for those who do not seem to benefit from adequate dosages of methadone (Praveen KT, Law F, Melichar J, O'Shea J, personal observation). Buprenorphine can be a good alternative to methadone in people with less chaotic lives, and in those who wish to stabilise for a short period before heading on to detoxification. Pharmacologically, buprenorphine differs from methadone. Buprenorphine is a partial opioid agonist, and has a high affinity for opioid receptors: this reduces the impact of additional illicit heroin/opioid use by preventing illicit opioids from occupying these receptors — the higher the buprenorphine dose used, the less of a subjective ‘high’ experienced from ‘on-top’ heroin use by the individual. Therefore, buprenorphine might be better suited to people who wish to stop using illicit heroin completely. Buprenorphine has a high affinity for opioid receptors and also has a prolonged duration of action at higher doses, which does not correlate with its plasma concentration. This permits alternate-day or even three times-weekly dispensing regimens with only minimal withdrawal symptoms on the intervening days at higher buprenorphine doses.

Substantive changes

Buprenorphine for stabilisation One systematic review updated. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011; 2011: 1015.
Published online 2011 September 20.

Methadone for stabilisation

Summary

Methadone helps to stabilise opioid use, as it decreases heroin use and helps to retain people in treatment programmes.

Methadone and buprenorphine seem equally effective at stabilising opioid use.

Benefits and harms

Methadone versus no opioid replacement therapy:

We found three systematic reviews and one subsequent RCT comparing methadone versus no opioid replacement therapy or placebo. The reviews reported on different outcomes and comparisons. The first systematic review (search date 2008, 11 RCTs, 1969 people) performed a meta-analysis and is reported in full. The second review (search date 2005) identified 12 systematic reviews. This review did not perform a meta-analysis, but reported that the systematic reviews found that methadone was more effective at increasing retention in treatment and at reducing self-reported opioid use compared with placebo or no drug treatment. The third systematic review (search date 2004, 8 RCTs) has been superseded by the first review, so will not be reported further here.

Mortality

Compared with no opioid replacement therapy We don't know whether methadone maintenance treatment is more effective than no methadone maintenance treatment at reducing mortality (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality

Systematic review
576 people
4 RCTs in this analysis
Mortality
3/287 (1%) with methadone maintenance treatment
8/289 (3%) with no methadone maintenance treatment

RR 0.48
95% CI 0.10 to 2.39
P = 0.37
Not significant

No data from the following reference on this outcome.

Opioid misuse

Compared with no opioid replacement therapy Methadone is more effective than control at reducing opioid misuse (high-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Opioid misuse

Systematic review
1129 people
6 RCTs in this analysis
Morphine-positive urine samples
218/615 (35%) with methadone
342/514 (67%) with control

RR 0.66
95% CI 0.56 to 0.78
P <0.00001
Moderate effect sizemethadone

No data from the following reference on this outcome.

Retention in treatment

Compared with no opioid replacement therapy Methadone seems more effective than control at increasing the proportion of people retained in treatment (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Retention in treatment

Systematic review
505 people
3 RCTs in this analysis
Proportion of people retained in treatment
173/254 (68%) with methadone
63/251 (25%) with control

RR 3.05
95% CI 1.75 to 5.35
Significant heterogeneity was found between RCTs (P = 0.02)
Moderate effect sizemethadone

Systematic review
750 people
4 RCTs in this analysis
Proportion of people retained in treatment
318/433 (73%) with methadone
52/317 (16%) with control

RR 4.44
95% CI 3.26 to 6.04
P <0.00001
Moderate effect sizemethadone

No data from the following reference on this outcome.

Criminality

Compared with no opioid replacement therapy We don't know whether methadone is more effective than control at reducing criminality (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Criminality

Systematic review
363 people
3 RCTs in this analysis
Criminal activity
5/178 (3%) with methadone
18/185 (10%) with control

RR 0.39
95% CI 0.12 to 1.25
P = 0.11
Not significant

RCT
319 people Mean number of arrests 6 months
0.20 with interim methadone
0.34 with control

P = 0.02
Effect size not calculatedinterim methadone

RCT
319 people Mean number of arrests 12 months
0.33 with interim methadone
0.39 with control

P = 0.16
Not significant

Adverse effects

No data from the following reference on this outcome.

Higher- versus lower-dose methadone:

We found three systematic reviews (search dates 2001 and 2005 ). The first systematic review included 21 trials, 10 of which were prospective controlled trials, and 11 RCTs (2279 people); the RCT data are reported in full below. The second systematic review identified 9 systematic reviews. It did not perform a meta-analysis or report data from any identified studies, but reported that the systematic reviews found that higher doses of methadone increased the proportion of people retained in treatment and reduced heroin abstinence rates (self-reported heroin use and urine-confirmed opioid abstinence). The third review included 24 articles, of which 12 were randomised, controlled, or double-blind clinical trials. The review did not perform a meta-analysis but reported a consensus of methadone dosing in the range of 60 mg to 100 mg daily to improve the proportion of people retained in treatment.

Mortality

No data from the following reference on this outcome.

Opioid misuse

Higher-dose methadone compared with lower-dose methadone Higher-dose methadone (60–109 mg/day) may be more effective than lower-dose methadone (1–39 mg/day) at increasing heroin abstinence (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Heroin use

Systematic review
237 people
3 RCTs in this analysis
Heroin abstinence (method of determining abstinence unclear) time of assessment unclear
with higher-dose (60–109 mg/day) methadone
with lower-dose (1–39 mg/day) methadone

RR 1.59
95% CI 1.16 to 2.18
Small effect sizehigher-dose methadone

Retention in treatment

Higher-dose methadone compared with lower-dose methadone Higher-dose methadone (60–109 mg/day) may be more effective than lower-dose methadone (1–39 mg/day) at increasing the proportion of people retained in treatment at 3 to 26 weeks, but we don't know whether it is more effective at 1 year (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Retention in treatment

Systematic review
496 people
5 RCTs in this analysis
Treatment retention rates 3 to 26 weeks
with higher-dose (60–109 mg/day) methadone
with lower-dose (1–39 mg/day) methadone

RR 1.36
95% CI 1.13 to 1.63
Small effect sizehigher-dose methadone

Systematic review
75 people
Data from 1 RCT
Treatment retention rates 52 weeks
with higher-dose (60–109 mg/day) methadone
with lower-dose (1–39 mg/day) methadone

RR 1.62
95% CI 0.95 to 2.77
Not significant

Criminality

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Methadone versus buprenorphine:

See option on buprenorphine versus methadone for stabilisation.

Further information on studies

Higher- versus lower-dose methadone: Two RCTs included in the review reported that heroin use was lower by two uses weekly with higher-dose rather than lower-dose methadone (no further data reported). Retention rates ranged from 20% with lower-dose methadone to 71% with higher-dose methadone. The review found no significant difference in adverse effects between higher- and lower-dose methadone (1 RCT, 110 people; no further data or adverse effects reported).

Comment

One large cohort study found that acquisitive crime was reduced by 23% of initial levels at 4 to 5 years of following a methadone maintenance programme.

