Blanken, P., Hendriks, V.M., van Ree, J.M., van den Brink, W.(2010). Outcome of long-term heroin-assisted treatment offered to chronic, treatment-resistant heroin addicts in the Netherlands. Addiction, 105, 300-308.

Study design

Observational cohort study

Setting: out-patients treatment in specialized treatment centres Location: The Netherlands

Number of patients

149

Patient characteristics

Age: average 39.2 years old

Sex: 83% males

Ethnicity: 89,9% were Dutch or Western European

Inclusion

Heroin dependent patients who had responded positively to the HAT in two randomized controlled trials were eligible for long-term heroin-assisted treatment

Intervention(s)

-   Methadone plus injectable or inhalable heroin offered 7 days per week, three times a day.

-   The average doses of heroin prescribed was 268 mg per visit an 502 mg per day.

-   Patients were supplemented with individual psychosocial and medical support.

Follow-up

After 4 years

Outcome

Prognostic factor: injectable methadone treatment or inhaling heroin, three times a day, 7 days a week. Long-term response (4 years) to heroin-assisted treatment (HAT) in chronic therapy resistant heroin- dependent patients.

Response was defined as:

-   improvement (compared to baseline) of at least 40% at the 4-year follow-up in at least one of the domains of inclusion at baseline assessment, i.e. physical, mental or social health;

-   no serious deterioration (>40%) in any of the other outcome domains, compared to baseline;

-   no substantial increase (>6 days/month) of cocaine or amphetamine use compared to baseline.

Outcome measure: improvement of the physical, mental and social health and reduction of illicit drug use and alcohol consumption

Results

-   56% of clients (83), completed the 4 years HAT treatment.

-  Response was significantly better for patients continuing 4 years of HAT compared to patients who discontinued treatment: 90.4% versus 21.2% (difference 69.2%; odds ratio (OR) = 48.4; 95% CI: 17.6¬159.1).

-   Following the HAT treatment was associated with an increasing % healthy patient who stopped illegal drugs and excessive alcohol consumption, 12% after the first year to 25% after 4 years HAT.

Quality assessment

There is no feedback from all clients who are not working, this may have influenced the results.

Quality of evidence

[Additional comments]

Follow-up:

-   nearly half the patients who discontinued long-term HAT were not reached or refused to cooperate in the 4-year follow-up assessment. The outcome status of these patients could not be determined. But even in the unlikely ‘worst-case' scenario, where all non-reached patients who discontinued HAT were considered to be responders, 4-year outcome status of patients who continued long-term HAT was still significantly better;

-   HAT 4 years is associated with a stable, physical, mental and social health;

-   prevent illicit heroin use and provides a significant reduction in cocaine use;

-     HAT should be continued as long as there is no compelling reason to stop treatment.

Ferri e.a. (2010). Heroin maintenance for chronic heroin-dependent individuals.

Study aim

To assess what treatment (heroin maintenance versus. Methadone or other replacement therapy) is effective for heroin users, so the health and social functioning improve.

Study design

Systematic review of RCTs

Analysis: the studies could not be analysed cumulatively because of heterogeneity of interventions and outcomes.

Number of studies

4 RCT’s

Number of patients

N = 577

Patient characteristics

Study 1:

-   N = 174;

-   gender = male 82.2%;

-   age = 38.5 years (5.7 SD). Study 2:

-   N = 256.

-   gender: 79.7% male.

-   age: 39.6 (5.7 DS).

Study 3:

-   N = 96;

-   age = 18-35 years; mean 23.9;

-   sex = 75% male; 25% female. Study 4:

-   N = 51;

-   age > 20.

Inclusion

Inclusion:

-   chronic heroin users;

-   18 years and older.

Exclusion:

-  design of study not in the inclusion criteria of this review;

-  study outcomes or participants differing from inclusion criteria;

-   seven studies are ongoing

Intervention(s)

Intervention:

-  heroin (single or combined with heroin, methadone) maintenance treatment regardless of dosage, preparation, route of administration, establishment and duration of treatment.

Control:

-   no intervention;

-   methadone treatment;

-   waiting list for conventional treatment;

-   other pharmacological treatment for heroin dependence

Outcome

Outcome measures:

-   retention in treatment;

-   relapse to street heroin use;

-   use of other substances;

-   death;

-   medical adverse events

Results

-   One study showed a statistically significant higher retention in treatment for heroin treatment in clients due methadone, while one of the most recent large studies was statistically significantly higher retention in methadone patients.

-   Relapse to heroin was analyzed in two studies.

-   One of the two studies analyze results showing heroin treatment helps to keep people away from illegal activities.

