A Systematic Review of Observational Studies on Treatment of … · A Systematic Review of...

A Systematic Review of Observational Studies on

Treatment of Opioid Dependence

Anna Maria Bargagli, Marina Davoli, Silvia Minozzi, Simona Vecchi, and Carlo A Perucci

Department of Epidemiology, ASL RM E, Rome

BACKGROUND DOCUMENT PREPARED FOR THIRD MEETING OF TECHNICAL DEVELOPMENT GROUP (TDG) FOR THE

WHO "GUIDELINES FOR PSYCHOSOCIALLY ASSISTED PHARMACOTHERAPY OF OPIOID DEPENDENCE"

17-21 SEPTEMBER 2007 GENEVA, SWITZERLAND

A STYSTEMATIC REVIEW OF OBSERVATIONAL STUDIES ON TREATMENT OF

OPIOID DEPENDENCE


Department of Epidemiology, ASL RM E, Rome

SUMMARY

Background

Evidence of effectiveness of substitution treatment with or without psychological treatment is derived

mainly from systematic reviews of randomised controlled trials. Long term outcomes or rare events are

not easily suitable for being evaluated within experimental studies and ancillary evidence can be drawn

from observational studies.

Aim

To conduct a systematic reviews of observational studies to evaluate effectiveness of treatment for

opioid dependence on overall mortality, fatal or non fatal overdose occurrence.

Methods

Medline (1966 to May 2006), Embase (1988 to May 2006), and CINAHL (1982 to May 2006) were

searched to identify cohort and case-control studies evaluating the relationship between treatments for

opioid dependence and overall or overdose mortality. The Newcastle-Ottawa Scale (NOS scale; NOS)

for assessing quality of non-randomized studies in meta-analysis was used. Quality assessment was not

used as exclusion criteria.

Results

We screened a total number of 1040 studies, and included 18 studies; four studies have been conducted

in the USA, three in Australia, two in Sweden, two in Spain, two in Italy, three in The Netherlands and

two in England. All the included studies were cohort studies but one case-control study. Fourteen

studies analysed the occurrence of overdose mortality and four non fatal overdose episodes.

A total of 80,919 opioid addicts were enrolled in the included studies (range: 102-23,529). Median of

mean age was 29.3 years (range of mean 23- 45). Median of proportion of male was 76,5% (range

50%- 99%). The studies were conducted in the period 1966 to 2002, most of them after the 80’s.

Fourteen studies were conducted after the spread of the HIV epidemic, but only 5 of these reported

information on HIV status, the proportion of infected patients ranging from 8% to 68% . Median length

of follow up was 6.5 years (range 6 months, for the study evaluating occurrence of serious adverse

events, to 21 years).

Most studies analysing the effect of treatment on mortality compared patients in methadone

maintenance treatment (MMT) with patients out of treatment (discharged voluntarily, involuntarily or

not in treatment): they all, but one, show significant excess risk of mortality for patients not in

treatment as compared with those in treatment, both for overall and overdose mortality. The two studies

comparing different interventions do not show conclusive evidence of differences across different

treatments. Overall, being in methadone treatment showed a strong significant protective effect (5

studies, 43035 participants): RR=0.37; 95%CI: 0.29-0.48 towards mortality for any cause as compared

to being out of treatment (either discharged or not in treatment). Pooling of results was not possible for

overdose mortality because of strong heterogeneity, however all studies but one (RR=0.95; 95%CI:

0.58, 1.54) reported significant protective effect ranging from 0.36 (95% CI 0.13-0.97) to 0.02

(95%CI: 0.01-0.09).

Studies analysing non fatal overdose use different comparisons. Three studies compare occurrence of

non fatal overdose episodes before and after the start of treatment, NTX or MMT, all showing

reduction in the number of overdose episodes. However, the study analysing the effect of NTX implant

shows significant increase in the occurrence of sedative overdose after the start of treatment. One study

compares occurrence of non fatal overdose and other serious adverse events out NTX and agonist

treatment compared with occurrence in treatment showing higher occurrence out of NTX treatment as

compared with out of agonist treatment.

Conclusions

This systematic review provides additional evidence on the effectiveness of methadone maintenance

treatment in reducing overall and overdose mortality; results are derived from studies conducted in

different countries and contexts; the protective effect of treatment on mortality from any cause can

range from 2 to five time less mortality among patients in methadone maintenance treatment as

compared to patients out of treatment, while the magnitude of the protective effect of treatment on

overdose mortality can range from virtually no effect (one study) to 3-50 time reduction in overdose

mortality in the remaining studies.

The evidence on reducing non fatal overdose is less striking, mainly due to the limited number of

studies and problems related to the methodological quality of the studies. In particular the effectiveness

of naltrexone appears to be controversial.

Unfortunately we did not find data on the effectiveness of different durations of treatment, different

intensities of treatment or different models of treatment.

The studies on mortality show consistently that the major risk factor is cessation of treatment, which is

associated with high risk of overdose death particularly in the first period after drop out. Limited

evidence suggests higher risk of death in the first two weeks of methadone treatment.

A STYSTEMATIC REVIEW OF OBSERVATIONAL STUDIES ON TREATMENT OF

OPIOID DEPENDENCE


BACKGROUND

It is well documented that heroin users are at substantially greater risk of premature mortality than their

general population peers (Bargagli AM, 2001; Frischer M, 1997). Longitudinal studies indicate yearly

mortality rates of between 1% and 3% among heroin users (Hulse GK, 1999). The excess mortality risk

among heroin users have been estimated to be between 6 and 20 times higher than in the general

population of the same age and gender (Hulse GK, 1999). Deaths attributed to overdose remain a major

cause of mortality for heroin users, and in many countries is the leading cause of death (Sporer KA,

1999; Darke S, 2003).

Treatment for heroin dependence is a highly effective public health response. The efficacy of different

pharmacological and psychosocial treatment modalities have been evaluated in randomised clinical

trials (RCT) and results from these studies have been synthesised in systematic reviews. Main outcome

measures considered in RCT include retention in treatment, illegal drug use and criminal activity. The

reduction of mortality rate is an important outcome in the evaluation of treatment effectiveness. Despite

the fact that death represents the more relevant effect of abuse and the more reliable outcome

measurable in population studies, mortality is rarely reported in RCTs of treatment of opioid

dependence and is seldom taken into account to assess the efficacy of treatments. Although randomised

controlled trials are considered the reference study design to evaluate treatment effectiveness, the

relationship between drug treatment and mortality can reasonably be considered an exception (Black N,

1996) because of the very low death rates, demanding extremely large sample sizes, and long follow-

ups to be tested by RCTs. Most of evidence on the effectiveness of treatments for opiate addiction in

reducing mortality rates, comes from observational studies and is mainly concerning methadone

maintenance. Very few studies have compared the effectiveness of different treatment types in

preventing mortality from overdose, and only other pharmacological treatments have been considered

(Digiusto E, 2004; Ritter AJ, 2002).

Since evidence is lacking on reduction of mortality from randomised controlled trials a systematic

review of non-experimental studies can provide useful information about the effectiveness of

treatments when implemented in uncontrolled, or real-world, conditions.

Observational studies are susceptible to biases mainly arising from selection of study participants and

uncontrolled confounding factor. A careful evaluation of the study quality is needed to judge the

reliability of evidence provided by observational studies.

OBJECTIVES

To evaluate the effects of treatment for opioid dependence on overall and overdose mortality and on

non fatal overdose occurrence.

CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW

Types of studies

Literature was reviewed for all cohort and case-control studies evaluating the relationship between

treatments for opioid dependence and overall and overdose mortality.

Types of participants

Opioid dependents. Studies including a low proportion of dependents from other substances (<=20%)

were also included. Studies focused on pregnancy status were excluded from the review. No other

restriction were imposed in terms of inclusion or exclusion criteria.

Types of intervention

Any pharmacological intervention with or without psychosocial treatments compared with others

pharmacological interventions with or without psychosocial treatments or no-treatment for opioid

dependence.

Psychosocial treatments without pharmacological treatment were not considered in this review.

Types of outcome measures

1. Overall mortality assessed by record linkage with Local or National Mortality Registers,

Forensic Institutes, Coroners’ Offices

2. Overdose death identified by ICD IX or ICD X codes in Local or National Mortality Registers,

Forensic Institutes, Coroners’ Offices

3. Side effects as reported in the included studies (scores, symptoms..)

SERCH METHODS FOR IDENTIFICATION OF STUDIES

The following sources were used:

• Medline (1966 to May 2006)

• Embase (1988 to May 2006)

• CINAHL (1982 to May 2006)

MEDLINE 1966-May 2006 1 Exp opioid-related disorders/ 2 ((heroin adj2 (dependen$)).ti,ab 3 (drug or substance$) adj2 (abuse$ or addict$ or dependen$).ti,ab 4 1 or 2 or 3 5 exp narcotics/ 6 exp Heroin/ 7 heroin.ti,ab. 8 (opioid$ or opiate$).ti,ab. 9 exp methadone/ 10 Methadone.ti,ab 11 5 or 6 or 7 or 8 or 9 or 10 12 Death$.ti,ab 13 Exp mortality/ 14 Mortalit$.ti,ab 15 (overdos$ or over-dos$).ti,ab 16 12 or 13 or 14 or 15 17 Exp naltrexone or naltrexone.ti,ab 18 Exp methadyl acetate/ 19 Laam.ti,ab 20 Exp buprenorphine or buprenorphine.ti,ab 21 Exp Narcotic antagonist/ 22 17 or 18 or 19 or 20 or 21 23 4 and 11 and 16 and 22 24 Limit 23 to human EMBASE 1988-May 2006 1 Exp Addiction/ 2 Exp opiate addiction/ 3 (heroin adj2 (abuse$ or addict$ or dependen$).ti,ab 4 1 or 2 or 3 5 Narcotic$.ti,ab 6 Heroin.ti,ab 7 Exp Diamorphine/ 8 Exp opiate/ 9 (opioid$ or opiate$).ti,ab 10 Exp methadone/ or methadone.ti,ab 11 Exp methadone treatment/ 12 5 or 6 or 7 or 8 or 9 or 10 or 11 13 Exp buprenorphine/ or buprenorphine.ti,ab 14 Exp naltrexone or naltrexone.ti,ab 15 exp Levacetylmethadol/ or laam.ti,ab 16 Exp opiate antagonist/ 17 13 or 14 or 15 or 16

18 Death$.ti,ab 19 Exp mortality/ or mortalit$.ti,ab 20 (overdose$.ti,ab or over-dos$).ti,ab 21 Exp intoxication/ 22 18 or 19 or 20 or 21 23 4 and 12 and 17 and 22 24 Limit 23 to human Cinahl 1982 to May 2006 1 exp “Substance Use Disorders 2 ((heroin) adj2 (addict$ or dependen$ or abuse$ or misuse)).ti,ab. 3 (opioid adj2 dependen$ or addict$).ti,ab 4 1 or 2 or 3 5 Heroin.ti,ab 6 (opioid$ or opiate$).ti,ab 7 Narcotic$.ti,ab 8 5 or 6 or 7 9 Exp methadone/ or methadone.ti,ab 10 Exp Naltrexone/ or naltrexone.ti,ab 11 Exp narcotic antagonist/ 12 Buprenorphine.ti,ab 13 Laam.ti,ab 14 9 or 10 or 11 or 12 or 13 15 Death$.ti,ab 16 Exp Mortality/ or mortalit$.ti,ab 17 (overdos$ or over-dos$).ti,ab 18 15 or 16 or 17 19 4 and 8 and 14 and 18

We did not impose any language restriction. We checked the reference lists of all potentially eligible

studies obtained as full reports to identify any further studies not retrieved by the electronic search. We

also obtained full reports of review articles retrieved by the search and checked these for other relevant

citations. One unpublished study was included, related to a multisite national evaluation study

(Bargagli in press, Schifano 2006).

