Best practice portal:
Treatment options for opioid users

This page refers to the current evidence on the effectiveness of the available treatment options for opioid users. We refer here to the broad family of opioids including heroin, fentanyl, morphine, etc. Information on the methodology used and the definition of terms can be found on the methodology page.

Date of last update: 11.05.2012.     Next update:  March 2013.

Available treatments for opioid users – evidence base

Summary: The current available evidence strongly supports opioid agonist maintenance treatment, combined with psychosocial assistance for keeping patients in treatment and reducing illicit opioid use, and mortality.

What's new: Updated information on pharmacologycal treatment with Naltrexone.

Note: The GRADE symbol indicates that a GRADE profile is available for the intervention. Learn more about GRADE.

Beneficial

Buprenorphine maintenance therapy

Buprenorphine maintenance  therapy was found in one RCT (N=366) to be more effective than placebo in the synthesis of evidence (WHO, 2009) in:

• reducing heroin use and improving retention in treatment (RR 1.52, 95 % CI 1.23 to 1.88);
• reducing the number of morphine-positive urines (SMD –0.65, 95 % CI –0.86 to –0.44) than a placebo.

View the GRADE profile for this intervention (reproduced with permission from WHO).

Case management for reducing drug use

Case management proved to be more effective than psycho-education and drug counselling in reducing drug use in a systematic review including one trial of around 500 patients (RR 0.24, 95 % CI 0.06 to 0.42) (Hesse et al., 2007).

Methadone maintenance therapy

Methadone maintenance therapy was found in a systematic review of three RCTs (N=505) (WHO, 2009) to be more effective than opioid withdrawal followed by placebo in:

• increasing retention in treatment (RR 3.05, 95 % CI 1.75 to 5.35);
• reducing illicit opioid use (RR 0.32, 95 % CI 0.23 to 0.44).

Observational studies found the mortality rate in methadone treatment to be approximately one-third the rate out of treatment (RR 0.37, 95 % CI 0.29 to 0.48).

Methadone was found in one RCT (N=253) to reduce the risk of HIV infection by approximately 50 % (RR 0.45, 95 % CI 0.35 to 0.59) and a similar reduction in seroconversion rates was found in 3 observational studies (N=43.035) (RR 0.36, 95 % CI 0.19 to 0.66) when compared to withdrawal or no treatment.

View the GRADE profile for this intervention (reproduced with permission from WHO).

Naltrexone for patients forced to adhere to treatment

Pharmacologycal treatment with Naltrexone was found in a sub-analysis of patients forced to adhere to treatment (Minozzi et al., 2011) effective in:

• achieving retention in treatment and abstinence (RR 2.93, 95 % CI 1.66 to 5.18, 3 RCTs, N=230).

Opioid assisted withdrawal with buprenorphine

Buprenorphine for opioid assisted withdrawal was found WHO (2009) in a pooled analysis of eight studies (N=884 participants) to be effective in:

• achieving higher completion rates than alpha-2 agonists (RR 1.67, 95 % CI 1.24 to 2.25, moderate-quality evidence);
• lowering the peak of objective withdrawal scores (SMD –0.61, 95 % CI –0.86 to –0.36, moderate-quality evidence);
• lowering overall self-reported levels of opioid withdrawal (SMD –0.59, 95 % CI –0.79 to –0.39, high-quality evidence).

Psychosocial interventions in maintenance treatment

Methadone treatment plus psychosocial intervention compared with methadone treatment only was found in a systematic review of three studies (N=388), to be more effective in reducing heroin use (RR 0.69, 95 % CI 0.53 to 0.91) (WHO, 2009).

View the GRADE profile for this intervention (reproduced with permission from WHO).

Psychosocial assistance in addition to pharmacological assistance for opioid withdrawal

WHO (2009) found combined psychosocial (contingency management, community reinforcement, psychotherapeutic counselling and family therapy) and pharmacological assistance were found to be effective in a systematic review of five randomised control trials (N=184 participants) in:

• increasing rates of completion of treatment (RR 1.68, 95 % CI 1.11 to 2.55, moderate quality evidence);
• reducing rates of relapse at follow-up (RR 0.41, 95 % CI 0.27 to 0.62, moderate-quality evidence).

View the GRADE profile for this intervention (reproduced with permission from WHO).

Likely to be beneficial

Maintenance agonist treatments for opiate dependent pregnant women

Three studies (N = 96) were considered in a systematic review (Minozzi et al., 2009) on maintenance treatment and pregnant women: two compared methadone with buprenorphine (48 participants) and one compared methadone with oral slow release morphine (48 participants).