Adverse effects:

In general, most studies did not report on adverse effects. Instead, most looked at harm-reduction issues, such as the concurrent use of cocaine, and mortality. We found one RCT (164 people) comparing the safety and adverse-effect profiles of buprenorphine (84 people) and methadone (80 people) in the maintenance treatment of opioid dependence in an outpatient setting over 16 weeks. Outcomes measured included liver function tests, vital signs (blood pressure, heart rate, temperature, or respiratory rate), and self-reported adverse effects. The RCT found that both buprenorphine and methadone had similar safety profiles, and found no significant difference in adverse effects between the two drugs (reported as not significant for liver function tests, vital signs, and self-reported adverse effects; data tabulated in original paper for all 3 outcomes).

Clinical guide:

NICE recommends flexible dosing regimens of methadone and buprenorphine as part of a programme of supportive care. They advise that administration of the drug should be on a daily basis under supervision for at least the first 3 months, and when compliance is assured, daily administration can be relaxed (see comment on buprenorphine for stabilisation). The UK ‘Orange Guidelines’ from the Department of Health state that the clinical need for supervision should be reviewed regularly, and may be relaxed following assessment of the patient's compliance and individual circumstances, and may be as little as 2 weeks in highly compliant patients. Because the half-life of methadone is on average 26 hours, daily dosing is necessary, and supervised consumption is recommended. The half-life of methadone does, however, depend on many factors, and may rarely be as short as 12 hours in some individuals (‘rapid metabolisers’) or as long as 36 hours or more. To find the optimum dosage for individuals, clinical judgement is required. Induction to methadone should be in a stepwise fashion, and people should be assessed regularly, along with urinalysis if indicated, for detection of continued opioid use. Methadone is a full opioid agonist, and therefore has potential to produce and/or maintain dependence. Patients typically experience withdrawal symptoms if they miss a dose, and detoxification can be a lengthy process by gradual reductions of 2 mg to 5 mg every 1 to 2 weeks. Rapid detoxification from methadone is now the preferred technique, because a slow detoxification is associated with an increased relapse rate. Rapid detoxification techniques include alpha2-adrenergic agonists such as lofexidine and clonidine (see option on lofexidine/clonidine for withdrawal), or converting from lower-dose methadone (20–40 mg) to buprenorphine for the final 2 weeks or so of the detoxification. Although it is accepted by most clinicians that withdrawal severity is reduced using this technique, there has been minimal research in this area. Unlike buprenorphine, there is also no ceiling to the level of respiratory depression or sedation that methadone can induce, and methadone overdose is therefore potentially fatal. The inconvenience of daily dosing on patient lifestyle and the potential disruption to employment from attending a pharmacy daily should also be noted, along with the fact that take-away dosing results in the problem of diversion of the drug for illicit use by those not in treatment.

Substantive changes

Methadone for stabilisation One systematic review updated. New evidence added. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011; 2011: 1015.
Published online 2011 September 20.

Buprenorphine versus methadone for stabilisation

Summary

Methadone and buprenorphine seem equally effective at stabilising opioid use.

Benefits and harms

Buprenorphine versus methadone for stabilisation:

We found three systematic reviews (search dates 2002, 2005, and 2006) and 4 subsequent RCTs comparing buprenorphine versus methadone. The first systematic review (14 RCTs, number of people not reported) was also identified by the second systematic review. The first review did not perform a meta-analysis but reported that "low-dose methadone (20 mg/day) is less effective than buprenorphine (2–8 mg/day), and that higher doses of methadone (50–65 mg/day or more) are slightly more effective than buprenorphine (2–8 mg/day)". As this review did not include a meta-analysis, we have not reported it further.

Mortality

Buprenorphine compared with methadone We don't know whether buprenorphine is more effective at reducing longitudinal mortality in heroin-dependent people (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality

RCT
405 heroin-dependent people aged at least 18 years Mortality 10 years
16/200 (8%) with buprenorphine
14/205 (7%) with methadone

Mortality of 8.84 deaths per 1000 person-years of follow-up
Reported as not significant
Not significant

No data from the following reference on this outcome.

Opioid misuse

Buprenorphine compared with methadone Buprenorphine and methadone may be equally effective at reducing opioid misuse as measured by urinalysis or self-reported heroin use (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Morphine-positive urine samples

Systematic review
837 people
6 RCTs in this analysis
Morphine-positive urine samples
with flexible-dose buprenorphine
with flexible-dose methadone
Absolute results not reported

SMD –0.12
95% CI –0.26 to +0.02
P = 0.083
Not significant

Systematic review
59 people
Data from 1 RCT
Morphine-positive urine samples
with low-dose buprenorphine
with low-dose methadone
Absolute results not reported

SMD –0.35
95% CI –0.87 to +0.16
P = 0.18
Not significant

Systematic review
57 people
Data from 1 RCT
Morphine-positive urine samples
with low-dose buprenorphine
with medium-dose methadone
Absolute results not reported

SMD 0.88
95% CI 0.33 to 1.42
P = 0.0016
Effect size not calculatedmedium-dose methadone

Systematic review
317 people
3 RCTs in this analysis
Morphine-positive urine samples
with medium-dose buprenorphine
with low-dose methadone
Absolute results not reported

SMD –0.23
95% CI –0.45 to –0.01
P = 0.04
Significant heterogeneity between trials: P = 0.04
Effect size not calculatedmedium-dose buprenorphine

Systematic review
314 people
3 RCTs in this analysis
Morphine-positive urine samples
with medium-dose buprenorphine
with medium-dose methadone
Absolute results not reported

SMD 0.27
95% CI 0.05 to 0.50
P = 0.017
Significant heterogeneity between trials: P = 0.01
Effect size not calculatedmedium-dose methadone

RCT
361 people Morphine-positive urine samples 6 months
with flexible-dose buprenorphine
with flexible-dose methadone
Absolute results not reported

OR 2.13
95% CI 1.50 to 3.02
P = 0.000
Moderate effect sizeflexible-dose buprenorphine

RCT
140 people Morphine-positive urine samples 6 months
with flexible-dose buprenorphine
with flexible-dose methadone
Absolute results not reported

Reported as not significant
P value not reported
Not significant
Self-reported heroin use

Systematic review
420 people
3 RCTs in this analysis
Self-reported heroin use
with flexible-dose buprenorphine
with flexible-dose methadone
Absolute results not reported

SMD –0.12
95% CI –0.31 to +0.07
P = 0.22
Not significant

Systematic review
48 people
Data from 1 RCT
Self-reported heroin use
with low-dose buprenorphine
with low-dose methadone
Absolute results not reported

SMD –0.45
95% CI –0.12 to +1.03
P = 0.12
Not significant

Systematic review
46 people
Data from 1 RCT
Self-reported heroin use
with low-dose buprenorphine
with medium-dose methadone
Absolute results not reported

SMD +0.10
95% CI –0.48 to +0.68
P = 0.73
Not significant

Systematic review
40 people
Data from 1 RCT
Self-reported heroin use
with medium-dose buprenorphine
with medium-dose methadone
Absolute results not reported

SMD –0.27
95% CI –0.90 to +0.35
P = 0.39
Not significant

RCT
116 people Mean days of self-reported heroin use 3 months
13.7 days with flexible-dose buprenorphine
14.4 days with flexible-dose methadone

Reported as not significant
P value not reported
Not significant

No data from the following reference on this outcome.