Assessment of the methodological quality

One author assessed (SM) the quality of the included studies:

The Newcastle-Ottawa Scale (NOS scale; NOS) for assessing quality of non-randomized studies in

meta-analysis was used (Wells 2005). Criteria for quality assessment and characteristics for each single

study are shown in table 1 and 2 and annex 1.

Data extraction

Two authors extracted data from the studies, using a data extraction form (Table 3, 4 and Annex 2)

Results

We identified a total number of 1039 studies of which 949 not considered because randomised

controlled trials or not related to the topic under study, 48 because cross-sectional or ecologic study

design, letters or reviews. Out of the remaining 42 studies, 17 were excluded for the following reasons:

- data on mortality were not reported;

- there was not a comparison group;

- opiate and other drug users were analyzed altogether;

- data on mortality were not separated for treatment group;

- the study population was already analysed in other studies

and 8 are waiting assessment (1 conference proceeding, 4 waiting full text, 2 in German language, 1

Norwegian language).

We also included a study that has been submitted for publication (Davoli 2006).

Overall, we included 18 studies.

Characteristics of included studies (Table 5)

Eighteen reporting data on 80,919 opioid addicts (102-23,529) have been included in our review.

Country

Four studies have been conducted in the USA, three in Australia, two in Sweden, two in Spain, two in

Italy, three in The Netherlands and two in England.

Study Design

All the included studies but one were cohort studies. One study was a case-control designed within a

cohort mortality study (Davoli 1993).

Outcome of interest

Fifteen studies analysed overdose mortality; most of them assessed vital status and causes of death by

record linkage with local or national population and mortality registries; in some studies other sources

of information on the cause of death were used as forensic and hospital records (Buster 2002, Esteban

2003, Fugelstad 1998, Langedam 2001, van Ameijden 1999, Zanis 1998). Three studies evaluated the

occurrence of non-fatal overdose before and after starting treatment through a pre-post study design

(Stewart 2002, Hulse 2005, Hutchinson 2000).

Types of participants

80,919 opioid addicts. Median of mean age was 29.3 years (range of mean 23- 45). Three studies did

not provide information on age of participants. Median of proportion of male was 76.5% (range 50%-

99%). Three studies did not provide information on gender of participants. Information on HIV status

was reported only by 7 studies: the proportion of infected patients ranged from 8% to 68% . Three of

the studies which did not reported this information ended the follow up by December 1976, before the

spread of HIV infection. Calendar periods of the study went from 1966 to 2002, with the great majority

of studies conducted after the 80’s.

Length of follow-up in cohort studies

The median length of follow up was 6.5 years (range 6 months - 21 years). The studies with a follow-

up period lasting 6 months assessed the occurrence of Severe Adverse Events (including overdose) and

non-fatal overdose, through both structured interviews and linkage with hospital and emergency

departments.

Types of treatment

Eleven studies compared mortality rate of opiod dependents in methadone maintenance outpatient

treatment (MMT) with that of opioid addicts voluntarly or involuntarly discharged from MMT or not

treated. One study (Fugelstad 1998) compared the mortality rate of people entering compulsory

inpatient treatment for 2-6 months with those discharged from treatment and those who never received

it. One study compared mortality rates of opioid addicts during MMT, therapeutic community, other

drug free treatment, withdrawal treatment and while out of treatment (Watterson 1975). One study

compared mortality rates of opioid addicts while in different treatment (MMT, TC, methadone

detoxification, other pharmacological, psychosocial treatment) and out of treatment (Davoli 2006).

Four studies considered as outcome non-fatal overdose. One study compared Severe Adverse Events

(SAE) during MMT, buprenorphine, LAAM, naltrexone treatment and while out of treatment (Digiusto

2004). One used a pre-post design with data prospectively collected to compare rates of non-fatal

overdose in patients before and after naltrexone implants (Hulse 2005). Another study compared rates

of non-fatal overdose of opioid addicts continuously and discontinuously attending MMT (Hutchinson

2000). The fourth study compared non-fatal overdose rates of clients treated in residential (inpatients

and rehabilitation units) or community (methadone maintenance and detoxification) setting (Stewart

2002).

Methodological quality:

13 studies were prospective cohort studies (Concool 1979, Brugal 2005, Watterson 1975, Fugelstad

1998, Davoli 2006, Digiusto 2004, Buster 2002, Langendam 2001, van Ameijden 1999, Caplehorn

1994, Hulse 2005, Stuart 2002, Zanis 1998), 4 were retrospective cohort studies (Gronbladh 1990,

Esteban 2003, Appel 2000, Hutchison 2000) and one study (Davoli 1993) was a case control study.

Cohort studies

14 out of 17 studies included truly representative exposed cohort of the average opioid dependent

people receiving any treatment in the community. One (Fugelstad 1998) included only severe

intravenous opioid addicts who met the Sweden criteria for compulsory treatment. All studies enrolled

the non exposed cohort from the same community as the exposed cohort.

All but two studies ascertained the exposure by secure records (clinical records), one by structured

interview (Brugal 2005) and one did not describe the method of ascertainment (Appel 2000).

Nine out of 17 studies adjusted the results for the most important potential confounding factors (age,

gender, HIV status, length of use); 8 studies did not. (Appel 2000, Caplehorn 1994, Digiusto 2004,

Gronbladh 1990, Hulse 2005, Hutchinson 2000, Stewart 2002, Watterson 1975, Zanis 1998).

Mortality rate was assessed by record linkage in all studies. Three studies had complete follow up for

all subjects (Esteban 2003, Fugelstad 1988, Grondbladh 2000). Two studies (Davoli 2006, Zanis 1998)

had lost at follow up ≤ 5%. Five studies had more than 5% lost to follow up without description of

losses (Langedam 2001 (6%), Brugal 2005 (7%), Concool 1979 (9%), Hutchinson 2000 (27-58%),

Stewart 2002 (30%)). The remaining 7 studies gave no information on lost at follow up.

Occurrence of non fatal overdose or other serious adverse events was assessed through record linkage

with emergency registry (Digiusto 2004, Hulse 2005,) and through self report in the remaining two

studies (Hutchinson 2000, Stewart 2002).

Case control study

The case definition is adequate, made by record linkage, cases are consecutive overdose death in a

cohort of opiate addicts, controls are defined as 4 patients for each case matched for sex and years of

birth not dead for overdose at the date of death of case; Odds Ratio are adjusted for the most important

factors (age, gender, duration of treatment, age at first drug use, marital status); exposure was

ascertained by secure record (clinical records), the same method of ascertainment of exposure was used

for cases and controls and the non response rate was the same for both groups.

Summary considerations on study quality

In general, the studies did not show major problems of selection bias, the majority use the same

population comparing time in treatment with time out of treatment, limiting also problems of

comparability. However, since many prognostic factors can change over time and can themselves lead

to drop out from treatment, adjustment for confounding factors is a relevant quality indicator. No study

analysing the occurrence of non fatal overdose provides adjusted measures, and 6 out of 14 analysing

mortality do. Ascertainment of outcome has not major biases in relation to the assessment of mortality

because mortality is often ascertained through record linkage. However, losses to follow-up might

represent a problem, which appears to be minor for mortality studies, being ascertained through record

linkage with mortality registry usually providing fairly complete follow-up; despite this, in most studies

the amount of losses to follow-up is not reported and the possible risk of bias is not predictable. .For

non fatal overdose, outcome was ascertained in two studies through record linkage with hospital or

emergency records, but in the other two studies through self reporting; high proportion of losses to

follow-up is reported in the two study providing the information. An additional problem might rise

from the classification of the cause of death when overdose death is used as outcome; this might be

heterogeneous across studies.

Comparative results

Results are reported separately for each included study and for the two outcomes: mortality or non fatal

overdose (Table 6 and 7).

Meta-analysis was conducted for those studies reporting raw data; only studies on mortality could be

considered for the purpose of meta-analysis (Table 8). Pooling of results was done only for any cause

of mortality. Overall, being in methadone treatment showed a strong significant protective effect (5

studies, 43035 participants): RR=0.37; 95%CI: 0.29-0.48, towards mortality for any cause as compared

to being out of treatment (either discharged or not in treatment). Pooling of results was not possible for

overdose mortality because of strong heterogeneity, however all studies but one reported significant

protective effect ranging from 0.36 (95% CI 0.13-0.97) to 0.02 (95%CI: 0.01-0.09). Data considered in

the metanalysis were not adjusted because of lack of proper data; however, in those studies reporting

adjusted measures, crude estimates did not differ substantially from the adjusted ones.

The other studies not included in the meta-analysis show a protective effect of treatment as well.

The studies analysing non fatal overdose occurrence use different comparisons, three show reduction of

overdose occurrence after the start of treatment and one shows increase of overdose occurrence out of

treatment as compared to patients in treatment. However, the study analysing the effect of NTX

implant shows significant increase in the occurrence of sedative overdose after the start of treatment.

