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 and buprenorphine seem equally effective at stabilising opioid use.
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.
Clinical context
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.[1] 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.[1] [2] 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.[3] 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.[4] The UK drug strategy reported 100,000 to 200,000 problem drug users in the mid-1990s.[5] 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.[6] 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).[7] 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.[8] 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.[9]
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.[10]
Prognosis
Addictive disorders are chronic relapsing conditions with no known "cure".[11] Naturalistic studies have demonstrated that over a 5-year period, approximately half of individuals recover from the dependence.[12]
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 (into 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). 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.
| Important outcomes | Criminality, Mortality, Opioid misuse, Retention in treatment, Severity of withdrawal symptoms | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of drug treatments for stabilisation (maintenance) in people with opioid dependence? | |||||||||
| at least 4 RCTs (at least 620) | Opioid misuse | Buprenorphine versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
| at least 5 (at least 1131) | Retention in treatment | Buprenorphine versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (92) | Opioid misuse | Frequency of buprenorphine | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (92) | Retention in treatment | Frequency of buprenorphine | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 4 (576) | Mortality | Methadone versus no opioid replacement therapy | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for small number of events (11 in total) |
| 6 (1129) | Opioid misuse | Methadone versus no opioid replacement therapy | 4 | 0 | 0 | 0 | 0 | High | |
| at least 6 RCTs (at least 1013) | Retention in treatment | Methadone versus no opioid replacement therapy | 4 | 0 | –1 | –1 | +1 | Moderate | Consistency point deducted for heterogeneity between RCTs. Directness point deducted for diverse population in control group. Effect-size point added for RR >2 |
| 4 (682) | Criminality | Methadone versus no opioid replacement therapy | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for diverse population in control group |
| 3 (237) | Opioid misuse | Higher- versus lower-dose methadone | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for incomplete reporting of results. Directness points deducted for unclear outcome measurement (heroin abstinence) and wide range of dosages used in each group |
| at least 5 (at least 496) | Retention in treatment | Higher- versus lower-dose methadone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for wide range of dosages in each group |
| 1 (405) | Mortality | Buprenorphine versus methadone for stabilisation | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| at least 8 (at least 1338) | Opioid misuse | Buprenorphine versus methadone for stabilisation | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of data and heterogeneity between trials |
| at least 13 (at least 1822) | Retention in treatment | Buprenorphine versus methadone for stabilisation | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of data and heterogeneity between trials. |
| 2 (325) | Criminality | Buprenorphine versus methadone for stabilisation | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of data |
| What are the effects of drug treatments for withdrawal in people with opioid dependence? | |||||||||
| 5 (264) | Retention in treatment | Buprenorphine versus methadone | 4 | 0 | 0 | 0 | 0 | High | |
| 4 (432) | Severity of withdrawal symptoms | Buprenorphine versus methadone | 4 | 0 | 0 | 0 | 0 | High | |
| 11 (1206) | Retention in treatment | Buprenorphine versus clonidine | 4 | 0 | 0 | 0 | 0 | High | |
| 5 (776) | Severity of withdrawal symptoms | Buprenorphine versus clonidine | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (27) | Retention in treatment | Buprenorphine versus oxazepam | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (unclear) | Severity of withdrawal symptoms | Buprenorphine versus oxazepam | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for incomplete reporting of results. Directness points deducted for unclear outcome assessment (timing and application of measuring tool) and unclear clinical relevance |
| 1 (516) | Opioid misuse | Different rates of buprenorphine dose reduction | 4 | 0 | 0 | 0 | 0 | High | |
| 2 (38) | Retention in treatment | Methadone versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and heterogeneity between trials |
| 2 (97) | Opioid misuse | Methadone versus any other drug treatment | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for broad comparison group (including any other pharmacological treatment) |
| 14 (890) | Retention in treatment | Methadone versus any other drug treatment | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for broad comparison group including any other pharmacological treatment |
| 5 (204) | Retention in treatment | Methadone versus other opioid agonists | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for broad comparison group (including all other opioid agonists) |
| 1 (24) | Retention in treatment | Methadone versus chlordiazepoxide | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for small number of events (9 in total) |
| 149 (3) | Retention in treatment | Alpha2-adrenoceptor agonists versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 10 (690) | Opioid misuse | Alpha2-adrenoceptor agonists versus methadone | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for diverse study designs and assessment and reporting of outcomes |
| at least 7 (at least 577) | Retention in treatment | Alpha2-adrenoceptor agonists versus methadone | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for diverse study designs and assessment and reporting of outcomes |
| 1 (50) | Opioid misuse | Lofexidine versus clonidine | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 3 (90) | Retention in treatment | Lofexidine versus clonidine | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (80) | Severity of withdrawal symptoms | Lofexidine versus clonidine | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting. Directness point deducted for no statistical analysis between groups |
| 1 (210) | Retention in treatment | Lofexidine versus buprenorphine | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and sparse data |
| 5 (342) | Opioid misuse | Ultra-rapid withdrawal versus standard withdrawal | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for conflicting results |
| 1 (100) | Retention in treatment | Ultra-rapid withdrawal versus standard withdrawal | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for sparse data. Consistency point deducted for conflicting results |
| What are the effects of drug treatments for relapse prevention in people with opioid dependence? | |||||||||
| 8 at most (315 at most) | Opioid misuse | Naltrexone (with or without psychosocial treatment) versus placebo (with or without psychosocial treatment) | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for conflicting results |
| 4 at most (281 at most) | Retention in treatment | Naltrexone (with or without psychosocial treatment) versus placebo (with or without psychosocial treatment) | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for unclear comparison group (with or without psychological treatment) and use of co-intervention (psychological treatment) |
| 2 (86) | Criminality | Naltrexone (with or without psychosocial treatment) versus placebo (with or without psychosocial treatment) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (126) | Opioid misuse | Different doses of naltrexone | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and unclear analysis (missing samples not considered positive) |
| 2 (108) | Retention in treatment | Different doses of naltrexone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for no direct comparison between groups in 1 RCT |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
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.
Disclaimer
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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