Retention in treatment

Buprenorphine compared with methadone Methadone may be more effective at increasing the proportion of people retained in treatment (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Retention in treatment

Systematic review
253 people
3 RCTs in this analysis
Retention in treatment
54/142 (38%) with low-dose buprenorphine
62/111 (56%) with low-dose methadone

RR 0.67
95% CI 0.52 to 0.87
P = 0.0027
Small effect sizelow-dose methadone

Systematic review
305 people
3 RCTs in this analysis
Retention in treatment
75/169 (44%) with low-dose buprenorphine
96/136 (71%) with medium-dose methadone

RR 0.67
95% CI 0.55 to 0.81
P = 0.000027
Small effect sizemedium-dose methadone

Systematic review
1068 people
8 RCTs in this analysis
Retention in treatment
281/531 (53%) with flexible-dose buprenorphine
340/537 (63%) with flexible-dose methadone

RR 0.85
95% CI 0.73 to 0.98
P = 0.027
Significant heterogeneity between trials: P = 0.03
Small effect sizeflexible-dose methadone

Systematic review
976 opiate-dependent people
7 RCTs in this analysis
Retention in treatment
310/492 (63%) with flexible-dose methadone
255/484 (53%) with flexible-dose buprenorphine

RR 1.20
95% CI 1.07 to 1.33
Small effect sizeflexible-dose methadone

RCT
361 people Retention in treatment or detox 6 months
with flexible-dose buprenorphine
with flexible-dose methadone
Absolute results not reported

OR 0.34
95% CI 0.20 to 0.59
P <0.001
Moderate effect sizeflexible-dose methadone

RCT
140 people Completed treatment 6 months
55% with flexible-dose buprenorphine
48% with flexible-dose methadone
Absolute numbers not reported

P = 0.42
Not significant

No data from the following reference on this outcome.

Criminality

Buprenorphine compared with methadone Buprenorphine and methadone seem equally effective at reducing criminal activity (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Criminality

Systematic review
212 people
Data from 1 RCT
Self-reported criminal activity
with flexible-dose buprenorphine
with flexible-dose methadone
Absolute results not reported

SMD –0.14
95% CI –0.41 to +0.14
Not significant

RCT
113 people Mean self-reported arrest 3 months
0.69 with flexible-dose buprenorphine
0.71 with flexible-dose methadone

Reported as not significant
P value not reported
Not significant

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Further information on studies

The review divided doses into treatment groups in the following way: in the case of methadone doses between 20 mg and 35 mg were classified as low dose, between 50 mg and 80 mg as medium dose, and 120 mg or more as high dose. In the case of buprenorphine studies where methadone was the comparator, doses of buprenorphine between 2 mg and 6 mg were classified as low dose, between 7 mg and 15 mg as medium dose, and 16 mg as high dose. For the comparison of high-dose buprenorphine versus low-dose methadone, the review reported significant heterogeneity between RCTs for retention data, so did not report a meta-analysis for this outcome.

This review reported the same meta-analysis for morphine-positive samples as the first systematic review. The review did not identify any additional RCTs for this comparison.

Comment

See comments under buprenorphine and methadone for stabilisation.

Clinical guide:

NICE recommends flexible-dose regimens of methadone and buprenorphine as part of a programme of supportive care. They advise that administration of the drug should be on a daily basis under supervision for at least the first 3 months, and when compliance is assured, daily administration can be relaxed (see comments on buprenorphine and methadone for stabilisation).

Substantive changes

Buprenorphine versus methadone for stabilisation One systematic review updated. New evidence added. Categorisation unchanged (Unknown effectiveness) as there remains insufficient good-quality evidence to assess the effects of buprenorphine versus methadone for stabilisation.

BMJ Clin Evid. 2011; 2011: 1015.
Published online 2011 September 20.

Buprenorphine for withdrawal

Summary

Buprenorphine can help people to withdraw from dependence on illicit opioids.

Lofexidine and clonidine may be less effective than buprenorphine in withdrawal, although evidence is weak.

We found no direct information from RCTs about whether buprenorphine is better than no active treatment for people withdrawing from opioids.

Benefits and harms

Buprenorphine versus placebo:

We found no systematic review or RCTs.

Buprenorphine versus methadone:

We found two systematic reviews comparing buprenorphine versus methadone for the management of opioid withdrawal. The first review (search date 2006, 23 RCTs, 2112 people) included slightly different evidence from the second review (search date 2008, 22 RCTs, 1736 people), so both are reported here.

Mortality

No data from the following reference on this outcome.

Opioid misuse

No data from the following reference on this outcome.

Retention in treatment

Buprenorphine compared with methadone Buprenorphine and methadone are equally effective at increasing the proportion of people who complete treatment (high-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Proportion of people completing treatment

Systematic review
168 people
4 RCTs in this analysis
Proportion completing treatment
52/85 (61%) with buprenorphine
43/83 (52%) with methadone

RR 1.18
95% CI 0.93 to 1.49
P = 0.18
Not significant

Systematic review
96 people
3 RCTs in this analysis
Completion of treatment
31/54 (57%) with buprenorphine
30/42 (71%) with methadone

OR 0.92
95% CI 0.03 to 29.30
Not significant

Criminality

No data from the following reference on this outcome.

Severity of withdrawal symptoms

Buprenorphine compared with methadone Buprenorphine is more effective at improving the mean peak score for severity of withdrawal (high-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Withdrawal scores

Systematic review
432 people
4 RCTs in this analysis
Mean peak withdrawal score
with buprenorphine
with methadone

SMD –0.45
95% CI –0.64 to –0.25
P <0.00001
Effect size not calculatedbuprenorphine

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Systematic review

3 RCTs in this analysis
Adverse events
with buprenorphine
with methadone

No data from the following reference on this outcome.

Buprenorphine versus clonidine:

We found two systematic reviews comparing buprenorphine versus clonidine for the management of opioid withdrawal. The first review (search date 2006, 23 RCTs, 2112 people) included slightly different evidence from the second review (search date 2008, 22 RCTs, 1736 people), so both are reported here.

Mortality

No data from the following reference on this outcome.

Opioid misuse

No data from the following reference on this outcome.

Retention in treatment

Buprenorphine compared with clonidine Buprenorphine is more effective than clonidine at increasing the length of time people stay in outpatient treatment and at increasing the proportion of people who complete treatment (high-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Retention in treatment

Systematic review
725 people
6 RCTs in this analysis
Proportion of people who completed outpatient treatment
233/406 (57%) with buprenorphine
137/319 (43%) with clonidine

RR 1.45
95% CI 1.12 to 1.88
P = 0.005
Small effect sizebuprenorphine

Systematic review
481 people
5 RCTs in this analysis
Proportion of people who completed inpatient treatment
208/260 (80%) with buprenorphine
94/221 (43%) with clonidine

RR 1.93
95% CI 1.27 to 2.92
P = 0.002
Small effect sizebuprenorphine

Systematic review
829 people
8 RCTs in this analysis
Proportion of people who completed treatment
344/424 (81%) with buprenorphine
169/405 (42%) with clonidine

OR 2.22
95% CI 1.10 to 4.26
Moderate effect sizebuprenorphine

Criminality

No data from the following reference on this outcome.