Quality assessment

Study question:+

Search: +

Selection: +

Quality assessment: +

Data extraction: +

Description of original studies: +

Handling heterogeneity: +

Statistical pooling: +

Funding/conflicts of interest: no conflicts

Quality of evidence

A2

Haasen e.a. (2007). Heroin-assisted treatment for opioid dependence: Randomised controlled trial.

Study aim

To study heroin-assisted treatment in people on methadone who continue intravenous heroin and in those who are heroin dependent but currently not in treatment.

Study design

Open-label RCT injectable heroin or oral methadone Analysis: intention to treat Location: Germany

Number of patients

Injectable heroin: N = 515 Oral methadone N = 500

Patient characteristics

Age: mean age 36 years Sex: 80% male

Inclusion

Inclusion:

-   minimum 23 years;

-   ICD-10 diagnosis of opioid dependence for at least 5 years;

-   poor physical and / or mental health, with a minimum of 13 symptoms of the Opiate Treatment Index;

-   for methadone treatment:

-  they did not succeed in treating intravenous use of street heroin.

Exclusion:

-   people a prison sentence hangs over;

-   those who were abstinent for more than 2 months;

-   serious physical illness (no/failure);

-   pregnant women and lactating women.

Baseline characteristics:

-   participants came from two groups:

-  people with heroin dependence with an inadequate response to treatment with continuous intravenous heroin use (n = 492);

-   people with a heroin addiction that were not handled during the previous 6 months (n = 540)

Intervention(s)

Intervention:

-   injectable heroin, max. 3 times a day, 7 days a week;

-   max. single dose: 400 mg;

-   max. daily dose of 1000 mg. Could be given up to 60 mg of methadone for the night.

Control:

-   oral methadone, minimum dose of 60 mg. per day. Participants from both groups were randomized to receive one of two treatments:

-   psycho-education and individual guidance;

-   case management and motivational interviews

Follow-up

12 months

Outcome

Primary: improve the physical and/or mental health secondary: a decline in illicit drug use.

Secondary: a decline in illicit drug use.

Results

-   Treatment retention was higher in the heroin (67.2%) than in the methadone group (40.0%).

-   The heroin group showed a significantly greater response to both outcomes.

-   Effects during ITT: Improving health:

-   heroin: 80%;

-   methadone: 74%.

-   Reducing illicit drug use:

-   heroin: 69.1%;

-   methadone: 55.2%.

-   More serious side effects were found in the heroin group and were mainly associated with intravenous use.

-   Limitations displayed properly.

-   Other findings indicated

Quality assessment

Randomization: +

Allocation concealed: +

Clinician blinded:?

-   Double blinding was not possible because of medication method.

Patient blinded:?

-   Patient knows what treatment he gets: you can't ignore it. Impact assessor blinded: ?

Intervention and control groups were similar: +

Adequate follow-up: +

Intention-to-treat analysis: +

Funding: Working Group of the German Ministry of Health and the seven participating cities.

Quality of evidence

B

Haasen e.a. (2009). Effects of heroin-assisted treatment on alcohol consumption: Findings of the German randomized controlled trial.

Study aim

In-depth analysis of the German HAT trail to determine if alcohol effect in patients who undergo the HAT and MMT.

Study design

RCT

Blinding: not possible Analysis:

-   self-reported data with alcohol consumption units (CU = consumption or alcohol units used);

-   Addiction Severity Index composite scores (ASI CSS);

-   carbohydrate-deficient transferrin (CDT) measures. Duration: 12 months

Setting: clinics (7)

Location: Germany

Number of patients

1015

Patient characteristics

Age: average age about 36 years Sex: about 80% male participants came from two groups:

-   people with heroin dependence with an inadequate response to treatment with continuous intravenous heroin use (n = 492);

-   people with a heroin addiction that were not handled during the previous 6 months (n = 540).

Data collected from 902 patients about alcohol use in 12 months and 955 months in August. Information from two months in 850 patients known.

Intervention(s)

Intervention, HAT group (N = 515):

-   maximum 3 times a day, 7 days a week;

-   max. Single dose: 400 mg;

-   max. daily dose of 1000mg. Could be given up to 60mg of methadone for the night.

Control, MMT group (N = 500):

-   minimal-dose of 60 mg. per day;

-   average dose was 99mg/dag.

Alcohol Test 0 was required for people receiving methadone or diamordine.

Participants from both groups were randomized to receive one of two treatments:

-   psycho-education and individual guidance;

-   case management and motivational interviews

Outcome

Primary: effect of HAT compared with MMT in the possible reduction of alcohol consumption.

Calculated: with CU, CDT and ASI-CS.