There was significant difference between methadone and buprenorphine treatment in:

• use of primary substance (RR 2.50, 95 % CI 0.11 to 54.87)

Also oral slow morphine seemed superior to methadone in abstaining women from the use of heroin:

• use of primary substance (RR 2.40, 95 % CI 1.00 to 5.77).

Psychosocial interventions to retain patients in treatment

Psychosocial interventions in addition to Methadone maintenance treatment were found in a systematic review (WHO (2009) of three RCTs (N=500) to be no different from methadone maintenance treatment only in:

• retaining patients in treatment (RR 0.94, 95 % CI 0.85 to 1.02).

Trade-off between benefits and harms

Heroin maintenance treatment for chronic heroin users

Heroin plus methadone prescription for maintenance treatment in adult chronic opioid users who failed previous methadone treatment attempts was found to be effective in a systematic review (Ferri et al., 2011) of eight randomised control trials (N=2.007) in:

• remaining in treatment until the end of the study (RR 1.44, 95 % CI 1.19 to1.75);
• probably reducing the risk of death (RR 0.65,  95 % CI 0.25 to1.69).

The risk of adverse events was coherently high in all the seven studies providing comparable data (RR 13.50, 95 % CI 2.55 to 71.53).

Unknown effectiveness

Assisted opioid withdrawal with methadone or alpha-2 agonists

In a pooled analysis (seven studies, N=577 participants) (WHO, 2009), there was no significant difference between methadone and alpha-2 agonists in:

• treatment completion (RR 1.09, 95 % CI 0.90 to 1.32);
• relapse at follow-up (intention-to-treat analysis) (RR 1.06, 95 % CI 0.55 to 2.02, low-quality evidence).

View the GRADE profile for this intervention (reproduced with permission from WHO).

Assisted opioid withdrawal with methadone or buprenorphine

In a pooled analysis (two studies, N=63 participants) (WHO, 2009), there was no significant difference in:

• completion of treatment between methadone and buprenorphine (RR 0.88, 95 % CI 0.67 to 1.15).

View the GRADE profile for this intervention (reproduced with permission from WHO).

Maintenance agonist treatments (methadone compared with buprenorphine) for opiate dependent pregnant women

Three studies (N = 96) were considered in a systematic review (Minozzi et al., 2009) on maintenance treatment and pregnant women: two compared methadone with buprenorphine (48 participants) and one compared methadone with oral slow release morphine (48 participants). There was no significant difference between Methadone and Buprenorphine treatment in:

• drop out rate (RR 1.00, 95 % CI 0.41 to 2.44)

Naltrexone in place of methadone

No studies were found that compared methadone with naltrexone treatment.

View the GRADE profile for this intervention (reproduced with permission from WHO).

Naltrexone treatment for opioid dependence

In an updated version of a systematic review of 13 RCTs (N=1158) (Minozzi et al., 2011), pharmacologycal treatment with Naltrexone versus placebo or no pharmacological treatment in all patients was found to be not significantly different in:

• retaining patients in treatment (RR 1.18, 95 % CI 0.72 to 1.91, 2 studies, N=88 participants);
• achieving retention and abstinence (combined outcome) (RR 1.43, 95 % CI 0.72 to 2.82, 6 RCTs, N= 393 participants);
• achieving abstinence (RR 1.39, 95 % CI 0.61 to 3.17,4 RCTs, N=143 participants);
• achieving abstinence at follow up (RR 1.28, 95 % CI 0.80 to 2.08, 3 RCTs, N= 116 participants);
• reducing side effects (RR 1.29, 95 % CI 0.54 to 3.11, 4 RCTs, N=159 participants).

Naltrexone with psychotherapy versus psychotherapy alone

In an updated version of a systematic review (Minozzi et al., 2011), pharmacologycal treatment with Naltrexone was compared with psychotherapy only and was found not significantly different in:

• achieving abstinence at follow up (RR 1.63, 95 % CI 0.62 to 4,26, 1 RCT, N=38 participants);
• avoiding reincarceration (RR 0.65, 95 % CI 0.26 to 1.65, 1 RCT, N=38 participants).

Naltrexone with psychotherapy versus Benzodiazepines with psychotherapy

In an updated version of a systematic review (Minozzi et al., 2011), pharmacologycal treatment with Naltrexone in association with psychotherapy was compared with Benzodiazepines associated with psychotherapy and was found not significantly different in:

• achieving retention and abstinence (combined outcome) (RR 1.67, 95 % CI 0.96 to 2.89, 1 RCT, N=140 participants);
• reducing side effects (RR 3.00, 95 % CI 0.63 to 14.36, 1 RCT, N=140 participants).

