Study aim

To investigate the clinical effectiveness and cost-effectiveness of naltrexone for relapse prevention in detoxified formerly opioid-dependent individuals compared with any strategy that does not use naltrexone, including treatment with placebo, other pharmacological treatments, psychosocial interventions or no treatment.

Study design

Systematic review.

Blindness: researchers described for every study who was blinded for treatment. For most of the studies, there was no information on this subject.

Location: University of Birmingham, UK

Number of studies

Effectiveness of naltrexone: 21 citations reporting 17 different studies:

-  1 systematic review;

-  13 RCTs;

-  3 non-randomised comparative studies.

Effectiveness of interventions to enhance naltrexone compliance: 10 citations, reporting 9 RCTs.

N = 940 in the 13 included trials N = 841 in the other 9 RCTs.

Inclusion

Inclusion criteria:

-  controlled trials of the use of oral naltrexone compared with any other relapse-prevention strategy (pharmacological, psychosocial, etc.) without naltrexone in detoxified formerly opioid-dependent individuals in both arms;

-  systematic reviews of analytical observational studies looking at adverse events or other outcomes, e.g. crime rates, for naltrexone use for the same indication;

-  RCTs of any intervention designed to enhance compliance with naltrexone treatment with the same naltrexone regimen in both arms.

Exclusion:

-  studies of naltrexone treatment outside the licensed indications, such as subcutaneous implants or parenteral depot preparations;

-  studies of naltrexone use for alcohol dependence or other indication;

-  case reports and case series.

Intervention(s)

Intervention:

-  naltrexone.

-  Mean length of time for which patients stayed on naltrexone was 84-103 days with additional psychosocial therapy compared with 43-64 days for the control group.

-  The initial doses of naltrexone in the studies were fairly standard:

25 mg (half a tablet) on day 1, followed by 50 mg (one tablet) daily from day 2 onwards. A three-times-a-week dosing schedule may be considered if it is likely to result in better compliance (e.g. 100 mg on Monday, 100 mg on Wednesday and 150 mg on Friday).

Control:

-  any strategy that does not use naltrexone, including treatment with placebo, other pharmacological treatments, psychosocial interventions or no treatment.

Follow-up

The mean length of follow-up in the RCTs was 29 weeks (range 3-52 weeks).

Outcome

Primary:

-  changes in illicit drug use;

-  drug-related morbidity;

-  drug-related mortality;

-  health-related quality of life.

Secondary outcomes were:

-  proportion of individuals being maintained opioid free;

-  concordance with and retention to treatment;

-  adherence to treatment, treatment dropout;

-  societal function;

-  criminal activity, (re)incarcerations.

Results

Naltrexon appears to have some effect in improving the risk of opioid use in naltrexone versus placebo.

The pooled relative risk from six RCTs was 0.72 (95% CI 058 to 0.90), which is a statistically significant difference favouring naltrexone.

The pooled HR from three RCTs for being free of opioid relapse was significantly different from placebo in favour of naltrexone (HR 0.53, 95% CI 0.34 to 0.82). However, this effect can be seen to fall off over time and its clinical significance is unclear.

A meta-analysis of 7 included RCTs showed that the relative risk of loss of retention in treatment in the naltrexone arm was 0.94 (95% CI 0.84 to 1.06). The pooled hazard ratio (HR) from the 5 included RCTs for retention in treatment data followed up to 35 weeks was calculated as 0.90 (95% CI 0.69 to 1.17) in favour of naltrexone and did not reach statistical significance.

Quality assessment

Study question:+

Search: +

Selection: +

Quality assessment: +

Data extraction: +

Description of original studies: ?

Handling heterogeneity: +

Statistical pooling: +

Finance: This report was commissioned by NHS R&D HTA Programme

Quality of evidence

A1

Conclusion review:

• Following successful withdrawal from opioids, naltrexone may be administered on a chronic basis to block any future effects of opioids.
• Naltrexone appears to have some limited benefit in helping formerly opioid-dependent individuals to remain abstinent, although the quality of the evidence is relatively poor and heterogeneous.
• The limited quality and extent of the studies precluded an analysis of subgroups likely to benefit from naltrexone prescribing. Oral naltrexone is used infrequently in current UK practice, and this review suggests that this is appropriate as there is little evidence to support its wider implementation. There is an important deficit in information about the quality of life of people who use illicit opioids and this would perhaps be a worthwhile area of research in informing policy questions about the cost-effectiveness of different programs and interventions

Study aim

To determine whether rapid detoxification under general anaesthesia results in higher levels of opioid abstinence than rapid detoxification without anaesthesia.