Results

-   Significant reduction of CU and CDT in both groups, but larger effects in the HAT group.

-   ASI CS shows a significant reduction in the HAT group, but not in the MMT group. Overall reduction in ASI alcohol CS is related to the reduction of CS for ASI drug use and legal problems.

-   Biggest advantage to back rings of alcohol in the HAT treatment may be due to the increased frequency of daily heroin.

Quality assessment

Randomization: +

Allocation concealed: +

Clinician blinded:?

Double blinding was not possible because of medication method.

Patient blinded:- Assessor blinded:?

Intervention and control groups were similar: +

Adequate follow-up: +

Intention-to-treat analysis: +

Funding: Working Group of the German Ministry of Health and the seven participating cities

Quality of evidence

B

Oviedo-Joekes e.a. (2009). Diacetylmorphine versus methadone for the treatment of opioid addiction.

Study aim

Compared injectable diacetylmorphine with oral methadone maintenance therapy in patients with opioid dependence that was refractory to treatment.

Study design

RCT

Analysis: Intention to treat

Location: Canada: Montreal, Quebec, and Vancouver, British Columbia

Number of patients

N = 251 clients

Patient characteristics

Age: average 39.7 years

Sex: 61% are men

Inclusion

Inclusion:

-   opioid dependence (3 or more criteria from the criteria list, Diagnostic and Statistical Manual of Mental Disorders, 4th edition;

-   25 years or older;

-   minimum 5 years opioid users;

-   use daily injections;

-   no change of city or residence last year;

-   at least 2 prior opioid dependence regimens including at least have a methadone maintenance program where they received 60mg daily minutes, for at least 30 days.

Exclusion:

-   methadone maintenance treatment undergone past six years;

-   serious medical or psychiatric disorders that a contradiction for diacetylmorphine;

-   pregnancy;

-   involvement in a criminal case that could result in imprisonment during the study period.

Intervention(s)

Intervention (not blind):

-   115 received injectable diacetylmorphine (45.8%);

-   average 2x per day;

-   the average daily dose was 365.5 mg.

Control (double blind):

-   111 clients received oral methadone (44.2%), average daily dose 96 mg;

-   25 clients received injectable hydromorphone (10.0%). Follow-up:

-   evaluations were performed at baseline and 3, 6, 9, and 12 months.

Outcome

Primary: retention in addiction treatment at 12 months Secondary: reduction in illegal drug use or other illegal activities (improvement at least 20% of the European Addiction Severity Index.

Results

Results (primary outcomes were determined in 95.2% of the

participants):

-   retention in addiction treatment after 12 months: diacetylmorphine 87.8%; methadone: 54.1%;

-   reduction of illegal drugs or other illegal activities: diacetylmorphine 67% methadone: 47.7%;

-   the use of street heroin in the diacetylmorphine clients decreased more than the methadone group;

-   cocaine use was virtually unchanged

Quality assessment

Randomization: +

Allocation concealed: +

Therapist blinded: +

Patient blinded: +

Intervention and control groups were similar: +

Follow-up adequate:+

Intention-to-treat analysis: +

Funding: Supported by grants from the Canadian Institute for Health Research.

Good quality article, almost all patients were included for follow-up

Quality of evidence

B

Perneger e.a.(1998). Randomised trial of heroin maintenance programme for addicts who fail in conventional drug treatments.

Study aim

Experimental evaluation of heroin-maintenance program.

Study design

Randomized trail Blindness: allocation blinded. Analysis: ITT Follow-up: 6 months Setting: outpatient Location: Geneva, Switzerland.

Number of patients

N = 51:

-   intervention N = 27;

-   control subjects N = 24

Patient characteristics

Age:

-   intervention group: 31.1 years;

-   control group: 32.8 years.

Sex:

-   intervention group: 67% male;

-   control group: 83% male

Inclusion

-   Stayed in the canton of Geneva since 1994

-   At least 20 years old

-   Minimum 2 years addicted to intravenous heroin

-   Daily use of opiates

-   Social anxiety and/or poor health

-   Failed in at least two previous treatments with medication.

Intervention(s)

Intervention: patients (N = 27) received intravenous heroin and other health and psychosocial support.

Daily average 480 mg.

Control: clients (N = 24) received another conventional drug treatment (usually methadone).

Outcome

Outcome measures:

-   all outcomes were self reported by the patients with the SF-36 health survey.

Outcome variables:

-   drug use;

-   use of street heroin in past month;

-   daily use past month;

-   health status (for example: numbers of days ill in past month, use of health services, workstatus, quality of social relationships, criminal behaviour)

Results

Street-heroin use:

-   1 person in intervention group and 10 (48%) in control group.