Naltrexone with psychotherapy versus Buprenorphine with psychotherapy

In an updated version of a systematic review (Minozzi et al., 2011), pharmacologycal treatment with Naltrexone in association with psychotherapy was compared with Buprenorphine treatment associated with psychotherapy and was found not significantly different in:

• achieving retention and abstinence (combined outcome) (RR 0.37, 95 % CI  0.13 to 1.08, 1 RCT, N=87 participants).

Opioid withdrawal with antagonists under heavy sedation

Opioid withdrawal with antagonists under heavy sedation or anaesthesia was compared to withdrawal managed with reducing doses of methadone in a systematic review of 9 studies (8

RCT

s N=1109) (

Gowing 2010

) and no difference was found:

• in heroin use after 6 months (RR 0.97, 95%CI 0.88 to 1.08);
• rates of retention in treatment at 12 months (RR 0.95, 95%CI 0.69 to 1.30).

Opioid withdrawal with antagonists under minimal sedation

In a systematic review of 4 studies (N=394) (Gowing 2009), there was no significant difference in:

• completion rate (RR 1.26, 95%CI 0.80 to 2.00);
• relapse to use rates (RR 0.83, 95%CI 0.52 to 1.35).

Pharmacological detoxification treatment for adolescent opioid users

Detoxification treatment alone or in combination with psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions was assessed in a systematic review of two RCT (involving 190 participants between 13–18 years of age) (Minozzi et al., 2006) finding no conclusive results on:

• completion of treatment;
• reducing the use of substances; and
• improving health and social status.

Among the studies enclosed in the review:

One compared Buprenorphine with Clonidine for detoxification and found no difference in:

• the number of patients leaving the study early (RR 0.45, 95 % CI: 0.20 to 1.04);
• acceptability of treatment (withdrawal score WMD 3.97, 95 % CI :1.38, 9.32).

More participants in the Buprenorphine group initiated naltrexone treatment (RR 11.00, 95 % CI 1.58, 76.55).

Another study compared maintenance treatment with detoxification treatment — Buprenorphine-Naloxone maintenance with buprenorphine detoxification. It found:

• the maintenance treatment group had fewer patients dropping out (RR 2.67, 95 % CI 1.85, 3.86);
• there were better results at follow-up (RR 1.36, 95 % CI 1.05, 1.76), but no differences were found for opioid use.

Therapeutic communities for the treatment of drug misuse and dependency

This intervention was found difficult to assess in a systematic review of seven trials with around 5 000 patients (Smith et al., 2006).

Therapeutic communities in prison

Therapeutic communities in prison for the treatment of drug misuse proved to be better than prison in avoiding re-incarceration at 12-months. Significantly fewer inmates assigned to prison therapeutic communities were re-incarcerated at 12 months post-release compared with prison inmates receiving no treatment or assigned to alternative services (Smith et al., 2006).

Evidence of ineffectiveness

Opioid withdrawal with antagonists under heavy sedation

Opioid withdrawal with antagonists under heavy sedation or anaesthesia was compared to withdrawal managed with reducing doses of methadone in a systematic review of 9 studies (8 RCTs N=1109) (Gowing 2010) and:

• heavy sedation or anaesthesia increased adverse effects (RR 3.21, 95%CI 1.13 to 9.12);
• heavy sedation groups showed higher risk of life threatening than the non-heavy sedation groups (RR 14, 95%CI 0.74 to 264).

References and definitions

List of references

• Ferri, M., Davoli, M. and Perucci, C.A. (2011) 'Heroin maintenance for chronic heroin-dependent individuals', Cochrane Database of Systematic Reviews, Issue 12. Art. No.: CD003410. DOI: 10.1002/14651858.CD003410.pub4.
• Gowing, L., Ali, R. and White, J.M. (2009) 'Opioid antagonists with minimal sedation for opioid withdrawal', Cochrane Database of Systematic Reviews, Issue 4, No.: CD002021. DOI: 10.1002/14651858.CD002021.pub3.
• Gowing, L.,Ali, R. and White, JM. (2010) 'Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal', Cochrane Database of Systematic Reviews, Issue 1, Art. No.: CD002022. DOI: 10.1002/14651858.CD002022.pub3.
• Hesse, M., Vanderplasschen, W., Rapp, R., Broekaert, E., Fridell, M. (2007) 'Case management for persons with substance use disorders', Cochrane Database of Systematic Reviews, Issue 4. Art. No.: CD006265. DOI: 10.1002/14651858.CD006265.pub2.
• Minozzi, S., Amato L, ,Vecchi, S., and Davoli M. (2009), 'Maintenance agonist treatments for opiate dependent pregnant women', Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD006318. DOI: 10.1002/14651858.CD006318.pub2
• Minozzi, S., Amato, L., Vecchi, S., Davoli, M., Kirchmayer, U., Verster, A. (2011), 'Oral Naltrexone maintenance treatment for opioid dependence', Cochrane Database of Systematic Reviews 2011, Issue 4. Art.No.: CD001333. DOI: 10.1002/14651858.CD001333.pub4
• Smith, L.A., Gates, S. and Foxcroft, D. (2006) ‘Therapeutic communities for substance related disorder’, Cochrane Database of Systematic Reviews, Issue 1, Art. No. CD005338, DOI: 10.1002/14651858.CD005338.pub2.
• WHO (2009), 'The WHO Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence', World Health Organization.