Study design

Randomized controlled open clinical trial Blinding: not possible Analysis: ITT

Study duration: September 1999 to August 2001

Setting: 4 addiction centres (Novadic, Jellinek, Parnassia and Kentron) in collaboration with three general hospitals in the Netherlands.

Number of patients

N = 272

Patient characteristics

Opioid-dependent patients whose previous attempts to abstain were unsuccessful

Age: mean age 36 years

Sex: 82% male

Inclusion

Inclusion:

-  diagnosed as opioid-dependent according to DSM-IV criteria;

-  underwent previously several unsuccessful attempts to become abstinent;

-  expressed the clear wish to be become abstinent;

-  were over 18 years of age;

-  were familiar with the Dutch language;

-  had at least one non-opioid user in their social network;

-  dependence on other drugs or drug abuse was not an exclusion factor.

Exclusion:

-  severe somatic diseases or psychiatric disorders;

-  pregnancy;

-  AIDS;

-  doubts about the patient's willingness to co-operate and contraindications regarding general anaesthesia

Intervention(s)

Intervention: rapid detoxification with general anaesthesia (RD-GA).

Control: rapid detoxification without general anaesthesia (RD).

Follow-up

1 year

All the patients were treated for 7 days at one of four addiction treatment centres. Opioid abstinence assessment took place 1 month after completion of detoxification treatment.

Outcome

Primary: the primary end-point was opioid abstinence assessed clinically by analysing urine samples.

Secondary: the secondary end-point was the intensity of the signs and symptoms of the withdrawal syndrome experienced prior to, during and after treatment. Patients completed the Subjective Opioid Withdrawal Scale (SOWS) with 16 items to determine how they experienced the withdrawal symptoms.

Results

Urine analysis 1 month after treatment: 37.2% in the RD-GA group and 40.0% in the RD group were using opioids.

86.1% of the RD-GA group was still using the naltrexone compared to 84.4% in the RD group.

Heroin-use: 38.7% in the RD-GA group and 43.7% in the RD group.

A combination of these two data sources showed rates of 46.0% in the RD-GA group versus 46.0% in the RD group.

The patients' subjective reports and the trained nurse observers' objective judgement about the intensity of withdrawal signs and symptoms were fairly similar The average 1-month cost for RD was € 2517 versus € 4439 for RD-GA.

Quality assessment

Randomization: +

Allocation concealed: - Therapist blinded: - - Not possible.

Assessor blinded: - Patient blinded: +/-

Intervention and control groups were similar: +

Follow-up adequate: +

Intention-to-treat analysis: +

Funding: Ministry of Health, Welfare and Sports (VWS) and the Netherlands Organization for Health Research and Development (ZonMw).

Quality of evidence

A2

Conclusion: rapid detoxification under general anaesthesia did not result in higher levels of opioid abstinence than rapid detoxification without anaesthesia. The cost of the former intervention was much higher.

Study aim

To assess the efficacy, safety, and patient-reported outcomes of an injectable, once monthly extended-release formulation of the opioid antagonist naltrexone (XR-NTX) for treatment of patients with opioid dependence after detoxification.

Study design

RCT

Blind: double blind Analysis: ITT

Study duration: between July 3, 2008, and Oct 5, 2009 Patients participated in the study for 24 weeks Setting: 13 clinical sites in Russia.

Number of patients

N = 250

Patient characteristics

Age: 18 < ; mean age 29 years

Sex: intervention: 90% male, control: 86% male

Inclusion

Inclusion: -

Exclusion:

-  pregnancy or breastfeeding;

-  significant medical conditions (eg, acute renal failure, endocarditis, and tuberculosis);

-  positive naloxone challenge (increases in vital signs or opioid withdrawal symptoms);

-  hepatic failure; past or present history of an AIDS-indicator disease;

-  active hepatitis or aspartate amino transferase or alanine aminotransferase more than three times the upper limit of normal;

-  known intolerance or hypersensitivity to naltrexone, carmellose, or polylactideco-glycolide; psychosis, bipolar disorder, major depressive