One study, comparing non fatal overdose and other serious adverse events among patients out of

naltrexone and out of agonist treatment showed higher risk among out of naltrexone.

As far as duration of treatment is concerned there are no studies directly comparing different duration

of treatment. However, since most of comparisons are made between continuous versus non continuous

treatment, and between retained in treatment and drop out from treatment, the evidence clearly favours

retention in treatment as major protective factor, but no clear data are available to identify the optimal

duration of treatment. Treatment of different intensity are not compared between them, therefore no

further evidence from this review is available as far as effectiveness of ancillary psychological

treatment towards mortality. Different models of treatment as well are not compared in the studies.

Moreover, characteristics of treatment in terms of duration and doses are rarely described.

Some limitations of this review should be considered in interpreting the results. First, even though the

search strategy was designed in order to be as comprehensive as possible, we cannot exclude that some

study has been missed, in particular we still have some studies awaiting assessment which might

eventually be included in this review. However, all these latter studies do present results favouring the

effect of methadone treatment in the abstract. Despite this, publication bias might be a more serious

problem for observational studies, than for randomised studies, and the likelihood of being published

for a negative observational study might be definitely lower than for a positive one.

Second, the studies included in the review are very heterogeneous as far as calendar period and country

is considered, and, eventually, we cannot exclude problems related to ascertainment of death

(proportion of losses to follow-up not always reported) and classification of cause of death. However

this heterogeneity seems not to affect the direction of the effect but rather the intensity of the effect.

Conclusions

This systematic review provides additional evidence on the effectiveness of methadone maintenance

treatment in reducing overall and overdose mortality; results are derived from studies conducted in

different countries and contexts; the protective effect of treatment on mortality from any cause can

range from 2 to five time less mortality among patients in methadone maintenance treatment as

compared to patients out of treatment, while the magnitude of the protective effect of treatment on

overdose mortality can range from virtually no effect (in one study) to 3-50 time reduction in overdose

mortality in the remaining studies.

The evidence on reducing non fatal overdose is less striking, mainly due to the limited number of

studies and problems related to the methodological quality of the studies. In particular the effectiveness

of naltrexone appears to be controversial.

Unfortunately we did not find data on the effectiveness of different duration of treatment, different

intensity of treatment or different models of treatment.

The studies on mortality show consistently that the major risk factor is cessation of treatment, which is

associated with high risk of overdose death particularly in the first period after drop out. Eventually,

there is some sparse evidence of increasing risk of death in the first two weeks of methadone treatment.

Potential conflict of interest

None identified

Sources of support

The review has been funded by World Health Organisation (WHO ref ID:A2-37-16) with the aim of

informing the process of development on psychosocially-assisted pharmacotherapy of opioid

dependence.

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Chappel JN, Mays VM, Senay EC. Death and the treatment of drug addiction: a five year study of

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Dore GM, Walker JD, Paice JR, Clarkson S. Methadone maintenance treatment: outcomes from

the otago methadone programme. N Z Medical J 1999;112(1100):442-5

Elias H. [Substitute drug-assisted treatment of drug dependent patients in general practice].

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Segest E, Mygind O, Bay H. The allocation of drug addicts to different types of treatment. An

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Servais D, Erkens M. Methadone-related deaths in the area of aachen, germany (1994-1998).

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Stenbacka M, Leifman A, Romelsjo A. The impact of methadone on consumption of inpatient care

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Webster IW, Waddy N, Jenkins LV, Lai LY. Health status of a group of narcotic addicts in a

methadone treatment programme. M J Aust 1977;2(15):485-91

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Table 1. Quality assessment scheme for cohort studies (Newcastle-Ottawa Scale)

Study (author and year):

Selection Comparability Outcome

Representativeness of the

exposed cohort

Selection of the

non exposed

cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of

cohorts on the basis of

the design or analysis

Assessment

of outcome

Adequacy of

follow up of

cohorts

a) truly representative of the average opioid dependent people receiving any pharmacological treatment in the community �� b) somewhat representative of the average opioid dependent people receiving any pharmacological treatment in the community �� c) selected group of opioid dependent people eg subjects in prison, parolees d) no description of the derivation of the cohort

a) drawn from the same community as the exposed cohort �� b) drawn from a different source c) no description of the derivation of the non exposed cohort

a) secure record (eg clinical records) �� b) structured interview �� c) written self report d) no description

a) yes ��

b) no

a) Most important factors of adjustment�� (route, frequency and length of use, health status - hiv status, psychiatric comorbidity, previous episodes of overdose -, age, gender) b) any additional factor: (educational level, living status, history of imprisonment, previous treatment episodes)

a)Independent blind assessment �� b) record linkage �� c) self report (for side effects) d) no description

a) complete follow up - all subjects accounted for �� b) subjects lost to follow up unlikely to introduce bias (lost to follow-

up ≤ 5%)�� c) subjects lost to follow up > 5% and description provided of those lost d) no statement

Table 2.Quality assessment for case-control studies (Newcastle-Ottawa Scale)

Study (author and year)

Selection Comparability Exposure

Is the case

definition

adequate?

Representativeness

of the cases

Selection of

controls

Definition

of Controls

Comparability of cases and

controls on the basis of the

design or analysis

Ascertainment of

exposure

Same method of

ascertainment for

cases and controls

Non-Response

rate

a) yes, with independent validation �� b) yes, eg record linkage c) no description

a) consecutive or obviously representative series of cases ��

b) potential for selection biases or not stated

a) community controls �� b) hospital controls

c) no description

a) no dead from overdose�� b) no description of source

a) Most important factors of adjustment�� (route, frequency and length of use, health status - hiv status, psychiatric comorbidity, previous episodes of overdose -, age, gender) b) any additional factor: (educational level, living status, history of imprisonment, previous treatment episodes)��

a) secure record (eg clinical records) �� b) structured interview (peer, relatives, friends) where blind to case/control status �� c) interview (peer, relatives, friends) not blinded to case/control status e) no description

a) yes ��

b) no

a) same rate for both groups ��

b) non respondents described c) rate different and no designation

Table 3. Data extraction form for cohort studies

Study (first author and year)

Type of study (prospective/retrospective)

Study site(s) and setting

Enrolment and follow-up periods

Length of follow-up

Number of subjects

Number of total person-years and by treatment typology

Number of lost to follow-up

Interventions (type, length, dosages, frequency and duration of sessions

Control interventions (no treatment, type of treatment) (see above

Outcome: - definition - number of subjects experiencing the outcome

Confounding factors controlled for

Results Crude Rate (specify,i.e mortality,…)

Standardised rate

Crude RR

Adjust RR

Risk difference

Proportion (i.e. side effects) Other

Quality

Table 4. Data extraction form for case control studies

Study (first author and year)

Study site

Sources of cases and controls selection

Number of cases and controls

Non response rate

Sources of information on exposure


Control interventions (no treatment, type of treatment)


Crude OR

Adjusted OR


Quality

Table 5. Characteristics of included studies

Author Type of

study

Participants

and setting

Enrolment

period

Length of

follow-up

Person-years Interventions

Outcomes Quality

Appel 2000, USA

Cohort Retrospective

1544 outpatient

1966-1976

10 years Total 8476,3 py In MMT 6118,40 person-years; Not MMT: 2357,90 person-years

Intervention:MMT1

Control: Discharged form MMT

Deaths for any cause, Duration of MMT for (months):

Selection: ** comparability:* outcome:*

Brugal 2005, Spain

Cohort Prospective

5049 outpatient

1992-1999 7 years Total 23048 py In MMT 5399.5 person-years; Not MMT: 17648.6 person-years

Intervention: MMT


Deaths for any cause

Selection ***; comparability * outcome *

Buster 2002, Netherlands

Cohort Prospective

5200 outpatient

1986-1998 12 years Total: 29.729 Treatment: 18.747; After treatment: 10.983

Intervention: MMT

Control: Discontinuation from MMT

Fatal overdoses Selection ***; comparability * outcome *

Caplehorn 1994, Australia

Cohort Prospective

307 outpatient

1970-1991 21 years Total. 4253 person-years In MMT: 1975 person-years; Not MMT 2279 person-years

Intervention: MMT



Selection: ***; comparability 0 outcome *

Concool 1979, USA

Cohort Prospective

1156 outpatient

1969-1976 7 years Not reported Intervention: MMT



Selection *** comparability 0 outcome *

Davoli 1993 Italy

Case-control Cases: 81; control: 324

1980-1988 Intervention: MMT; Control: No MMT

Selection: ***; comparability** exposure ***

Author Type of

study

Participants

and setting

Enrolment

period

Length of

follow-up


Outcomes Quality

Davoli 2006, Italy

Cohort Prospective

10,258 outpatient

1998-2001 2.5 years Total: 13,538.2 In treatment: 10,208 Out of treatment: 2914 In MMT: 5751.3 In TC: 1188.9 In Methadone detox: 1495.7 Other pharmacological: 422.6 Psychosocial : 1349.2

Intervention: MMT, TC4, methadone detoxification, other pharmacological, psychosocial treatments Control: in any treatment, out of treatment

Overdose mortality

Selection *** comparability**outcome **

Di Giusto 2004, Australia

Cohort Prospective

1244; (MMT 403, BMT2 402, LAAM 115, NTX3 324) outpatient

Not reported > 6 months Total 394 person-years NTX in treatment: 44.4py, out of treatment: 62.2py; Agonist in treatment: 267py, out of treatment: 19.7py

Intervention: MMT; BMT; NTX; Control: Patients out of treatment

Serious adverse events

Selection *** comparability 0 outcome*

Esteban 2003, Spain


1487, outpatient

1990-1997 7 years Not reported Intervention: MMT; Control: Discharged form MMT


Selection *** comparability * outcome **

Fugelstad 1998, Sweden

Cohort Prospective

101 inpatients 2-6 months, then outpatients

1986-1993 8 years Total: 503.7 MMT: 177.3. Involuntary discharged: 57.3. No MMT: 272.8.

For all Compulsory residential treatment for 2-6 months, then Intervention: no MMT; voluntary MMT; Control: involuntary discharged due to disrespect to the rules of treatment.