-   everyone stopped bezodiazepines street and took enormous overdose rate down.

Health, experimental group:

-   treatments for psychological problems has increased (from 15% to 65%);

-   the number of days with health declined (11.8% to 9.9%);

-   severe anxiety decreased (82% to 44%).

-   difficulties in controlling violent behavior decreased (30% to 18%);

-   number of suicide attempts (22% to 4%).

Control group:

-   minimal changes to the above are not present or even worse

Quality assessment

Randomization: +

-   sealed envelopes placed patients in one of the two groups Allocation concealed: +

Clinician blinded: -

-   self reported questionnaires Patient blinded:-

Assessor blinded:-

Intervention and control groups were similar: +

Adequate follow-up: +

Intention-to-treat analysis: +

Funding: Swiss Federal Office of Public Health

Quality of evidence

B

Study limitations:

-   small study;

-   self-reported outcomes may be biased;

-   this study assessed global programme effects it cannot differentiate between specific effects of heroin administration and those of other medical and social services, such as mental health care and benzodiazepine substitution.

Rehm e.a. (2001). Feasibility, safety, and efficacy of injectable heroin prescription for refractory opioid addicts: a follow-up study.

Study aim

To assess the feasibility, safety and efficacy of the treatment.

Study design

Follow-up study/cohort.

Number of patients

1969

Patient characteristics

Age: mean age: 32

Sex: 77% male

Intervention(s)

HAT treatment, psychosocial support, access to medical care. When patients needed it, they got methadone instead of heroin. Average daily intravenous heroin was 474 mg (SD 206.1) and an average of 2.6 intakes per day.

No control group.

Follow-up

Follow-up: after 7 years N = 237

Survival curves on Kaplan-Meier estimates, and residual analysis done on categorical variables.

Outcome

Primary: assessment of the somatic, mental health, social inclusion, and treatment outcomes (through questionnaires, interviews and medical examinations).

Results

The treatment is relatively high in participation in HAT: 1693 (86%) of patients followed the program at least three months, 1,378 (70%) at least one year, 985 (50%) at least 2.5 years, and 669 (34%) 5 years and longer.

Reasons for failure are described.

Socio-economic status is evaluated:

(N=37). Below you will find the measurements between brackets.

The first percentage reflects the measurement at baseline, the second percentage reflects the measurement at 18 months follow-up.

-   unstable housing situation (43%, 21%);

-   nomadic life (18%, 1%);

-   unemployment (73%, 45%);

-   receiving a benefit (63%, 54%);

-   being in debt (74%, 67%);

-   income from illegal activities (69%, 11%);

-   visiting illegal drug events (84%, 41%).

Disability allowance and increased (22%, 27%).

Quality of evidence

C

Conclusion: the treatment showed positive effects concerning the health and social impacts. A long stay in treatment was associated with a higher risk of initiating abstinence-oriented therapy than a short stay. HAT would be an effective treatment option for chronically addicted clients where other treatments have failed.

Strang e.a. (2010). Supervised injectable heroin or injectable methadone versus optimised oral methadone as treatment for chronic heroin addicts in England after persistent failure in orthodox treatment (RIOTT): A randomised trial.

Study aim

To compare the effectiveness of supervised injectable treatment with medicinal heroin (diamorphine or diacetylmorphine) or supervised injectable methadone versus optimised oral methadone for chronic heroin addiction.

Study design

RCT

Blindness: blind (open label study)

Analysis: intention to treat Setting: 3 supervised injecting clinics.

Location: England. Patients were enrolled from the local catchment areas of supervised injecting clinics in south London, Darlington, and Brighton.

Number of patients

N = 127

Patient characteristics

Age: 37.2

Sex: 73% men

Ethnicity: 96% white

Inclusion

Inclusion:

-   chronic heroin addicts;

-   receiving conventional oral maintenance treatment (> 6 months).

Baseline characteristics:

-   95% unemployed;

-   73% had spent time in prison;

-   patients had used opiates for a mean of 16.6 years and received treatment for mean of 9.8 years;

-   all were daily using street heroin;

-   43% also reported regular use of cocaine or crack cocaine;

-   all patients were receiving methadone treatment at enrolment (continuously for > 6 months), and 39% were receiving optimized methadone treatment

Intervention(s)

Intervention:

-   supervised injectable heroin, N = 43;

-   or injectable methadone, N = 42.

Control:

-   optimized oral methadone, N = 42

Follow-up

26 weeks

Outcome

Primary: 50% or more of negative specimens for street heroin on weekly urinalysis during weeks 14-26.