-  disorder with suicidal ideation, or present dependence on

-  substances other than opioids or heroin, including alcohol;

-  positive urine test for cocaine or amphetamines; and

-  naltrexone use within the past 6 months

Intervention(s)

Intervention:

-  N = 126;

-  380 mg injectable extended-release naltrexone (XR-NTX);

-   67 completed trial, 126 included in primary analysis. Control:

-   N = 124;

-   placebo;

-   47 completed trial, 124 included in primary analysis

Follow-up

24 weeks

Outcome

Primary: response profile for confirmed abstinence during weeks 5-24, assessed by urine drug tests and self report of non-use Secondary: self-reported opioid free days, opioid craving scores, number of days of retention, and relapse to physiological opioid dependence.

Results

Proportion of weeks of confirmed abstinence:

-    intervention: 90% (69.9 to 92.4);

-    control: 35% (11.4 to 63.8);

-    treatment effect: 55% (15.9 to 76.1).

Patients with total confirmed abstinence:

-    intervention: 45 (35.7%) (27.4 to 44.1);

-    control:28% (22.6%, 15.2 to 29.9);

-    treatment effect: 1.58 (1.06 to 2.36)

Secondary:

Proportion of self-reported opioid-free days over 24 weeks:

-    intervention: 99.2% (89.1 to 99.4);

-    control: 60.4% (46.2 to 94);

-    treatment effect: 38.7 (3.3 to 52.5).

Number of days of retention:

-    intervention: >168;

-    control: 96 (63 to 165);

-    treatment effect: 0.61 (0.44 to 0.86)

Quality assessment

Randomization: +

Allocation concealed: +

Therapist blinded: +

Assessor blinded: +

Patient blinded: +

Intervention and control groups were similar: +

Follow-up adequate: +

Intention-to-treat analysis: +

Funding: National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism

Quality of evidence

A2

Conclusions

• The percentage of opioid-free weeks was significantly higher in the XR-NTX group than the placebo group.
•  All four secondary endpoints also showed significant differences between the treatment groups.
• There was a substantial clinical response to placebo

Study aim

Evaluate the safety and effectiveness of a 6-month naltrexone implant in reducing opioid use after in-patient treatment.

Study design

RCT (open-label, trickle-inclusion study design)

Blinding: -

Analysis: ITT

Study duration: 6 months

Setting: receiving abstinence-oriented in-patient treatment Location: patients were recruited from in-patient drug clinics in south- eastern Norway from 1 January 2006 to 1 July 2007, in a coordinated effort between two centres: the Norwegian Centre for Addiction Research at the University of Oslo and the Addiction Unit, Sorlandet Hospital, Kristiansand

Number of patients

N = 56

Patient characteristics

Age: 34.2 (SD: 8,6).

Sex: 36% female (20)

Inclusion

Inclusion: patients who passed the initial assessment were contacted at the end of their detoxification or residential treatment stay for informed consent, baseline assessments of outcome instruments, and randomisation. Patients were allowed to talk freely about implantation and participation both prior to and after entering into the trial.

Exclusion criteria were: psychosis, pregnancy and serious hepatic disease.

Baseline characteristics intervention group: all participants had to pass an oral naltrexone challenge (25 mg) before starting implant treatment.

Intervention(s)

Intervention: naltrexon implants

Control: usual care

Follow-up

6 months

Outcome

Primary: heroin

-    timeline: days used in past 180 days;

-    ASI: days used in past 30 days. Secondary:

-    polydrug use

Results

Short results: patients receiving naltrexone had on average 45 days less heroin use and 60 days less opioid use than controls in the 180-day period (both P < 0.05). Blood tests showed naltrexone levels above 1 ng/ml for the duration of 6 months.

On the 180-day timeline follow-back, the implant group reported heroin use on an average of 17.9 days (SD = 41.8) and opioid use on 37 days (SD = 63.8), compared with 63.6 days (SD = 70.6) and 97.1 days (SD = 80.9) respectively for controls.