Selection ** comparability* outcome **

Gronbladh 1990, Sweden


166, voluntary discharged 34, involuntary discharged: 53, untreated and waiting list: 115

1967-1988 treated, voluntary and involuntary discharged 1979-1988 untreated, waiting list

20 y treated, voluntary and involuntary discharged 5-8y untreated, waiting list

Not reported Intervention: MMT; Control: waiting list, untreated


Selection *** comparability 0 outcome **

Author Type of

study

Participants

and setting

Enrolment

period

Length of

follow-up


Outcomes Quality

Hulse 2005, Australia

Pre-post design, data prospectively collected

361 outpatient

2001-2002 For each patients: 6 months before and after treatment with a sustained release naltrexone implant Pre-treatment: mean 490 days (SD 183) Post-treatment: mean 603 days (SD 183)

Not reported Intervention: Naltrexone implant with rapid opioid detoxification (ROD); Control: Same patients before naltrexone implants

Non fatal overdoses

Selection *** comparability* outcome*

Hutchinson 2000, UK


204 outpatient

February-December 1996

6 - 12 months Not reported Intervention: MMT a) continuous, b) non continuous; Control: Before starting treatment and MMT a) continuous, b) non continuous;

Non fatal overdoses

Selection*** comparability 0 outcome 0

Langedam 2001, Netherlands

Cohort Prospective

827 outpatient

1985-1996 11 years Total 4961 person-years Intervention:MMT



Selection *** comparability ** outcome *

Stewart 2002, UK

Cohort Prospective

913, Inpatients and outpatients

March-July 1995

1 year Not reported Intervention: Residential treatments, Community treatments; Control: not in treatment and all the treatments above

Non fatal overdoses

Selection *** comparability * outcome 0

van Ameijden 1999, Netherlands

Cohort Prospective

498, outpatient 1989-1995 6 years 1968 person-years Methadone Maintenance Treatment (MMT): 155 person-years Not MMT: 466 person-years

Intervention: MMT; Control: Discharged form MMT


Selection *** comparability ** outcome *

Author Type of

study

Participants

and setting

Enrolment

period

Length of

follow-up


Outcomes Quality

Watterson 1975, USA

Cohort Prospective

1970-71: 9276 1071-72:17684 1972-73:23529

3 cohorts 1970-71 1971-72, 1972-73

1 year Total 1970-71: 3287person-years Total 1071-72: 7400 person-years Total 1972-73: 10121 person-years

Intervention: MMT, Therapeutic Community, Other drug free, Withdrawal only (WD); Control: No treatment


Selection *** comparability 0 outcome *

Zanis 1998, USA

Cohort Prospective

507, MMT: 397, Discharged from MMT: 110

1993-1994 1 year Not reported Intervention: MMT; Control: Discharged from MMT


Selection *** comparability 0 outcome **

1. MMT= Methadone Maintenance Treatment 2. BMT= Buprenorphine Maintenance Treatment 3. NTX= Naltrexone 4. TC= Therapeutic community

Table 6. Results of the included studies: mortality

Author Lost to

follow-up

N (%)

Subjects

experiencing the

outcome

(N)

Confounding

factors controlled

for

Crude Rate

(1000 p-y)

Crude OR

Standardised rate

(1000 p-y)

Crude RR/OR Adjusted

RR/OR

Appel 2000 Not reported

Death for any

cause: 176 In MMT1: 93 Discharged from MMT: 83 Opiate-related

death: 38 In MMT1: 2 Discharged from MMT: 36

Age, gender, ethnicity

Death for any cause

In MMT: 15.2 Discharged from MMT: 35.2 Opiate-related death

In MMT: 0.3 Discharged from MMT: 15.3

Age 18-24 In MMT: 8.3 Discharged from MMT: 10.8 Age 25-44 In MMT:15.7 Discharged from MMT:38.6 Age 45-64 In MMT: 18.9 Discharged from MMT: 58.4 Gender Male In MMT 15.0 Discharged from MMT: 33.0 Female In MMT: 15.0 Discharged from MMT: 45.0 Ethnicity Black In MMT: 19/10000 Discharged from MMT: 47.0 White In MMT: 12.0 Discharged from MMT: 26.0 Hispanic In MMT 15.0 Discharged from MMT: 25.0

Discharged vs in MMT Death for any

cause: 2.3

Opiate-related

death: 51

Not calculated

Brugal 2005

353 (7) Death for any cause: 1005 Death for: AIDS: 386 Overdose: 349 Other causes: 270

Gender, age, years of consumption, HIV status, drugs injection, calendar year

Overdose death

In MMT: 0.2 Out MMT: 1.9

Not calculated Overdose death

Out MMT vs in MMT: 9.4 (95% CI 5.1-17.1)

Overdose death

Out MMT vs in MMT: 7.1 (95% CI 3.8-13.4)

Author Lost to

follow-up

N (%)

Subjects

experiencing the

outcome

(N)

Confounding

factors controlled

for

Crude Rate

(1000 p-y)

Crude OR

Standardised rate

(1000 p-y)


RR/OR

Buster 2002 Not reported

Overdose death: 68 In MMT: 42 Discontinuation from MMT: 22

Sex, born in the Netherlands, time since first treatment, treatment modality, first two weeks after (re)entering treatment

MMT: 2.2 Discontinuation MMT: 2.4 First 2 weeks after (re)entering MMT: 6.0 (95% CI 1.4-5.) > week 10: 2.1 (95% CI 1.4-3.1)

Not calculated Very low baseline rate, heroin inhaling

First two weeks after (re)entering treatment vs not during the first 2 weeks: 2.82 (95% CI 1.39- 5.70) Very low rates in and out of treatment (no difference)

First two weeks after (re)entering treatment: 2.86 95% CI 1.42- 5.78)

Caplehorn 1994

Not reported

Death for any

cause. 47 In MMT:11 Out MMT: 36

None Death for any cause

In MMT: 5.6 Out MMT: 15.8

Not calculated Death for any

cause in MMT

vs out 0.35 (95% CI: 0.18-0.69)

Not calculated

Concool 1979

102 (8.8) Death for any

cause: 45 In MMT: 23 After discharge: 22

Age Death for any cause In MMT: 20 After discharge: 19

Death for any cause All patients: 39 In MMT: 10.2

Not calculated In MMT vs overall: 0.26

Davoli 1993 4 Overdose death 81

Calendar year of first treatment, duration of treatment, age at first drug use, marital status, time since last treatment, age, gender

MMT vs no MMT: 3.55 (95% CI 1.82- 6.90) 1-12 months out of treatment vs in treatment: 7.98 (95% CI 3.40-18.73) > 12 months out of treatment vs in treatment: 2.54 (95% CI 1.25-5.15)

- - 1-12 months out of treatment vs in treatment:: 10.35 (95% CI 3.32-32.2 > 12 months out of treatment vs in treatment: 2.91 (95% CI 1.00-8.49)

Author Lost to

follow-up

N (%)

Subjects

experiencing the

outcome

(N)

Confounding

factors controlled

for

Crude Rate

(1000 p-y)

Crude OR

Standardised rate

(1000 p-y)

Crude RR/OR Adjusted RR/OR

Davoli 2006 379 (3.7%)

Overdose death

Total 41; 31 out of treatment, 10 in treatment In MMT: 7; out MMT: 9 In TC: 0; out TC: 5 In methadone detox: 1; out methadone detox: 7 In other pharmacol: 1; out other pharmacol: 7 In psychosocial: 1; out psychosocial: 3

Type of treatment, age, gender, cocaine use, HIV status, psychiatric diagnoses, route of administration, age at first heroin use, previous overdose, imprisonment, educational level, living situation, employment status

In treatment: 0.98 Out treatment: 10.6 In MMT: 1.22 Out MMT: 9.0 Out TC: 21.6 In methadone detox: 0.67 Out methadone detox: 8.6 In other pharmacol: 2.4 Out other pharmacol: 11.4 In psychosocial: 0.7 Out psychosocial: 12.0

Not calculated In treatment vs out of treatment: 0.09 In MMT vs out of treatment: 0.11 In methadone detox vs out of treatment: 0.06 In other pharmacol vs out of treatment: 0.22 In psychosocial vs out of treatment: 0.07 Out of treatment vs in treatment: 10.9 Out of MMT vs in treatment: 9.2 Out of TC vs in treatment: 22.0 Out of methadone detox vs in treatment: 8.8 Out other pharmacol vs in treatment: 11.7 Out psychosocial vs in treatment: 12.2

In treatment vs out of treatment: 0.09 (95% CI 0.04-0.19) In MMT vs out of treatment: 0.10 (95% CI 0.04-0.24) In methadone detox vs out of treatment: 0.07 (95% CI 0.01-0.50) In other pharmacol vs out of treatment: 0.37 (95% CI 0.05-2.76) In psychosocial vs out of treatment: 0.07 (95% CI 0.01-0.55) Out of treatment vs in treatment: 11.1 (95% CI 5.29-23.3) Out of MMT vs in treatment: 8.2 (95% CI 3.27-20.9) Out of TC vs in treatment: 23.0 (95% CI 7.63-69.3) Out of methadone detox: 9.3 (95% CI 3.4-25.3) Out other pharmacol vs in treatment: 12.1 (95% CI 4.5-32.6) Out psychosocial vs in treatment: 22.3 (95% CI 5.8-84.6)

Author Lost to

follow-up

N (%)

Subjects

experiencing the

outcome

(N)

Confounding

factors controlled

for

Crude Rate

(1000 p-y)

Crude OR

Standardised rate

(1000 p-y)


RR/OR

Esteban 2003

None Death for any

cause: 160 In MMT: 113 Discharged form MMT: 47

Gender, HIV status In MMT: 113/966 Discharged from MMT: 47/521

Not calculated Not calculated Not receiving vs receiving MMT: 3.2 (1.5-7.1) Retained vs drop out: 0.5 (95% CI 0.2-1.1)

Fugelstad 1998

None Death for any

cause: 40 In MMT: 7 Involuntary discharged: 4 No MMT: 27 In MMT male HIV+: 6; HIV- 1 In MMT female HIV+:1; HIV-: 0 Involuntary discharged male HIV+: 3; HIV-: 0; female HIV+ 1; HIV-:0 No MMT male HIV+: 9; HIV-:8 female HIV+: 6, HIV- :6

Gender, HIV status Not reported Not calculated Not reported MMT vs no MMT Male HIV+: 0.8 (95% CI 0.2-2.3) female HIV+: 0.2 (95% CI 0.004-1.3) Discharged vs no MMT Male HIV+: 0.6 (95% CI 0.1-2.3); female HIV+: 1.2 (95% CI 0.3-9.7)