Severity of withdrawal symptoms

Buprenorphine compared with clonidine Buprenorphine seems more effective than clonidine at reducing withdrawal scores (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Withdrawal scores

Systematic review
432 people
4 RCTs in this analysis
Mean peak withdrawal scores
with buprenorphine
with clonidine

SMD –0.45
95% CI –0.64 to –0.25
P <0.00001
Effect size not calculatedbuprenorphine

Systematic review
425 people
2 RCTs in this analysis
Mean overall withdrawal scores
with buprenorphine
with clonidine

SMD –0.59
95% CI –0.79 to –0.39
P <0.00001
Effect size not calculatedbuprenorphine

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Systematic review
113 people
Data from 1 RCT
Number of people with adverse effects as inpatients
4/77 (5%) with buprenorphine
4/36 (11%) with clonidine

RR 0.47
95% CI 0.12 to 1.76
P = 0.26
Not significant

Systematic review
345 people
2 RCTs in this analysis
Number of people with an adverse effect as outpatients
26/215 (12%) with buprenorphine
47/130 (36%) with clonidine

RR 1.20
95% CI 0.81 to 1.30
P = 0.86
Not significant

No data from the following reference on this outcome.

Buprenorphine versus lofexidine:

See option on lofexidine/clonidine for withdrawal.

Buprenorphine versus oxazepam:

We found one systematic review (search date 2008, 22 studies, 1736 people) comparing buprenorphine versus oxazepam for the management of opioid withdrawal.

Mortality

No data from the following reference on this outcome.

Opioid misuse

No data from the following reference on this outcome.

Retention in treatment

Buprenorphine compared with oxazepam We don't know how buprenorphine and oxazepam compare at increasing the proportion of people who complete treatment (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Proportion of people who completed treatment

Systematic review
27 people
Data from 1 RCT
Proportion of people who completed treatment
11/15 (73%) with buprenorphine
7/12 (58%) with oxazepam

Reported as not significant
P value not reported
Not significant

Criminality

No data from the following reference on this outcome.

Severity of withdrawal symptoms

Buprenorphine compared with oxazepam Buprenorphine may be more effective than oxazepam at reducing withdrawal severity scores (timeframe unclear). However, evidence was weak (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Withdrawal severity

Systematic review
Number of people unclear
Data from 1 RCT
Withdrawal severity (measured by Short Opiate Withdrawal Scale)
with buprenorphine
with oxazepam

Reported as withdrawal severity significantly lower with buprenorphine compared with oxazepam
No further data reported
Effect size not calculatedbuprenorphine

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Systematic review

Data from 1 RCT
Adverse events
with buprenorphine
with oxazepam
Absolute results not reported

Different rates of buprenorphine dose reduction:

The systematic review reported three RCTs of different rates of buprenorphine dose reduction, but did not report a meta-analysis; see further information on studies. We also identified one additional RCT (516 people), which compared the effects of a short (7-day) or long (28-day) taper schedule of buprenorphine withdrawal, after stabilisation.

Opioid misuse

Compared with 28-day taper buprenorphine Seven-day taper buprenorphine is more effective at increasing the proportion of people with urine samples free of illicit opiates at the end of taper; however, 7-day and 28-day taper buprenorphine are equally effective at 1 and 3 months of follow-up (high-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Opioid misuse

RCT
516 people Urine sample free of illicit opiates end of taper
113/255 (44%) with 7-day taper buprenorphine
78/261 (30%) with 28-day taper buprenorphine

P = 0.0007
Effect size not calculated7-day taper buprenorphine

RCT
516 people Urine sample free of illicit opiates 1 month
45/255 (17.6%) with 7-day taper buprenorphine
46/261 (17.6%) with 28-day taper buprenorphine

P = 0.99
Not significant

RCT
516 people Urine sample free of illicit opiates 3 months
31/255 (12%) with 7-day taper buprenorphine
35/261 (13%) with 28-day taper buprenorphine

P = 0.67
Not significant

No data from the following reference on this outcome.

Mortality

No data from the following reference on this outcome.

Retention in treatment

No data from the following reference on this outcome.

Criminality

No data from the following reference on this outcome.

Severity of withdrawal symptoms

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Further information on studies

Different rates of buprenorphine dose reduction: One RCT found that participant-rated withdrawal severity was significantly worse with rapid-tapered compared with gradual-tapered buprenorphine. Another RCT found that people stayed in withdrawal for a similar length of time with rapid-tapered and gradual-tapered buprenorphine. The review reported that one RCT gave no information about adverse effects, a second RCT reported no adverse effects associated with buprenorphine, and a third RCT found no significant difference in adverse effects between different doses of buprenorphine.

Comment

Frequency of buprenorphine:

We found one further crossover RCT, which gave 16 people single doses of buprenorphine, a double dose every 48 hours, or a triple dose every 72 hours, in random order. It found no significant difference between groups in withdrawal effects at 24 hours, and it found no significant difference between double dose compared with triple dose after 48 hours (results and significance assessment between groups not reported). It reported no discontinuation in any treatment arm due to adverse effects of treatment.

Clinical guide:

The authors of the systematic review also concluded that even low doses of buprenorphine (1–2 mg/day) are more effective than clonidine in ameliorating the signs and symptoms of opioid withdrawal. However, higher doses (6–8 mg/day) seem necessary at the outset of withdrawal to achieve patient comfort and to suppress illicit opioid use. The partial agonist buprenorphine has been shown to be an effective withdrawal medication in patients with opioid dependency. Research activity has primarily focused on the use of buprenorphine as a maintenance pharmacotherapy, but there is growing interest in the use of buprenorphine for short periods of time in managing withdrawal from opioids. This is because it has morphine-like effects, and so will reduce the symptoms of opioid withdrawal. Additionally, because it is a long-acting partial agonist, when it is itself withdrawn, it will produce limited withdrawal symptoms compared with full agonists, such as methadone and heroin. The lower level of withdrawal symptoms during buprenorphine detoxification has meant that buprenorphine has been favoured clinically in patients who are likely to be ready for detoxification in the near future. However, lower-dose methadone patients (20–40 mg) can also be converted to buprenorphine before the detoxification, and it is thought that such patients also get the advantage of lower levels of withdrawal symptoms, although this has yet to be confirmed through research.

Substantive changes

Buprenorphine for withdrawal One systematic review updated. New evidence added. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011; 2011: 1015.
Published online 2011 September 20.

Methadone for withdrawal

Summary

Methadone can help people to withdraw from dependence on illicit opioids.

Lofexidine and clonidine may be less effective than methadone in withdrawal, although evidence is weak.

Benefits and harms

Methadone versus placebo:

We found one systematic review (search date 2007, 20 RCTs, 1907 people). The RCTs were conducted over 3 to 30 days, and the mean starting dose of methadone was 29 mg daily.

Mortality

No data from the following reference on this outcome.

Opioid misuse

No data from the following reference on this outcome.

Retention in treatment

Compared with placebo Methadone at tapered doses may be more effective than placebo at increasing the proportion of people who complete treatment (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Completed treatment

Systematic review
38 people
2 RCTs in this analysis
Completion of treatment
18/19 (95%) with tapered methadone
9/19 (47%) with placebo

RR 1.95
95% CI 1.21 to 3.13
P = 0.0058
Significant heterogeneity: P = 0.04
Small effect sizemethadone

Criminality

No data from the following reference on this outcome.