These were reflected in significant differences in the ASI 30-day variable, with the implant group reporting a mean of 3.5 days (SD = 7.4) and 6.3 days (SD = 1.5) of heroin and opioid use respectively compared with the control group's 11.4 days (SD = 13.9) and 17.4 days (SD = 14.3). Polydrug use: At the 6-month follow-up assessment, 18 of 27 controls v. 9 of 29 implant patients in the ITT group met criteria for DSM-IV opioid dependence using MINI (OR = 0.225, P = 0.015, 95% CI 0.07-0.69). In the naltrexone completers group, only 3 of 23 patients qualified for this diagnosis, compared with the 17 (of 26) who met sufficient criteria in the control completers group (OR = 0.08, P < 0.001). On this basis the NTT was 2.8 (95% CI 2-9) for the ITT analysis and 2.36 (95% CI 2-6) for the treatment completion sample.

Quality assessment

Patient blinded: -

Intervention and control groups were similar: +

Follow-up adequate: +

Intention-to-treat analysis: +

Funding: the study was approved by the regional ethics committee of southern Norway, and funded by a grant from the south-eastern Norway regional health authority.

Quality of evidence

B (A2)

There is not much information about blindness.

Conclusions: naltrexone implant treatment safely and significantly reduces opioid use in a motivated population of patients.

Number of studies

N = 17 articles were included

Number of patients

Between 30 and 1791 for a treatment

Inclusion

Inclusion: adults or adolescents with opioid dependence:

-   study of effectiveness of sustained-release naltrexone for opioid dependence;

-   studies of adverse effects of sustained-release NTX.

Exclusion; reasons for exclusion of the remaining 50 reports were:

-   publication was no clinical trial (25 reports);

-   adverse effect data not provided (11 reports);

-   intervention was oral naltrexone (9 reports);

-   publication on pharmacokinetics of a non-recommendable formulation (3 reports);

-   abstract available only (1 report);

-   two references to same publication (1 report)

Intervention(s)

Types of interventions:

-   sustained-release naltrexone versus oral naltrexone;

-   sustained-release naltrexone versus placebo;

-   sustained-release naltrexone versus agonist replacement therapy;

-   sustained-release naltrexone versus psychosocial interventions;

-   sustained-release naltrexone versus no treatment.

Retrieved from literature search, but not predefined in protocol:

-   low-dose versus high-dose sustained-release naltrexone.

The investigated drugs included 3 depot formulations (Alkermes, Biotek, Drug Abuse Sciences) containing 150 to 400 mg of naltrexone and 2 implant formulations (GoMedical, Wedgewood) containing 1000 to approximately 2200 mg of naltrexone.

Control:

-  opioid dependent samples;

-  alcohol dependent samples;

-  healthy volunteers

Outcome

Primary, effectiveness outcomes:

-   opioid use during and after treatment;

-   treatment adherence.

Secondary, safety outcomes:

-   use of illicit drugs other than opioids during and after treatment;

-   criminal activity and incarceration;

-   quality of life;

-   mental health;

-   duration of achieved therapeutic naltrexone blood levels

Results

Effectiveness, 1 report met inclusion criteria. Two dosages of naltrexone depot injections (192 and 384 mg) were compared to placebo. High-dose significantly increased days in treatment compared to placebo (WMD 21.00, 95% CI 10.68 to 31.32, p < 0.0001).

High-dose compared to low-dose significantly increased days in treatment (WMD 12.00, 95% CI 1.69 to 22.31, p = 0.02). Number of patients retained in treatment did not show significant differences between groups.

For adverse effects, seventeen reports met inclusion criteria analyses, six were RCTs. Side effects were significantly more frequent in naltrexone depot groups compared to placebo. In alcohol dependent samples only, adverse effects appeared to be significantly more frequent in the low-dose naltrexone depot groups compared to placebo (RR 1.18, 95% CI 1.02 to 1.36, p = 0.02). In the opioid dependent sample, group differences were not statistically significant. Reports on systematic assessment of side effects and adverse events were scarce.

Quality assessment

Statistical pooling: +

Finance:

-   Unit for Addiction Medicine, University of Oslo, Norway;

-   Norwegian Knowledge Centre for the Health Services, Norway

Quality of evidence

A1

Authors' conclusion: there is insufficient evidence to evaluate the effectiveness of sustained-release naltrexone for treatment of opioid dependence. For naltrexone injections, administration site-related adverse effects appear to be frequent, but of moderate intensity and time limited.

For a harm-benefit evaluation of naltrexone implants, more data on side effects and adverse events are needed.