Explanation of terms used

Below you can find definitions and further explanation for some of the terms used in this section of the Best practice portal. A more general glossary for the best practice portal is also available.

Affective-focused prevention intervention

A type of prevention intervention which aims to they aim to modify inner qualities (personality traits such as self-esteem and self-efficacy, and motivational aspects such as the intention to use drugs).

BA

Before-after (BA) study design

Beneficial

Interventions for which precise measures of the effects in favour of the treatment were found in the systematic review of randomised controlled trials (RCTs), and that were recommended in guidelines with reliable methods for assessing evidence (such as GRADE). A treatment ranked as 'beneficial' is suitable for most patients.

CBA

Controlled before-after (CBA) study design

CCT

Controlled clinical trials (CCT)

Confidence Interval (CI)

The Confidence Interval (CI) is a measure of the precision (or uncertainty) of study results. It is the interval that most likely includes the true value of the parameter we are calculating, where 'most likely' is taken by common usage to be a 95% probability. Thus the current expression of '95 % CI'. A wide CI indicates less precise estimates of effect and vice versa.

Practical interpretation

• If the RR (the relative risk) = 1, or the CI (the confidence interval) = 1, then there is no significant difference between treatment and control groups
• If the RR > 1, and the CI does not include 1, events are significantly more likely in the treatment than the control group
• If the RR < 1, and the CI does not include 1, events are significantly less likely in the treatment than the control group

CPS

Current population survey (CPS)

Evidence of ineffectiveness

Interventions that gave negative results if compared with a placebo, for example.

Additional information for prevention
For ethical reasons this category in prevention should be considered as interventions with negative and undesired (iatrogenic) effect.

ITS

Intermittent time series design (CPS)

Knowledge-focused prevention intervention

A type of prevention intervention which aims to to enhance knowledge of drugs, and drug effects, and consequences.

Likely to be beneficial

Interventions that were shown to have limited measures of effect, that are likely to be effective but for which evidence is limited, and those that are recommended with some caution in guidelines with reliable methods for assessing evidence (such as GRADE). A treatment ranked as 'likely to be beneficial' is suitable for most patients, with some discretion.

Number Needed to Treat (NNT)

The Number Needed to Treat (NNT)indicates the number of patients that needs to be treated to obtain one respondent patient. Numerically the NNT is the reciprocal of the difference between the proportion of events in the experimental and the comparison group (absolute risk reduction). Taking into consideration that the ideal NNT would be 1 (the unreal situation in which every single patient succeeded) it is easily understood that a NNT value close to 3 or 4 would be very good.

Adjusted Odds Ratio (AOR)

The Adjusted Odds Ratio is a way of comparing whether the probability of a certain event is the same between two groups, yet they are calculated adjusting for or controlling for other possible contributions from other variables (tipically demographic variables) in the model. An AOR equal to 1 implies that the the event is equally probable in both groups. An AOR greater than 1 implies that the event is more likely in the first group. An AOR less than 1 implies that the event is less likely in the first group.

Odds Ratio (OR)

The Odds Ratio is a way of comparing whether the probability of a certain event is the same between two groups. Like the Relative Risk, an OR equal to 1 implies that the the event is equally probable in both groups. A OR greater than 1 implies that the event is more likely in the first group. A OR less than 1 implies that the event is less likely in the first group. In medical research, the odds ratio is commonly used for case-control studies, as odds, but not probabilities, are usually estimated. Relative risk is used in randomized controlled trials and cohort studies.

p value

A p-value is a measure of how much evidence we have against the null hypothesis. The null hypothesis represents the hypothesis of no change or no effect. The smaller the p-value, the more evidence we have against the null hypothesis thus it is more likely that our sample result is true. Traditionally, researchers will reject a null hypothesis if the p-value is less than 0.05.