Gronbladh 1990

None Death for any

cause

In MMT: 16 Voluntary discharged: 6 Involuntary discharged: 26 Untreated and waiting list: 48

None In MMT: 0.14 per treatment year Survival of treated vs untreated higher (p<0.0001)

Not calculated Not calculated Not calculated

Author Lost to

follow-up

N (%)

Subjects

experiencing the

outcome

(N)

Confounding

factors controlled

for

Crude Rate

(1000 p-y)

Crude OR

Standardised rate

(1000 p-y)


RR/OR

Langedam 2001

53 (6) Death for any cause: 150 Death for natural

cause (AIDS, pneumonia, liver failure, cerebral/neural): 89 Overdose death: 39

Gender, age, calendar year, nationality, ethnicity, homelessness, HIV status, body mass index, years since first drug use, current use

Death for any cause: 30.2 Natural cause: 17.9 Overdose death : 6.3

Not calculated Not calculated Death for Natural cause: not current receiving vs receiving: methadone: 2.38 (95% CI 1.28-4.55) Overdose Injectors not current receiving vs receiving methadone: 4.55 (95%CI 1.89-10.0)

Watterson 1975

Not reported

Death for any

cause

1970-71: 50 1971-72: 91 1972-73: 134

Total 1970-71: 15 Total 1071-72: 12 Total 1972-73: 13 MMT: 15 TC4: 2 DF5: 18 NINT6: 13


Author Lost to

follow-up

N (%)

Subjects

experiencing the

outcome

(N)

Confounding

factors controlled

for

Crude Rate

(1000 p-y)

Crude OR

Standardised rate

(1000 p-y)


RR/OR

Van Ameijden 1999

Not reported

Death for any

cause: 44 (15 overdose, 7 suicide, 12 medical cause, 4 accident, 6 other) Overdose death in MMT: 8 not in MMT: 7

Age gender, prostitution, stable housing, duration of dependence, poli-drug use

All causes:: 22.4 Overdose: 7.6 Overdose not MMT: 1.5 Overdose in MMT: 0.53

Not calculated Overdose death: 0.35 vs in MMT vs not in MMT

All cause In MMT vs not MMT: 0.83 Overdose In MMT vs not in MMT 5-55 mg: 0.35 (95% CI: 0.11-1.08) 55-70 mg: 0.13 (95% CI: 0.02-1.13) >75 mg 0.11 (95% CI: 0.01-0.93)

Zanis 1998 5 (4.5) among discharged

Death for any

cause

In MMT: 4 Discharged: 9

None In MMT: 1.0% Discharged: 8.1%

Not calculated In MMT vs discharged: 0.12

Not calculated

1. MMT= Methadone Maintenance Treatment

2. NTX= Naltrexone

3. Agonist = methadone, LAAM, buprenorphine

4. Therapeutic community

5. Other drug-free

6. Non in treatment

Table 7. Results of the included studies: non fatal overdose or serious adverse events

Author Lost to

follow-up

N (%)

Subjects

experiencing the

outcome

(N)

Confounding

factors controlled

for

Crude Rate

(1000 p-y)

Crude OR

Standardised

rate

(1000 p-y)


Digiusto 2004

Not reported

Total Serious

Adverse effects

(SAEs): 96 Heroin overdose: 32 Fatal SAE: 5

None NTX2: Total SAE: 20/100 p-y

Overdose in: 6.8/ p-y Overdose out: 38.6/100 p-y

Other SAE in: 13.5/100 p-y Other SAE out: 11.3/100 p-y Agonist3: Total SAE: 14/100 p-y

Overdose in: 1.9/100 p-y Overdose out: 0 Other SAE in: 11.2/100 p-t Other SAE out: 20.3/100 p-y In any treatment: Total SAE: 14.4/100 p-y Out of any treatment: Total SAE: 42.7/100 p-y Fatal SAE: 1.3/100 p-y

Not calculated Overdose: out of NTX treatment vs in NTX: 5.7 (95% CI 1.7-29.6) out of agonist vs in agonist treatment 0.0 (95% CI 0.0-14.8) Other SAE out of NTX treatment vs in NTX: 0.8 (95% CI 0.2-3.0) Out of agonist vs in agonist treatment 1.8 (95% CI 0.5-5.1) Total SAE out of any treatment vs in of any treatment: 3.0 (95% CI 1.8-4.7) NTX vs agonist out of treatment: 7.6 (95% CI 1.2-312.6)

Not calculated

Author Lost to

follow-up

N (%)

Subjects

experiencing the

outcome

(N)

Confounding

factors

controlled for

Crude Rate

(1000 p-y)

Crude OR

Standardised

rate

(1000 p-y)


Hulse 2005 Not reported

Non fatal

overdose (20 people) in the 6 months pre-treatment: 21 Opioid overdose in the 6 months post-treatment: 0

Measures on the same subjects

Opioid overdose 5.5% in the 6 months pre NTX implant vs 0 post treatment Sedative overdose

1.9% pre treatment vs 4.4% post NTX implant (p=.004)


Hutchinson 2000

After treatment 6 months: 55 (27) 12 months: 82 (58.3) 6 and 12 months: 83 (41)

Non fatal

overdose

Continuous MMT group before starting treatment: 12 6-months after starting treatment: 0 12-months after starting treatment: 1 Non-continuous MMT group before starting treatment: 16 6-months after starting treatment: 11 12-months after starting treatment: 4

Adjustment for the lost to follow-up bias (assuming that individuals not followed-up made non improvement)

Non fatal overdose

Continuous MMT group before starting treatment 24% 12-months after starting treatment 2% Non-continuous MMT group before starting treatment 28% 6-months after starting treatment 19% 12-months after starting treatment 7%

Not calculated At 6 months after starting treatment vs before starting treatment= 0.55 At 12 months after starting treatment vs before starting treatment= 0.55 Continuous MMT group vs non-continuous at 12 months= 0.28

Not calculated

Author Lost to

follow-up

N (%)

Subjects

experiencing the

outcome

(N)

Confounding

factors

controlled for

Crude Rate

(1000 p-y)

Crude OR

Standardised

rate

(1000 p-y)


Stewart 2002

322 (30) Non fatal

overdose before starting treatment: 112 Non fatal overdose 1 years after starting treatment: 43

None Before starting treatment: 15% One year after treatment entry: 5.7% No difference in the rate of overdose for clients treated in residential or community setting

Not calculated After entering treatment vs before starting treatment: 0.38

Not calculated

1. MMT= Methadone Maintenance Treatment 2. NTX= Naltrexone 3. Agonist = methadone, LAAM, buprenorphine

4. Therapeutic community 5. Other drug-free

Table 8. Results of meta-analysis

Review: Observational studies on treatment for opioid dependence and mortality Outcome: Comparison:

any cause mortality

in methadone maintenance vs out of methadone maintenance

Study in MMT out MMT RR (random) Weight RR (random) or sub-category n/N n/N 95% CI % 95% CI

Davoli, Italy 1998-2001

27/5751 24/998 15.04 0.20 [0.11, 0.34]

Caplehorn, Australia 1970-1991 11/1975 36/2279 11.17 0.35 [0.18, 0.69]

Fugelstad, Sweden 1986-1993 7/177 33/330 8.60 0.40 [0.18, 0.88]

Appel, USA 1966-1976

93/6118 83/2358 28.72 0.43 [0.32, 0.58]

Brugal, Spain 1992-1999

119/5400 887/17649 36.46 0.44 [0.36, 0.53]

Total (95% CI) 19421 23614 100.00 0.37 [0.29, 0.48] Total events: 257 (in MMT), 1063 (out MMT) Test for heterogeneity: Chi² = 7.98, df = 4 (P = 0.09), I² = 49.9% Test for overall effect: Z = 7.44 (P < 0.00001)

0.001 0.01 0.1 1 10 100 1000

Favours treatment Favours control

Outcome:

Overdose mortality Comparison in methadone maintenance vs out of methadone maintenance

Study in MMT out MMT RR (random) Weight RR (random) or sub-category n/N n/N 95% CI % 95% CI

Davoli, Italy 1998-2001

7/5751 9/998 19.78 0.13 [0.05, 0.36]

Appel, USA1966-1976 2/6118 36/2358 17.62 0.02 [0.01, 0.09]

Brugal, Spain1992-1999

11/5400 338/17649 21.30 0.11 [0.06, 0.19]

Van Ameijdem, The Netherlands 1989-1995 8/1500 7/466 19.67 0.36 [0.13, 0.97]

Buster, The Netherlands. 1986-1998 42/18747 26/10983 21.63 0.95 [0.58, 1.54]

Total (95% CI)

Total events: 70 (in MMT), 416 (out MMT) Test for heterogeneity: Chi² = 53.93, df = 4 (P < 0.00001), I² = 92.6% Test for overall effect: Z = 2.66 (P = 0.008)

0.001 0.01 0.1 1 10 100 1000

Favours treatment Favours control

ANNEX I

METHODOLOGICAL

QUALITY OF INCLUDED STUDIES

Cohort study

Study (author and year): Appel 2000



exposed cohort

Selection of the non

exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome

Adequacy of

follow up of

cohorts

a) truly representative of the average opioid dependent people receiving any pharmacological treatment in the community �� b) somewhat representative of

the average opioid dependent

people receiving any

pharmacological treatment in

the community �� c) selected group of opioid dependent people eg subjects in prison, parolees d) no description of the derivation of the cohort

a) drawn from the

same community as

the exposed cohort ��

b) drawn from a different source c) no description of the derivation of the non exposed cohort

a) secure record (eg clinical records) �� b) structured interview �� c) written self report

d) no

description

a) yes ��

b) no

a) Most important factors

of adjustment��

(route, frequency and

length of use, health

status - hiv status,

psychiatric comorbidity,

previous episodes of

overdose -, age, gender)

b) any additional factor��: (educational level, living status, history of imprisonment, previous treatment episodes)

a)Independent blind assessment �� b) record

linkage �� c) self report (for side effects) d) no description

a) complete follow up - all subjects accounted for �� b) subjects lost to follow up unlikely to introduce bias (lost to follow-up

≤ 5%)�� c) subjects lost to follow up > 5% and description provided of those lost d) no statement