Severity of withdrawal symptoms

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Methadone versus buprenorphine:

See option on buprenorphine for withdrawal.

Methadone versus any other drug treatment:

We found one systematic review (search date 2007, 20 RCTs, 1907 people). The RCTs were conducted over 3 to 30 days, and the mean starting dose of methadone was 29 mg daily.

Mortality

No data from the following reference on this outcome.

Opioid misuse

Methadone compared with any other drug treatment We don't know whether tapered methadone is more effective than any other pharmacological treatment (results of all combined in analysis) at reducing the number of people abstinent at follow-up (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
People abstinent at follow-up

Systematic review
97 people
2 RCTs in this analysis
Abstinent at follow-up
21/50 (42%) with tapered methadone
17/47 (36%) with other drug treatment

RR 1.17
95% CI 0.72 to 1.92
Not significant

Retention in treatment

Methadone compared with any other drug treatment Tapered methadone seems as effective as any other pharmacological treatment (results of all combined in analysis) at increasing the proportion of people who complete treatment (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Proportion of people completing treatment

Systematic review
890 people
14 RCTs in this analysis
Proportion of people completing treatment
244/393 (62%) with tapered methadone
283/497 (57%) with other drug treatment

RR 1.08
95% CI 0.95 to 1.24
P = 0.26
Significant heterogeneity: P = 0.02
Not significant

Criminality

No data from the following reference on this outcome.

Severity of withdrawal symptoms

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Methadone versus adrenoceptor agonists:

See option on lofexidine/clonidine for withdrawal.

Methadone versus other opioid agonists:

We found one systematic review (search date 2007, 20 RCTs, 1907 people). The RCTs were conducted over 3 to 30 days, and the mean starting dose of methadone was 29 mg daily.

Mortality

No data from the following reference on this outcome.

Opioid misuse

No data from the following reference on this outcome.

Retention in treatment

Methadone compared with other opioid agonists We don't know how tapered methadone and other opioid agonists (results for all combined in analysis) compare at increasing the proportion of people who complete treatment (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Proportion of people completing treatment

Systematic review
204 people
5 RCTs in this analysis
Proportion of people completing treatment
50/102 (49%) with tapered methadone
44/102 (43%) with other opioid agonists

RR 1.06
95% CI 0.66 to 1.69
P = 0.81
Not significant

Systematic review
72 people
Data from 1 RCT
Proportion of people completing treatment
25/36 (69%) with tapered methadone
15/36 (42%) with propoxyphene

RR 1.67
95% CI 1.07 to 2.60
Small effect sizemethadone

Criminality

No data from the following reference on this outcome.

Severity of withdrawal symptoms

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Cardiovascular adverse effects

Systematic review
Number of people unclear
Data from 1 RCT
Blood pressure
with tapered methadone
with other opioid agonists

Methadone versus chlordiazepoxide:

We found one systematic review (search date 2007, 20 RCTs, 1907 people). The RCTs were conducted over 3 to 30 days, and the mean starting dose of methadone was 29 mg daily.

Mortality

No data from the following reference on this outcome.

Opioid misuse

No data from the following reference on this outcome.

Retention in treatment

Methadone compared with chlordiazepoxide We don't know how tapered methadone and chlordiazepoxide compare at increasing the proportion of people who complete treatment (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Proportion of people completing treatment

Systematic review
24 people
Data from 1 RCT
Proportion of people completing treatment
5/13 (38%) with tapered methadone
4/11 (36%) with chlordiazepoxide

RR 1.06
95% CI 0.37 to 3.00
Not significant

Criminality

No data from the following reference on this outcome.

Severity of withdrawal symptoms

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Cardiovascular adverse effects

Systematic review
Number of people unclear
Data from 1 RCT
Bradycardia 4 and 7 days
with tapered methadone
with chlordiazepoxide

Further information on studies

The review also pooled data from two RCTs (47 people), which compared the effects of methadone versus anxiolytics (chlordiazepoxide and buspirone) on the proportion of people who completed treatment (RR 0.63, 95% CI 0.18 to 2.24; P = 0.48).

The RCT comparing methadone versus placebo, and the RCT comparing methadone versus chlordiazepoxide, were small and might have been underpowered.

Comment

Clinical guide

:

Many people return to regular heroin use shortly after detoxification, and it seems that a brief, inexpensive intervention is unlikely to alter the course of a chronic relapsing disorder such as heroin addiction. Whether people relapse into heroin use has a lot to do with the degree of preparation for detoxification and a life of abstinence, the robustness of the ‘aftercare plan’, and the extent of the ‘recovery capital’, which includes personal and life skills, beliefs and desires around recovery, and supports and engagement in family and community. For people who are not fully ready for abstinence, the investment into addiction treatment could be more justified if more modest goals were being achieved, such as temporary reduction of daily heroin dosage, with its consequent reduction in dependence and illegally obtained income, and the possibility of reaching drug-dependent people who would otherwise not have accessed treatment. Managed withdrawal or detoxification is not in itself a treatment for dependence, but can serve two useful functions in the recovery journey. First, detoxification can be a brief transitional stage between a dependent state and an abstinent state, which may itself involve longer-term treatment, and is likely to be particularly applicable in patients who are well prepared for a life of abstinence or those entering therapy in a protective environment such as a residential drug rehabilitation centre. Second, detoxification may be used as a ‘learning experience’ in order to help patients decide whether they are ready for a lifestyle of abstinence or need to work on their recovery capital during a period of stabilisation or maintenance on a prescribed opioid. In both groups it is particularly important that the patient is fully aware of the risks of detoxification (e.g., opioid overdose), and that steps are put in place to mitigate these risks — including rapid access back into opioid substitution treatment if required.

Substantive changes

Methadone for withdrawal One systematic review updated. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011; 2011: 1015.
Published online 2011 September 20.

Lofexidine/clonidine for withdrawal

Summary

Alpha 2 -adrenoceptor agonists (lofexidine, clonidine) can help people to withdraw from dependence on illicit opioids.

Lofexidine and clonidine may be less effective than methadone and buprenorphine in withdrawal, although evidence is weak.

Lofexidine and clonidine are better than no active treatment in people withdrawing from opioids.

Benefits and harms

Alpha2-adrenoceptor agonists versus placebo:

We found one systematic review (search date 2008, 24 studies, 21 RCTs, 1631 people) comparing alpha2-adrenoceptor agonists versus tapering doses of methadone.

Mortality

No data from the following reference on this outcome.

Opioid misuse

No data from the following reference on this outcome.

Retention in treatment

Compared with placebo Alpha2-adrenoceptor agonists seem more effective at increasing the proportion of people who complete treatment (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Completion of treatment

Systematic review
149 people
3 RCTs in this analysis
Proportion of people who completed treatment
41/76 (54%) with alpha2-adrenoceptor agonists
21/73 (29%) with placebo

RR 1.90
95% CI 1.28 to 2.81
P = 0.0014
Small effect sizealpha2-adrenoceptor agonists

Criminality

No data from the following reference on this outcome.