RCT

Randomised controlled trial (RCT)

Relative Risk (RR)

The Relative Risk (RR) is used to compare the risk in the two different groups of people, i.e. treated and control groups to see if belonging to one group or another increases or decreases the risk of developing certain outcomes. This measure of effect will tell us the number of times an outcome is more likely (RR > 1) or less likely (RR < 1) to happen in the treatment group compared with the control group.

Practical interpretation

• If the RR (the relative risk) = 1, or the CI (the confidence interval) = 1, then there is no significant difference between treatment and control groups
• If the RR > 1, and the CI does not include 1, events are significantly more likely in the treatment than the control group
• If the RR < 1, and the CI does not include 1, events are significantly less likely in the treatment than the control group

Trade-off between benefits and harms

Interventions that obtained measures of effects in favour of treatment and are recommended in guidelines with reliable methods for assessing evidence (such as GRADE), but that showed some limitations or adverse effects that need to be assessed before providing them to patients.

Unknown effectiveness

Interventions for which there are not enough studies or where available studies are of low quality (with few patients or with uncertain methodological rigour), making it difficult to assess if they are effective or not. Interventions for which more research should be undertaken are also grouped in this category.

Additional information for prevention
For prevention interventions,  this  is also known as 'zero effect'.

Skill-focused prevention intervention

A type of prevention intervention which aims to enhance students’ abilities in generic skills, refusal skills and safety skills.

Standardised Mean Difference (SMD)

The Standardised Mean Difference (SMD) is the difference in means divided by a standard deviation. Note that it is not the standard error of the difference in means (a common confusion). The standardized mean difference has the important property that its value does not depend on the measurement scale. It may be useful if there are several trials assessing the same outcome, but using different scales.

z score (Standard Score)

The z-score (aka, a standard score) indicates how many standard deviations an element is from the mean of the population.

About opioid use

Case definition

Opioids, mainly heroin, continue to be cited as the principal drug by the majority of those seeking treatment in Europe. Considerable differences exist across Europe in the proportion of drug users entering treatment. Of the approximately 300 000 treatment entries for which the primary drug is known, 49 % cited heroin as their primary drug.

Aetiology

The mean age of clients entering outpatient treatment for primary opioid use is 33 years, and almost all countries have reported an increase since 2003.

Almost all opioid users entering treatment report initiation before the age of 30 and about half before the age of 20. An average time lag of about eight years is reported between first use of opioids and first contact with drug treatment (EMCDDA, 2009).

Prevalence

The average prevalence of problem opioid use in the countries providing data is estimated to be between four and five cases per 1 000 of the population aged 15–64. Injecting is frequently reported as the usual mode of administration by opioid users entering treatment, accounting for over half of opioid clients in most countries.

Treatment

In Europe, many opioid users are enrolled in programmes providing long-term care. Treatment is mostly conducted in outpatient settings, which can include specialist centres, general practitioners and low-threshold facilities.

Outcomes

Treatments may not be effective in achieving all the desired outcomes, these outcomes are prioritised.

Primary outcomes

• Retention in treatment (observational studies* showed that people in treatment are less likely to take risks, and to be involved in crimes).
• Mortality.
• Relapse to use.
• Criminal activity.

* studies such as National Treatment Outcome Research Study – NTORS, Australian Treatment Outcome Study – ATOS

Prognosis

Opioid use leads to tolerance, and after a period of use to dependence (National Institute Drug Abuse, 2008). Opioid dependence has been considered a chronic medical illness, benefiting from the same kind of long-term treatment and supportive care (McLellan, 2000). Untreated patients can have a relapse rate >90 % (McLellan, 1983).

References

American Psychiatric Association (2000), Diagnostic and statistical manual of mental  disorders, 4th edition, text revision, American Psychiatric Association, Washington, DC.

Cochrane systematic reviews

National Institute of Drug Abuse 2008

EMCDDA statistical bulletin

EMCDDA , Annual report: the state of the drugs problem in Europe, EMCDDA, Lisbon

McLellan, A. T., Luborsky, L., Woody, G. E., O’Brien, C. P. and Druley, K. A. (1983), Predicting response to alcohol and drug abuse treatments: role of psychiatric severity, Archives of General Psychiatry 40 (6), pp. 620–5.

McLellan, A. T., Lewis, D. C., O’Brien, C. P. and Kleber, H. D. (2000), Drug dependence, a chronic medical illness: Implications for treatment, insurance, and outcomes evaluation, Journal of the American Medical Association 284 (13), pp. 1689–95.

Ongoing trials

Related ongoing trials (PDF, updated January 2011)

Observational studies

Related observational studies (PDF, updated June 2011)