Selection: ��

Comparability: ��

Outcome: ��

Cohort study

Study (author and year) Brugal 2005



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome

Adequacy of

follow up of

cohorts

a) truly representative of the

average opioid dependent



the community ��

b) somewhat representative of the average opioid dependent people receiving any pharmacological treatment in the community �� c) selected group of opioid dependent people eg subjects in prison, parolees d) no description of the derivation of the cohort

a) drawn from the

same community as



a) secure record (eg clinical records) �� b) structured

interview ��

c) written self report d) no description

a) yes ��

b) no


of adjustment��




psychiatric comorbidity,

previous episodes of

overdose -, age, gender)

b) any additional factor: (educational level, living status, history of imprisonment, previous treatment episodes)��


linkage ��

c) self report (for side effects) d) no description


≤ 5%)��

c) subjects lost

to follow up >

5% and

description

provided of

those lost d) no statement

Selection: ��


Outcome: ��

Cohort study

Study (author and year): Buster 2002



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome

Adequacy of

follow up of

cohorts





the community �� b) somewhat representative of the average opioid dependent people receiving any pharmacological treatment in the community �� c) selected group of opioid dependent people eg subjects in prison, parolees d) no description of the derivation of the cohort

a) drawn from the

same community as



a) secure

record (eg

clinical

records) ��

b) structured interview �� c) written self report d) no description

a) yes ��

b) no


of adjustment��




psychiatric

comorbidity, previous

episodes of overdose -,

age, gender) b) any additional factor: (educational level, living status, history of imprisonment, previous treatment episodes��)


linkage ��




Selection: �� Comparability: ��

Outcome: ��

Cohort study

Study (author and year): Caplehorn 1994



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome

Adequacy of

follow up of

cohorts







a) drawn from the

same community as



a) secure

record (eg

clinical

records) ��


a) yes ��

b) no



linkage ��




Selection: ��

Comparability: - Outcome: ��

Cohort study

Study (author and year): Concool 1979



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome

Adequacy of

follow up of

cohorts







a) drawn from the

same community as


b) drawn from a

different source

c) no description of the derivation of the non exposed cohort

a) secure

record (eg

clinical

records) ��


a) yes ��

b) no



linkage ��



≤ 5%)��

c) subjects lost

to follow up >

5% and

description

provided of


Selection: �� Comparability: -

Outcome: ��

Case-control study

Study (author and year) Davoli 1993

Selection Comparability Exposure

Is the case

definition

adequate?

Representativeness

of the cases

Selection of

controls

Definition

of Controls

Comparability of cases and

controls on the basis of the

design or analysis

Ascertainment of

exposure

Same method of

ascertainment

for cases and

controls

Non-Response

rate

a) yes, with independent validation �� b) yes, eg

record linkage

c) no description

a) consecutive or

obviously

representative series

of cases �� b) potential for selection biases or not stated

a)

community

controls ��

b) hospital controls

c) no description

a) no dead

from

overdose��

b) no description of source

a) Most important factors of

adjustment��

(route, frequency and length

of use, health status - hiv

status, psychiatric


episodes of overdose -, age,

gender)

b) any additional factor��:

(educational level, living

status, history of

imprisonment, previous

treatment episodes)

a) secure record (eg

clinical records) ��

b) structured interview (peer, relatives, friends) where blind to case/control status �� c) interview (peer, relatives, friends) not blinded to case/control status e) no description

a) yes ��

b) no

a) same rate for

both groups ��

b) non respondents described c) rate different and no designation

Selection: ��


Exposure: ��

Cohort study

Study (author and year): Davoli 2006



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of cohorts

on the basis of the design

or analysis

Assessment

of outcome

Adequacy of

follow up of

cohorts






a) drawn from the

same community as



a) secure

record (eg

clinical

records) ��


a) yes ��

b) no


of adjustment��


length of use, health status

- hiv status, psychiatric



gender)

b) any additional factor:


status, history of


treatment episodes)��


linkage ��


a) complete follow up - all subjects accounted for �� b) subjects lost to

follow up

unlikely to

introduce bias

(lost to follow-up

≤ 5%)��

c) subjects lost to follow up > 5% and description provided of those lost d) no statement

Selection: ��

Comparability: �� Outcome: ��

Cohort study

Study (author and year): Di Giusto 2004



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome

Adequacy of

follow up of

cohorts






c) selected group of opioid dependent people eg subjects in prison, parolees d) no description of the derivation of the cohort

a) drawn from the

same community as



a) secure

record (eg

clinical

records) ��


a) yes ��

b) no

a) Most important factors of adjustment�� (route, frequency and length of use, health status - hiv status, psychiatric comorbidity, previous episodes of overdose -, age, gender) b) any additional factor: (educational level, living status, history of imprisonment, previous treatment episodes��


linkage ��




Selection: ��


Cohort study

Study (author and year): Esteban 2003



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome Adequacy of

follow up of

cohorts







a) drawn from the

same community as

the exposed cohort �� b) drawn from a different source c) no description of the derivation of the non exposed cohort

a) secure

record (eg

clinical

records) ��


a) yes ��

b) no


of adjustment��




psychiatric



age, gender) b) any additional factor: (educational level, living status, history of imprisonment, previous treatment episodes)��


linkage ��


a) complete

follow up - all

subjects

accounted for ��

b) subjects lost to follow up unlikely to introduce bias (lost to follow-up


Selection: ��


Outcome: ��

Cohort study

Study (author and year): Fugelstad 1998



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome

Adequacy of

follow up of

cohorts

a) truly representative of the average opioid dependent people receiving any pharmacological treatment in the community �� b) somewhat representative of the average opioid dependent people receiving any pharmacological treatment in the community ��

c) selected group of opioid

dependent people eg

subjects in prison, parolees d) no description of the derivation of the cohort

a) drawn from the

same community as



a) secure

record (eg

clinical

records) ��


a) yes ��

b) no


of adjustment��




psychiatric



age, gender) b) any additional factor: (educational level, living status, history of imprisonment, previous treatment episodes)


linkage ��


a) complete

follow up - all

subjects




Selection: ��


Outcome: ��

Cohort study

Study (author and year): Gronbladh 1990



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome

Adequacy of

follow up of

cohorts







a) drawn from the

same community as



a) secure

record (eg

clinical

records) ��


a) yes ��

b) no



linkage ��


a) complete

follow up - all

subjects




Selection: ��


Cohort study

Study (author and year) Hulse 2005



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome

Adequacy of

follow up of

cohorts





the community �� c) selected group of opioid dependent people eg subjects in prison, parolees d) no description of the derivation of the cohort

a) drawn from the

same community as



a) secure

record (eg

clinical

records) ��


a) yes ��

b) no


of adjustment��




psychiatric



age, gender) b) any additional factor:�� (educational level, living status, history of imprisonment, previous treatment episodes)


linkage ��




Selection: ��


Outcome: ��

Cohort study

Study (author and year): Hutchinson 2000



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome

Adequacy of

follow up of

cohorts







a) drawn from the

same community as




interview ��


a) yes ��

b) no

a) Most important factors of adjustment�� (route, frequency and length of use, health status - hiv status, psychiatric comorbidity, previous episodes of overdose -, age, gender) b) any additional factor��: (educational level, living status, history of imprisonment, previous treatment episodes)

a)Independent blind assessment �� b) record linkage ��

c) self report

(for side

effects) d) no description


≤ 5%)��

c) subjects lost

to follow up >

5% and

description

provided of


Selection: ��

Comparability: - Outcome: -

Cohort study

Study (author and year): Langedam 2001



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome

Adequacy of

follow up of

cohorts






a) drawn from the

same community as



a) secure

record (eg

clinical

records) ��


a) yes ��

b) no


of adjustment��




psychiatric



age, gender) b) any additional

factor��:


status, history of


treatment episodes)


linkage ��



≤ 5%)��

c) subjects lost

to follow up >

5% and

description

provided of


Selection: ��


Outcome: ��

Cohort study

Study (author and year): Stewart 2002



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome

Adequacy of

follow up of

cohorts






a) drawn from the

same community as




interview ��


a) yes ��

b) no


of adjustment��




psychiatric



age, gender)

b) any additional factor��: (educational level, living status, history of imprisonment, previous treatment episodes)

a)Independent blind assessment �� b) record linkage ��

c) self report

(for side

effects) d) no description


≤ 5%)��

c) subjects lost

to follow up >

5% and

description

provided of


Selection: ��


Outcome: -

Cohort study

Study (author and year): van Amejiden 1999



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of cohorts

on the basis of the design

or analysis

Assessment

of outcome

Adequacy of

follow up of

cohorts






a) drawn from the

same community as



a) secure

record (eg

clinical

records) ��


a) yes ��

b) no


of adjustment��


length of use, health status

- hiv status, psychiatric



gender)

b) any additional factor:


status, history of


treatment episodes)��


linkage ��




Selection: ��

Comparability: �� Outcome: ��

Cohort study

Study (author and year): Watterson 1975



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome

Adequacy of

follow up of

cohorts







a) drawn from the

same community as



a) secure

record (eg

clinical

records) �� b) structured interview �� c) written self report d) no description

a) yes ��

b) no

a) Most important factors of adjustment�� (route, frequency and length of use, health status - hiv status, psychiatric comorbidity, previous episodes of overdose -, age, gender) b) any additional factor��: (educational level, living status, history of imprisonment, previous treatment episodes)


linkage ��




Selection: ��


Cohort study

Study (author and year): Zanis 1998



exposed cohort


exposed cohort

Ascertainment

of exposure

Demonstration

that outcome

of interest was

not present at

start of study

(for side

effects)

Comparability of



Assessment

of outcome

Adequacy of

follow up of

cohorts






a) drawn from the

same community as



a) secure

record (eg

clinical

records) ��


a) yes ��

b) no

a) Most important factors of adjustment�� (route, frequency and length of use, health status - hiv status, psychiatric comorbidity, previous episodes of overdose -, age, gender) b) any additional factor:�� (educational level, living status, history of imprisonment, previous treatment episodes)


linkage ��


a) complete follow up - all subjects accounted for �� b) subjects lost to

follow up

unlikely to

introduce bias

(lost to follow-up

≤ 5%)��

c) subjects lost to follow up > 5% and description provided of those lost d) no statement

Selection: ��


ANNEX II

DATA EXTRACTION OF INCLUDED STUDIES

COHORT STUDY

Study (first author and year) Appel PW 2000


Retrospective


New York, USA. Outpatients


1966 - 1976

Length of follow-up 10 years

Number of subjects 1544

Number of total person -years and by treatment typology

Total 8476,3 py In MMT 6118,40 person-years Not MMT: 2357,90 person-years

Age, sex , HIV status Not reported

Number of lost to follow-up Not reported Interventions (type, length, dosages, frequency and duration of sessions