Severity of withdrawal symptoms

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Systematic review
149 people
3 RCTs in this analysis
Adverse effects
with alpha2-adrenoceptor agonists
with placebo
Absolute results not reported

The review reported that alpha2-adrenoceptor agonists seemed to be associated with more adverse effects than placebo

Alpha2-adrenoceptor agonists versus methadone:

We found three systematic reviews (search date 2008, 24 studies, 21 RCTs, 1637 people; search date 2007, 20 RCTs, 1907 people; and search date 2006, 23 RCTs, 2112 people) comparing alpha2-adrenoceptor agonists versus tapering doses of methadone. All the reviews included slightly difference evidence, so all are reported here; however, the third review did not report any outcomes of interest for this review, for this comparison.

Mortality

No data from the following reference on this outcome.

Opioid misuse

Alpha2-adrenoceptor agonists compared with methadone We don't know how alpha2-adrenoceptor agonists and tapered methadone compare at increasing the proportion of people who complete withdrawal from opioids (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Rates of withdrawal from opioids

Systematic review
690 people
10 RCTs in this analysis
Proportion of people who completed withdrawal
210/386 (54.4%) with alpha2-adrenoceptor agonists
164/304 (53.9%) with tapered methadone

RR 0.95
95% CI 0.81 to 1.12
P = 0.56
Meta-analysis limited by diversity in study design and in assessment and reporting of outcomes
Not significant

No data from the following reference on this outcome.

Retention in treatment

Alpha2-adrenoceptor agonists compared with methadone Alpha2-adrenoceptor agonists may be less effective than tapered methadone at increasing time in treatment, but we don't know whether they are more or less effective at increasing the proportion of people retained in treatment or at increasing the proportion of people who complete treatment (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Retention in treatment

Systematic review
311 people
3 RCTs in this analysis
Length of time in treatment
with alpha2-adrenoceptor agonist
with tapered methadone
Absolute results not reported

SMD –1.07
95% CI –1.31 to –0.83
Meta-analysis limited by diversity in study design and in assessment and reporting of outcomes
Effect size not calculatedmethadone

Systematic review
399 people
5 RCTs in this analysis
Proportion retained in treatment
104/192 (54%) with alpha2-adrenoceptor agonists
135/207 (65%) with tapered methadone

RR 0.81
95% CI 0.64 to 1.04
Meta-analysis limited by diversity in study design and in assessment and reporting of outcomes
Heterogeneity: P = 0.03
Not significant

Systematic review
577 people
7 RCTs in this analysis
Proportion of people completing treatment
168/251 (67%) with tapered methadone
192/326 (59%) with alpha2-adrenoceptor agonists

RR 1.10
95% CI 0.90 to 1.32
P = 0.34
Significant heterogeneity: P = 0.01
Not significant

No data from the following reference on this outcome.

Criminality

No data from the following reference on this outcome.

Severity of withdrawal symptoms

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Systematic review
525 people
7 RCTs in this analysis
Adverse effects
41/315 (13%) with alpha2-adrenoceptor agonists
15/210 (7%) with methadone

RR 2.13
95% CI 1.30 to 3.48
P = 0.0026
Moderate effect sizemethadone

Systematic review
1907 people Blood pressure
with clonidine
with methadone

No data from the following reference on this outcome.

Lofexidine versus clonidine:

We found two systematic reviews (search date 2008, 24 studies, 21 RCTs, 1631 people; and search date 2007, 23 RCTs, 2112 people) comparing lofexidine versus clonidine.

Mortality

No data from the following reference on this outcome.

Opioid misuse

Lofexidine compared with clonidine Lofexidine and clonidine seem equally effective at increasing the proportion of people who complete withdrawal at 4 weeks (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Rates of withdrawal from opioids

RCT
50 people
In review
Proportion of people completing withdrawal 4 weeks
17/26 (65%) with lofexidine
12/24 (50%) with clonidine

P = 0.20
Not significant

No data from the following reference on this outcome.

Retention in treatment

Lofexidine compared with clonidine We don't know whether lofexidine is more effective at increasing the proportion of people who complete treatment (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Completion of treatment

Systematic review
90 people
3 RCTs in this analysis
Completion of treatment
with lofexidine
with clonidine
Absolute results not reported

OR 1.50
95% CI 0.53 to 4.11
Not significant

No data from the following reference on this outcome.

Criminality

No data from the following reference on this outcome.

Severity of withdrawal symptoms

Lofexidine compared with clonidine We don't know how lofexidine and clonidine compare at reducing opioid withdrawal symptoms (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Severity of withdrawal symptoms

RCT
80 people
In review
Opioid withdrawal symptoms (measured by the Abstinence Symptoms Rating Scale)
with lofexidine
with clonidine

Reported similar scores with both groups (further data not reported)
Not significant

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Systematic review
1709 people Hypotension
with lofexidine
with clonidine

RCT

In review
Adverse effects
with lofexidine
with clonidine

P <0.05
Data not clear
Effect size not calculatedlofexidine

Systematic review
Number of people not reported
Data from 1 RCT
Doses omitted due to low blood pressure
4% with lofexidine
9% with clonidine

P <0.001
Effect size not calculatedlofexidine

No data from the following reference on this outcome.

Lofexidine versus buprenorphine:

We found one systematic review (2006, 23 RCTs, 2112 people).

Mortality

No data from the following reference on this outcome.

Opioid misuse

No data from the following reference on this outcome.

Retention in treatment

Lofexidine compared with buprenorphine We don't know how lofexidine and buprenorphine compare at increasing the proportion of people who complete treatment (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Completion of treatment

Systematic review
210 people
Data from 1 RCT
Proportion of people who completed treatment
47/103 (46%) with lofexidine
70/107 (65%) with buprenorphine

OR 1.40
95% CI 0.009 to 193.3
Not significant

Criminality

No data from the following reference on this outcome.

Severity of withdrawal symptoms

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Clonidine versus buprenorphine:

See option on buprenorphine for withdrawal.

Further information on studies

None.

Comment

Clinical guide:

The use of alpha2-adrenoceptor agonists, such as clonidine (doses of 50–100 micrograms 3 times daily increased to a maximum of 400 micrograms 2 times daily) and lofexidine (doses of 200 micrograms once daily increasing to a maximum of 600 micrograms once daily), in the treatment of opioid withdrawal has developed since the late 1970s and 1980s. Opioids inhibit noradrenaline release, and discontinuing them causes a rebound release of noradrenaline. Alpha2-adrenoceptor agonists help to reduce the noradrenergic storm that occurs when opioids are discontinued. The clinical objective is to ensure that the peak dose of the alpha2-adrenoceptor agonist coincides with the period of peak opiate withdrawal symptoms, so the dose needs to be titrated against the anticipated or actual level of withdrawal symptoms. In addition, dose levels need to be increased gradually over a few days because of the risk of hypotension and sedation, and reduced gradually on termination because rapid reductions of the alpha2-adrenoceptor agonist dose produce opiate-like withdrawal symptoms. Patients need to be monitored for hypotension, sedation, and the small risk of bradycardia, particularly while dose levels are increasing. Most studies of alpha2-adrenoceptor agonists have reported on the adverse-effect profiles, especially the problems associated with blood pressure changes, which are smaller for lofexidine than clonidine. If blood pressure changes are identified, these typically resolve rapidly even when staying on the same dose level — at least with lofexidine. Both lofexidine and clonidine have been shown to be effective treatments in helping to reduce physical withdrawal symptoms. These withdrawal symptoms include: tachycardia, sweating, restlessness, pupil dilation, bone and joint pains, rhinorrhoea, gastrointestinal upset, tremor, yawning, anxiety or irritability, and gooseflesh skin. Alpha2-adrenoceptor agonists do not eliminate most withdrawal symptoms, so adjunctive medications such as analgesics and hypnotics are often needed, and sometimes also smooth muscle relaxants for stomach cramps, antiemetics, antidiarrhoeal agents, and anxiolytics. For people who are well prepared for withdrawal and seeking earlier resolution of withdrawal symptoms, alpha2-adrenoceptor agonist treatment might be preferred. Alpha2-adrenoceptor agonists are also used in all situations where opiate withdrawal symptoms occur, and where it is considered important to avoid the use of an opioid substitute. Clonidine and lofexidine seem equally effective for inpatient settings, but the lower incidence of hypotension and sedation makes lofexidine more suited for use in outpatient settings.