Secondary: examined more stringent tests of reduction of regular use of street heroin.

Outcome measures: percentages were calculated with Rubin's rules and were then used to estimate numbers of patients in the multiple imputed samples.

Results

Results:

-   self-reported: abstinence from street heroin at weeks 23-26 was recorded in a significantly higher proportion of patients on injectable heroin (51% [n = 22]) than in those on injectable methadone (29% [n = 12] or oral methadone (17% [n = 7]);

-   urine sample: injectable heroin was associated with the greatest proportion of participants with urine samples negative for street heroin within the first 6 weeks of treatment and thereafter. The injectable heroin group was associated with the largest increase in abstinence by the end of 6 weeks.

Other results:

-   for injectable heroin versus injectable methadone, a significant difference was recorded (4.26, 1.63, 11.14, p = 0.003), but the study was not powered for this comparison.

Quality assessment

Randomization: +

Allocation concealed: +

Clinician blinded: -

Patient blinded: -

Assessor blinded: -/+ -/+

-   urinalysis was done by laboratory personnel who were masked to treatment allocation;

-   statistician analysing primary outcome data was masked to injectable group but not to oral versus injectable treatment for the entirety of the primary analysis.

Intervention and control groups were similar: +

Adequate follow-up: +

Intention-to-treat analysis: +

Funding:

-   Community Fund (Big Lottery) Research section, through Action on Addiction.

Quality of evidence

A2

Conclusion:

Good quality article. The study was open-label, which meant that patients' awareness of their treatment allocation could have affected expectancy and behavior.

Van den Brink e.a.(2003). Medical prescription of heroin to treatment resistant heroin addicts: two randomised controlled trials.

Number of patients

N = 549

Patient characteristics

Age: mean age 39

Sex: 80% male

Inclusion

Inclusion:

-   last 6 months attending a methadone treatment program;

-   at least 25 years old;

-   minimum 5 years diagnostic criteria for heroin dependence;

-   use at least 50 mg (inhaling trial) or 60 mg (injecting trial) methadone per day for a uninterrupted period of at least four weeks in the last 5 years;

-   use (almost) daily illicit heroin;

-   poor physical or mental health or poor social functioning;

-   last year voluntarily waived heroin for more than two months. Exclusion:

-   pregnant or breastfeeding women

Intervention(s)

Intervention:

Two separate open label randomized controlled groups:

-   Inhaling heroin (n = 375) with methadone. Within the group; there were 3 treatment groups:

-   group A: control group (N = 139); only methadone (up to 150mg per day);

-   group B:experimental group (N = 117) methadone and heroin;

-   group C Comparison group (N = 119). Six months of methadone alone followed by 6 months of methadone and heroin.

-   Injectable heroin (n = 174) with methadone. Within the group; there were 2 treatment groups:

-   group A: Control group (N = 98); only methadone (up to 150mg per day);

-   group B:experimental group (N = 76) methadone and heroin. Doses:

-   heroin: max 1000mg per day;

-   methadone up to 150mg per day.

Clients were 2.1x average daily heroin use and get an average of 260 mg per visit.

Period of 12 months.

All patients also received psychotherapy.

Outcome

Primary: dichotomous, multidomain response index, including validated indicators of physical health, mental status, and social functioning.

Results

Results:

-   treatment with heroin plus methadone was significantly more effective than treatment with methadone alone in the trial of inhalable heroin and in the trial of injectable heroin treatment. Inhalable heroin: (response rate 49.7% vs. 26.9%; 95% confidence interval 11% to 34.6%, NNT: 4.4, 2.9 to 9.1);

-   injectable heroin (response rate 55.5% vs. 31.2%; 9.6% to 39.0%, NNT: 4.1 2.6 to 10.4).

Further decline after 12 months of illegal activities and daily cocaine use. Patients also made more personal contact;

-   cessation of heroin prescription led to a rapid deterioration of 82% (94/115);

-   heroin should be prescribed long before the positive results remain stable.

Conclusion article:

-   monitoring prescribing heroin is feasible, effective, and probably as safe as methadone alone in reducing the many physical, mental and social problems of treatment resistant heroin addicts.

Quality assessment

Randomization: +

Allocation concealed: ?

Clinician blinded: ?

Patient blinded - Assessor blinded:+

Intervention and control groups were similar: +

Adequate follow-up: +

Intention-to-treat analysis: +

Funding: the study was commissioned by the Ministry of Health, Welfare and Sport and also financed by them.

Quality of evidence

B (?)

Conclusion:

-   the study is clear and the quality seems good;

-   it wasn't a double-blind study;

-   and only self reported data were used (collected by researchers).