Methadone Maintenance Treatment (MMT)


Discharged form MMT


Death for any cause, AIDS excluded before the follow up ended in 1976 , before the diffusion of the HIV infection Total: 176 In MMT: 93 Discharged form MMT: 83 Duration of MMT for (months): died in MMT: 41±33 died after MMT: 24±23

Confounding factors controlled for Age, gender, ethnicity


MMT: 15.2 /1000 py Discharged form MMT: 35.2 /1000 py

Standardised rate

Stratified by: - age18-24 MMT: 8.3/1000py not MMT 10.8/1000 py 25-44 MMT :15.7/1000py not MMT 38.6 /1000 py 45-64 MMT: 18.9 /1000 py not MMT 58.4 /1000 py - sex: male MMT 15/1000 py not MMT 33/1000py female: MMT 15/1000 py not MMT 45/1000 py - ethnicity: black : MMT 19/10000py not MMT 47/1000py white : MMT 12/1000 py not MMT 26 /1000py Hispanic : MMT 15/1000 py not MMT 25 /1000py

Crude RR In MMT vs discharged from MMT: 0.43

Adjust RR Not calculated Risk difference Not calculated


Not considered

Quality Selection: ** (no description of ascertainment of exposure); comparability:*; outcome:* (no statement of adequacy of follow up)

COHORT STUDY

Study (first author and year) Brugal MT 2005


Prospective


Spain, Barcelona. Outpatients


1992 -1999


Number of subjects

5049

Age, gender, HIV status Mean: 29 years; 77% male; 51% HIV positive

- Number of total person-years and by treatment typology

Total 23048 py In MMT 5399.5 person-years Not MMT: 17648.6 person-years

Number of lost to follow-up 7% Interventions (type, length, dosages, frequency and duration of sessions



Discharged from MMT


Dead for any cause; AIDS, overdose, other. Total: 1005 (38.4% AIDS, 34.7 %overdose, 27% other) In MMT: 119 Not MMT: 887

Confounding factors controlled for Gender, age, years of consumption, HIV status, drugs injection, calendar year


Overdose: In MMT: 0.2/1000py Not MMT: 1.9/1000 py

Standardised rate

Not calculated

Crude RR

Overdose: Not in MMT vs in MMT: 9.4 (95% CI 5.1-17.1)

Adjust RR Overdose: Not MMT vs in MMT: 7.1 (95% CI 3.77-13.45)

Risk difference Not calculated


Not considered

Quality Selection ***; comparability: * outcome * (more than 5%lost at follow up

COHORT STUDY

Study (first author and year) Buster MCA 2002


Prospective


Netherlands – Amsterdam. Outpatients


January 1986 – December 1998


Number of subjects

5200

Age, gender, HIV status 71% of the cohort between 30 and 39 years; 77% male


Total: 29.729 Treatment: 18.747 After treatment: 10.983




Discontinuation from MMT


Fatal overdose Total: 68 During MMT: 42 Discontinuation from MMT: 22

Confounding factors controlled for Gender, born in the Netherlands, time since first treatment (1-6 years, 7-11 years, >11 years), treatment modality (low or high threshold); first two weeks after (re)entering treatment


Total: 2.3/1000 person-years In MMT: 2.2/1000 person-years Out of MMT: 2.4/1000 person-years First 2 weeks after (re)entering MMT: 6.0 (95% CI 1.4-5.) > week 10: 2.1 (95% CI 1.4-3.1)

Standardised rate

Not calculated

Crude RR

First 2 weeks after (re)entering treatment vs not during the first 2 weeks: 2.82 (CI95% 1.39- 5.70)

Adjust RR

First two weeks after (re)entering treatment: 2.82 (95% CI 1.39- 5.70

Risk difference

Not calculated


Not considered

Quality Selection ***; comparability *; outcome * (lost at follow up not reported)

COHORT STUDY

Study (first author and year) Caplehorn JRM 1994


Prospective


Australia, Sidney . Outpatients


1970 - 1991


Number of subjects

307

Age, gender, HIV status Mean 23.4 (SD 4.3); 72% male;


Total. 4253 person-years In MMT: 1975 person-years Not MMT 2279 person-years




Discharged from MMT


Dead for any cause Total. 47 In MMT:11

Confounding factors controlled for None


Overall: 1.11/1000 In MMT: 0.56 /1000 py Out MMT: 1.58/1000 py

Standardised rate

Not calculated

Crude RR

0.35 (95% CI: 0.18-0.69)

Adjust RR

Not calculated

Risk difference

In the initial study episode of MMT: 0.75/1000 not significant In the subsequent episodes of MMT: 0.25/1000 not significant


Not considered

Quality Selection: *** comparability:0; outcome * (not clear if there are lost to follow up)

COHORT STUDY

Study (first author and year) Concool B 1979


Prospective


USA. Outpatients


1969-1976


Number of subjects

1156


Not reported

Number of lost to follow-up 102

Age, gender, HIV status Not reported Interventions (type, length, dosages, frequency and duration of sessions



Discharged from MMT


Death for any cause, overdose, violent, accident, medical Total: 45 In MMT: 23 After discharge: 22

Confounding factors controlled for Age


Overall: 39/1000 person-years In MMT: 20/1000 person-years After discharge: 19/1000 person-years

Standardised rate

Age-adjusted mortality rate: 39/1000 person-year Age-adjusted mortality rate in MMT: 10.2/1000 person-years

Crude RR

Not calculated

Adjust RR

Age-adjusted (in MMT vs overall): 0.26

Risk difference

Not calculated


Not considered

Quality Selection ***, comparability 0, outcome * (more than 5% lost at follow up)

CASE CONTROL STUDY

Study (first author and year) Davoli M 1993

- Study site

Italy

Sources of cases and controls selection

Cohort of 4200 IVDU attending methadone treatment during 1980-1988

Number of cases and controls

Cases: overdose deaths: 81 Controls: 4 subjects for each case matched for year of birth and sex from the same cohort still alive at the date of death: 324

Age, gender, HIV status Not reported

- Non response rate

4%

- Sources of information on exposure

Clinical records

- Interventions (type, length, dosages, frequency and duration of sessions


- Control interventions (no treatment, type of treatment)

No MMT


Calendar year of first treatment, duration of treatment, age at first drug use, marital status, time since last treatment, age, gender

Crude OR

MMT vs no MMT: 3.55 (CI95% 1.82- 6.90) Last treatment 1-12 months vs <1 month: 7.98 (CI95% 3.40-18.73) Last treatment > 12 months vs <1 month: 2.54 (CI95% 1.25-5.15)

Adjusted OR Last treatment 1-12 months vs <1 month: 10.35 (CI95% 3.32-32.2 Last treatment > 12 months vs <1 month: 2.91 (CI95%1.00-8.49)


Not considered

Quality

Selection: ***; comparability**; exposure ***

COHORT STUDY

Study (first author and year) Davoli M 2006


Prospective


Italy. Outpatients


September 1998 – March 2001

Length of follow-up 2.5 years

Number of subjects

10,258

Age, sex , HIV status Mean: 31.5 years; 80% male; 8% HIV positive


Total: 13,538.2 In treatment: 10,208 Out of treatment: 2914 In MMT: 5751.3 In TC: 1188.9 In Methadone detox: 1495.7 Other pharmacological: 422.6 Psychosocial : 1349.2

Number of lost to follow-up 379 (3.7%) Interventions (type, length, dosages, frequency and duration of sessions

Methadone Maintenance (MMT)

Therapeutic community (TC)

Methadone detoxification

Other pharmacological detoxification and treatment (including

naltrexone, in-patient detoxification, detoxification with non-opiate

drugs, therapy with psychotropic drugs)

Psychosocial treatments (including psychotherapy, counselling, social

advice and job guidance) Control interventions (no treatment, type of treatment) (see above)

In any treatment Out of treatment


Death for any cause Total: 100; 63 out of treatment, 37 in treatment Overdose Total 41; 31 out of treatment, 10 in treatment In MMT: 7; out MMT: 9 In TC: 0; out TC: 5 In methadone detox: 1; out methadone detox: 7 In other pharmacol: 1; out other pharmacol: 7 In psychosocial: 1; out psychosocial: 3


Type of treatment, age, gender, cocaine use, HIV status, psychiatric

diagnoses, route of administration, age at first heroin use, previous

overdose, imprisonment, educational level, living situation,

employment status

COHORT STUDY Davoli M 2006 Results Crude Rate (specify,i.e mortality,…)

Overdose In treatment: 0.98/1000 person-years Out treatment: 10.6/1000 person-years In MMT: 1.22/1000 person-years Out MMT: 9.0/1000 person-years In TC: 0 Out TC: 21.6/1000 person-years In methadone detox: 0.67/1000 person-years Out methadone detox: 8.6/1000 person-years In other pharmacol: 2.4/1000 person-years Out other pharmacol: 11.4/1000 person-years In psychosocial: 0.7/1000 person-years Out psychosocial: 12.0/1000 person-years

Standardised rate

Not calculated

Crude RR

Overdose In treatment vs out of treatment: 0.09 In MMT vs out of treatment: 0.11 In methadone detox vs out of treatment: 0.06 In other pharmacol vs out of treatment: 0.22 In psychosocial vs out of treatment: 0.07 Out of treatment vs in treatment: 10.9 Out of MMT vs in treatment: 9.2 Out of TC vs in treatment: 22.0 Out of methadone detox vs in treatment: 8.8 Out other pharmacol vs in treatment: 11.7 Out psychosocial vs in treatment: 12.2

Adjusted RR

Overdose In treatment vs out of treatment: 0.09 (95% CI 0.04-0.19) In MMT vs out of treatment: 0.10 (95% CI 0.04-0.24) In methadone detox vs out of treatment: 0.07 (95% CI 0.01-0.50) In other pharmacol vs out of treatment: 0.37 (95% CI 0.05-2.76) In psychosocial vs out of treatment: 0.07 (95% CI 0.01-0.55) Out of treatment vs in treatment: 11.1 (95% CI 5.29-23.3) Out of MMT vs in treatment: 8.2 (95% CI 3.27-20.9) Out of TC vs in treatment: 23.0 (95% CI 7.63-69.3) Out of methadone detox: 9.3 (95% CI 3.4-25.3) Out other pharmacol vs in treatment: 12.1 (95% CI 4.5-32.6) Out psychosocial vs in treatment: 22.3 (95% CI 5.8-84.6)