Substantive changes

Lofexidine/clonidine for withdrawal One systematic review updated. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011; 2011: 1015.
Published online 2011 September 20.

Ultra-rapid withdrawal

Summary

Ultra-rapid withdrawal can help in detoxification, although there are important safety risks in keeping people heavily sedated or under general anaesthesia for a few hours, and outcomes are no better.

Serious adverse effects may occur in people undergoing detoxification under anaesthesia.

Benefits and harms

Ultra-rapid withdrawal versus standard withdrawal:

We found two systematic reviews (search date 1997, 9 studies [2 of which were RCTs], 424 people; and search date 2009, 9 studies, 1109 people) comparing withdrawal with heavy sedation versus standard withdrawal. The first review did not perform a meta-analysis because of the short duration and the differing methods of ultra-rapid opioid detoxification; therefore, we have not reported data from this review. However, overall, it concluded that the existing literature on rapid detoxification and ultra-rapid detoxification is limited, in terms of the number of people evaluated, the variation in protocols studied, the lack of randomised design and use of control groups, and the short-term nature of the outcomes reported. Further research is needed, using more rigorous research methods, longer-term outcomes, and comparisons with other methods of treatment for opioid dependence. The second review did perform meta-analysis and is reported in full.

Mortality

No data from the following reference on this outcome.

Opioid misuse

Compared with conventional withdrawal Antagonist-induced withdrawal seems as effective at increasing the proportion of people who are retained in naltrexone maintenance or abstinent at 12 weeks (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Retained in naltrexone maintenance or abstinent

Systematic review
30 people
Data from 1 RCT
Retained in naltrexone maintenance or abstinent 12 weeks
10/15 (67%) with antagonist-induced withdrawal
5/15 (33%) with tapered methadone

RR 2.00
95 % CI 0.90 to 4.45
P = 0.09
Not significant

Systematic review
240 people
3 RCTs in this analysis
Retained in naltrexone maintenance or abstinent 12 weeks
26/122 (21%) with antagonist-induced withdrawal
9/118 (8%) with clonidine

RR 2.77
95% CI 1.37 to 5.61
P = 0.004
Moderate effect sizeantagonist-induced withdrawal

Systematic review
72 people
Data from 1 RCT
Retained in naltrexone maintenance or abstinent 12 weeks
7/35 (20%) with antagonist-induced withdrawal
9/37 (24%) with buprenorphine

RR 0.82
95% CI 0.34 to 1.97
P = 0.66
Not significant

Retention in treatment

Compared with standard conventional withdrawal We don't know whether antagonist-induced withdrawal is more effective at increasing the proportion of people who complete detoxification treatment (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Retention in treatment

Systematic review
30 people
Data from 1 RCT
Completion of detoxification
15/15 (100%) with antagonist-induced withdrawal
8/15 (53%) with tapered methadone

RR 1.82
95% CI 1.14 to 2.91
P = 0.012
Small effect sizeantagonist-induced withdrawal

Systematic review
70 people
Data from 1 RCT
Completion of detoxification
28/36 (78%) with antagonist-induced withdrawal
21/34 (62%) with clonidine

RR 1.26
95% CI 0.92 to 1.73
P = 0.15
Not significant

Criminality

No data from the following reference on this outcome.

Severity of withdrawal symptoms

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Systematic review
Number of people unclear
Data from 1 RCT
Adverse effects
with antagonist-induced withdrawal
with conventional withdrawal

1 RCT included in the review reported 3 potentially life-threatening adverse events: 1 person with a possible previous history of sleep apnoea developed severe pulmonary oedema and aspiration pneumonia; the second person, who had a history of bipolar affective disorder, developed a mixed bipolar state; and the third person, who had insulin-dependent diabetes, developed ketoacidosis

Further information on studies

None.

Comment

NICE states that ultra-rapid detoxification under general anaesthesia or heavy sedation (where the airway needs to be supported) must not be offered. This is because of the risk of serious adverse events, including death.

Clinical guide:

When detoxification is given to people with opioid dependence, other approaches, such as clonidine, methadone, or buprenorphine, are likely to be at least as effective as anaesthesia-assisted detoxification, and are also safer and far less costly. Because medical detoxification addresses only the very first steps of treatment, and many programmes, being privately provided, do not provide ongoing treatment beyond detoxification, this approach can be fundamentally flawed for most people, especially those with chronic relapsing opioid dependence. Most data on this treatment are in the form of case series and non-randomised studies. Safety concerns have also been raised. Along with the risks inherent in general anaesthesia, complications such as pulmonary and cardiac problems have been reported. However, despite the lack of evidence and important safety concerns, this form of treatment is still available. However, the effectiveness and safety of anaesthesia-assisted detoxification have been called into question. The additional risk, which should not be underestimated, is that the patient can see this as a "magic bullet", with no need to make any meaningful life changes.

Substantive changes

Ultra-rapid withdrawal (antagonist-assisted [naltrexone and naloxone only]) New evidence added. Categorisation unchanged (Unknown effectiveness), as there remains insufficient good-quality evidence to assess the effects of withdrawal under heavy sedation.

BMJ Clin Evid. 2011; 2011: 1015.
Published online 2011 September 20.

Naltrexone for relapse prevention

Summary

Naltrexone can help to prevent relapse of heroin use if combined with psychosocial treatment.

Benefits and harms

Naltrexone (with or without psychosocial treatment) versus placebo (with or without psychosocial treatment):

We found two systematic reviews (search date 2010, 13 RCTs, 696 people; and search date 2007, 7 RCTs) and one additional RCT, which assessed the effectiveness of naltrexone versus other interventions in opioid dependence.

Mortality

No data from the following reference on this outcome.

Opioid misuse

Compared with placebo (with or without psychological treatment) Naltrexone (with or without psychological treatment) may be more effective at reducing opioid misuse at up to 6 months of follow-up (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Opioid use

Systematic review
143 people
4 RCTs in this analysis
Abstinence
41/94 (44%) with naltrexone
19/49 (39%) with placebo

RR 1.39
95% CI 0.61 to 3.17
P = 0.44
Significant heterogeneity: P = 0.05
Small effect sizenaltrexone

Systematic review
116 people
3 RCTs in this analysis
Abstinence at follow-up
27/63 (43%) with naltrexone
18/53 (34%) with placebo

RR 1.28
95% CI 0.80 to 2.05
P = 0.31
Not significant

RCT
56 abstinence-oriented people who completed inpatient treatment for opioid dependence Self-reported opioid use 180 days
with naltrexone implant
with control
Absolute results not reported

SMD 60.2 days
95% CI 20.9 days to 99.5 days
Effect size not calculatednaltrexone

No data from the following reference on this outcome.

Retention in treatment

Compared with placebo We don't know whether naltrexone is more effective at increasing the proportion of people who are retained in treatment (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Retention in treatment

Systematic review
203 people
2 RCTs in this analysis
Proportion of people retained in treatment
26/50 (52%) with naltrexone
15/33 (45%) with placebo

RR 1.18
95% CI 0.72 to 1.91
P = 0.51
Not significant

Systematic review
40 people
Data from 1 RCT
Proportion of people retained in treatment
15/22 (68%) with high-dose naltrexone
7/18 (39%) with placebo

RR 1.75
95% CI 0.92 to 3.34
P = 0.88
Not significant

Systematic review
38 people
Data from 1 RCT
Proportion of people retained in treatment
12/20 (60%) with low-dose naltrexone
7/18 (39%) with placebo

RR 1.54
95% CI 0.78 to 3.05
Not significant

No data from the following reference on this outcome.

Criminality

Compared with placebo Naltrexone seems to reduce the proportion of people who are re-incarcerated (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Re-incarceration

Systematic review
86 people
2 RCTs in this analysis
Re-incarceration
13/54 (24%) with naltrexone
16/32 (50%) with placebo

RR 0.47
95% CI 0.26 to 0.48
P = 0.01
Moderate effect sizenaltrexone

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

Systematic review
159 people
4 RCTs in this analysis
Proportion of people with at least 1 adverse effect (not described)
43/96 (45%) with naltrexone
17/63 (27%) with placebo

RR 1.29
95% CI 0.54 to 3.11
P = 0.57
Not significant

Systematic review
40 people
Data from 1 RCT
Proportion of people with at least 1 adverse effect (not described)
15/22 (68%) with high-dose naltrexone
9/18 (50%) with placebo

RR 1.36
95% CI 0.79 to 2.35
P = 0.42
Not significant

Systematic review
38 people
Data from 1 RCT
Proportion of people with at least 1 adverse effect (not described)
13/20 (65%) with low-dose naltrexone
9/18 (50%) with placebo

RR 1.30
95% CI 0.74 to 2.28
P = 0.36
Not significant

No data from the following reference on this outcome.

Different doses of naltrexone:

We found one systematic review (search date 2007, 7 RCTs) and one additional RCT.

Mortality

No data from the following reference on this outcome.

Opioid misuse

Different doses of naltrexone compared with each other We don’t know whether any one dose of naltrexone is more effective than any other dose of naltrexone at reducing opioid misuse as we found insufficient evidence (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Heroin use

RCT
60 people, all of whom had detoxification and oral naltrexone for 3 days pre-randomisation
In review
Data from 1 RCT
Proportion of urine samples negative for heroin (missing samples were not considered positive)
73.5% with depot naltrexone 192 mg given at 1 and 5 weeks after detoxification
79.4% with depot naltrexone 384 mg given at 1 and 5 weeks after detoxification
74.2% with depot placebo given at 1 and 5 weeks after detoxification
Absolute numbers not reported

P = 0.85 for difference among groups
Not significant

RCT
66 people, all of whom had detoxification and naltrexone 50 mg daily for 1 week pre-randomisation
Data from 1 RCT
Heroin use over 6 months
with oral naltrexone 0.05 mg
with oral naltrexone 0.5 mg
with oral naltrexone 50 mg

P = 0.156
Not significant

Retention in treatment

Different doses of naltrexone compared with each other We don’t know whether any one dose of naltrexone is more effective than any other dose of naltrexone at increasing the proportion of people retained in treatment (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Retention in treatment

RCT
66 people, all of whom had detoxification and naltrexone 50 mg daily for 1 week pre-randomisation
Data from 1 RCT
Mean number of days retained in treatment
47.8 days with oral naltrexone 0.05 mg
46.6 days with oral naltrexone 0.5 mg
58.9 days with oral naltrexone 50 mg

P = 0.93 for difference among groups
Not significant

Systematic review
42 people
Data from 1 RCT
Proportion of people retained in treatment
15/22 (68%) with high-dose naltrexone
12/20 (60%) with low-dose naltrexone

RR 1.14
95% CI 0.72 to 1.80
P = 0.58
Not significant

Criminality

No data from the following reference on this outcome.

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects

RCT
66 people, all of whom had detoxification and naltrexone 50 mg daily for 1 week pre-randomisation
Data from 1 RCT
Ratings of adverse effects (depression, increased erections, increased thirst, low energy, and tiredness)
with oral naltrexone 0.05 mg
with oral naltrexone 0.5 mg
with oral naltrexone 50 mg
Absolute results reported graphically

P = 0.98 for difference among groups
Not significant

Systematic review
42 people
Data from 1 RCT
Adverse effects
15/22 (68%) with high-dose naltrexone
13/20 (65%) with low-dose naltrexone

RR 1.05
95% CI 0.68 to 1.16
P = 0.83
Not significant

Further information on studies

None.

Comment

Harms alert:

The FDA issued a drug safety alert on the increased risk of injection-site reactions, including cellulitis, induration, haematoma, abscess, sterile abscess, and necrosis associated with extended-release naltrexone injection (http://www.fda.gov).

The authors of the review discussed here concluded that the available studies included in their review did not provide an objective evaluation of naltrexone treatment in the field of opioid dependence, and felt that the conclusions were limited owing to the heterogeneity of the trials, both in the interventions and in the assessment of outcomes. Naltrexone is a pure mu-opioid receptor antagonist, is non-addictive, and produces no euphoric effects. From a pharmacological perspective, naltrexone works to block opioid use. However, in clinical practice, medication compliance and retention rates are poor.

Clinical guide:

Naltrexone is an effective treatment for relapse prevention in opioid addiction, but only for a limited group of people, because few seem able to continue taking it for extended periods of time. It appears, therefore, to be most successful in highly motivated people with a vested interest in remaining opioid-free. Doses of 50 mg daily seem most accepted and successful. The development of newer, longer-acting preparations might provide an alternative to the delivery of this form of treatment, and might improve compliance. Naltrexone might be an efficacious adjuvant therapy, especially in people who fear severe consequences if they relapse back to taking illicit opioids. This target group includes healthcare professionals, who could lose their jobs, or parolees, who risk re-incarceration. NICE recommends naltrexone as a detoxification treatment in people who are highly motivated. They recommend administration under adequate supervision, and people should be fully informed of its adverse effects. Effectiveness should be reviewed regularly and, if there is evidence of misuse, treatment with naltrexone should be discontinued.

Substantive changes

Naltrexone for relapse prevention One systematic review updated. New evidence added. Categorisation unchanged (Likely to be beneficial).


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