Risk difference

Not calculated


Not considered

Quality Selection ***; comparability **; outcome **

COHORT STUDY

Study (first author and year) Di Giusto E 2004


Prospective


Australia, outpatients


Not reported

Length of follow-up Up to 6 months Number of subjects

1244 (MMT 403, buprenorphine 402, levo-alpha acetyl methadol (LAAM) 115, naltrexone 324)

Age, sex, HIV status, ethnicity (range of mean or %)

Mean age: 30.4 Male: 65%


Total 394 person-years Naltrexone in treatment: 44.4py, out of treatment: 62.2py Agonist in treatment: 267py, out of treatment: 19.7py

Number of lost to follow-up Not reported


Maintenance treatment: methadone, buprenporphine, LAAM, naltrexone


Patients out of treatment


Serious adverse events: any untoward medical occurrence that results in death or persistent or significant disability/incapacity; is life-threatening; requires inpatients hospitalization; or is a congenital anomaly/birth defect: heroin overdose, accident, general illness, adverse drug reaction, psychiatric events, pregnancy related events, admission for inpatients detoxification

Total SAEs: 96 (32 overdose, 15 general illness, 17 admission for in-patient detox, 12 accident, 8 adverse drug reaction, 8 psychiatric events, 4 pregnancy related events) Fatal SAE: 5 (all occurred out of any treatment)

Confounding factors controlled for None


Unit of analysis is the event and not the patient Total SAE naltrexone: 20/100 p-y Total SAE agonist: 14/100 p-y Overdose during naltrexone: 6.8/100 p-y; out of naltrexone: 38.6/100 p-y Overdose during agonist: 1.9/100 p-y; out of agonist 0.0/100 p-y Other SAE during naltrexone: 13.5/100 p-y; out of naltrexone:11.3/100 p-y Other SAE during agonist: 11.2/100 p-y; out of treatment: 20.3/100 p-y Total SAE during any treatment: 14.4/100 p-y; out of any treatment: 42.7/100 p-y Fatal SAE: 1.3/100 p-y

Standardised rate

Not calculated

Crude RR

Overdose in naltrexone vs out of treatment: 5.7 (95% CI 1.7-29.6) Overdose in agonist vs out of treatment: 0.0 (95% IC 0.0-14.8) Other SAE naltrexone in vs out of treatment: 0.8 (95% IC 0.2-3.0) Other SAE in agonist vs out of treatment: 1.8 (95% IC 0.5-5.1) Total SAE in any treatment vs out of any treatment: 3.0 (95% IC 1.8-4.7)

Adjust RR Not calculated

Risk difference Not calculated


Quality Selection : *** (no demonstration that outcome of interest was not present at the start of the study). Comparability 0; outcome:* (no mention of lost to follow up)

COHORT STUDY

Study (first author and year) Esteban J 2003


Retrospective


Spain, Alicante. Outpatients


1990-1997


Number of subjects

1487


Not reported

Age, gender, HIV status Mean age: 30 years (SD 5): 79% male; HIV prevalence: from 68% in 1992 to 50% in 1997

Number of lost to follow-up None




Discharged form MMT


Death for any cause Total: 160 MMT: 113 Discharged form MMT: 47


gender, HIV status,


MMT : 113/966 Discharged from MMT : 47/521

Standardised rate

Nor calculated

Crude RR

Not calculated

Adjust RR

Retained vs drop out: HR: 0.5 (CI95% 0.2-1.1)

Risk difference

Not calculated


Not considered

Quality Selection ***; comparability *; outcome **

COHORT STUDY

Study (first author and year) Fugelstad A 1998


Prospective


Sweden- inpatients 2-6 months, then outpatients


1986-1993


Number of subjects

101 severe intravenous heroin users who met the criteria for compulsory treatment

Age, sex , HIV status Mean age: 29.2y, male 50%, HIV infected 56%


Total: 503.7 MMT: 177.3, male HIV+: 64.1, HIV-: 13.6. female HIV+: 55.7, HIV-: 43.9 Involuntary discharged: 57.3. , male HIV+: 42, HIV-: 5.9. female HIV+: 7.6, HIV-: 1.7 No MMT: 272.8. , male HIV+: 75, HIV-: 60.2. female HIV+: 53.5, HIV-: 82.1

Number of lost to follow-up None Interventions (type, length, dosages, frequency and duration of sessions

Compulsory residential treatment for 2-6 months followed by voluntary MMT Compulsory residential treatment for 2-6 months followed by involuntary discharged due to disrespect to the rules of treatment


Compulsory residential treatment for 2-6 months followed by no MMT


Death for any cause Total 40 MMT :7, involuntary discharged. 4, no MMT: 27 MMT male HIV+: 6, HIV- 1. MMT female HIV+:1 HIV-: 0 Involuntary discharged male HIV+: 3, HIV-:0; female HIV+ 1, HIV-:0 No MMT male HIV+: 9, HIV-:8; female HIV*: 6, HIV- :6

Confounding factors controlled for Sex, HIV status: subgroup analysis Results Crude Rate (specify,i.e mortality,…)

Not reported

Standardised rate

Nor calculated

Crude RR

Not reported

Adjusted RR

MMT vs no MMT Male HIV+: 0.8 (CI95% 0.2-2.3) female HIV+: 0.2 (CI95% 0.004-1.3) Discharged vs no MMT Male HIV+: 0.6 (CI95% 0.1-2.3); female HIV+: 1.2 (CI95% 0.3-9.7)

Risk difference

Nor calculated


Not considered

Quality Selection: ** (severe injection heroin users with compulsory treatment). Comparability:*, outcome: **

COHORT STUDY

Study (first author and year) Gronbladh 1990


Retrospective


Sweden


1967-1988 treated, voluntary and involuntary discharged 1979-1988 untreated, waiting list

Length of follow-up 20 y treated, voluntary and involuntary discharged 5-8y untreated, waiting list

Number of subjects

Treated: 166, voluntary discharged 34, involuntary discharged: 53, untreated and waiting list: 115

Age, sex, HIV status Treated: men 78%, mean age at entering: 27.5. voluntary discharged: men 76%, mean age 34; involuntary discharged: men: 79%, mean age 29.2; untreated and waiting list: men 61%, mean age. 26.3


Not calculated

Number of lost to follow-up 0




Waiting list, untreated


Death for any cause MMT: 16 Voluntary discharged: 6 Involuntary discharged: 26 Untreated and waiting list: 48


None


MMT: 1.4% per treatment year

Standardised rate

Not calculated

Crude RR

Not calculated

Adjust RR

Not calculated

Risk difference

Not calculated


Not considered

Quality Selection: ***; comparability 0; outcome **

COHORT STUDY

Study (first author and year) Hulse GK 2005


Pre-post design, data prospectively collected


Western Australia, outpatients


Enrolment period: January 2001 - December 2002 Follow-up period: July 2000 – 19 August 2003 (covering the period 6 months prior to and 6 months following treatment)

Length of follow-up For each patients: 6 months before and after treatment with a sustained release naltrexone implant Pre-treatment: mean 490 days (SD 183) Post-treatment: mean 603 days (SD 183)

Number of subjects

361

Age, gender, HIV status Males mean age: 28.5 (SD 7.2), females 26.6 (SD 7.9); 60% male;


Not reported



Naltrexone implant with rapid opioid detoxification (ROD)


The same patients before naltrexone implants


Non fatal overdose (identified and grouped using ICD-10 and ICD-9-CM codes) 21 opioid overdose (20 people) in the 6 months pre-treatment no opioid overdose in the 6 months post-treatment


Measures on the same subjects


Pre-treatment overdose: 5%

Standardised rate Not calculated

Crude RR Not calculated



Not considered

Quality Selection: ***, comparability*, outcome:* (no statement of adequacy of follow up)

COHORT STUDY

Study (first author and year) Hutchinson SJ 2000


Retrospective


Glasgow. Outpatients (General Practitioners- centred programme)


February-December 1996

Length of follow-up 6 and 12 months

Number of subjects

Total number of subjects N=204; Interviewed at 6 months N= 148 (72.5%) Interviewed at 12 months N= 119 (58.3%) Interviewed at both 6 and 12 months N= 118 (57.8%)

Number of total person -years and by treatment typology

Not reported

Age, gender, HIV status Mean age: 28.4 (SE 0.3); 74% male

Number of lost to follow-up At 6 months N= 55 (27.0%) At 12 months N= 82 (58.3%) At both follow-up periods: N= 83 (41%)


Methadone Maintenance Treatment (MMT) For the continuous group: dose= 43mg at recruitment and 65mg at 12 months

Control interventions (no treatment, type of treatment) (see above)

Before starting treatment Continuous MMT group N= 50/118 Non continuous MMT group N= 57/118


Non fatal overdose Continuous MMT group: before starting treatment N= 12 6-months after starting treatment N= 0 12-months after starting treatment N= 1 Non-continuous MMT group: before starting treatment N= 16 6-months after starting treatment N= 11 12-months after starting treatment N= 4


Adjustment for the lost to follow-up bias (assuming that individuals not followed-up made non improvement)


Continuous MMT group: before starting treatment 24% 12-months after starting treatment 2% Non-continuous MMT group: before starting treatment 28% 6-months after starting treatment 19% 12-months after starting treatment 7%

Standardised rate Not calculated

Crude RR

At 6 months after starting treatment vs before starting treatment= 0.55 At 12 months after starting treatment vs before starting treatment= 0.55 Continuous MMT group vs non-continuous at 12 months= 0.28



Not considered

Quality Selection***: ; comparability: 0; outcome: 0 ( subjects lost to follow up > 5% and description provided of those lost)

COHORT STUDY

Study (first author and year) Langedam MW 2001


Prospective


Amsterdam. Outpatients


1985-1996


Number of subjects

827

Age, gender, HIV status Mean age: 31.0 (SD 6.3, range= 16-57); 60% male; HIV positive: 27%


Total 4961 person-years

Number of lost to follow-up 53 (6%)




Discharged form MMT


Death for any cause, natural cause, overdose Any cause: 150 Natural cause: 89 Overdose: 39


Gender, age, calendar year, nationality, ethnicity, homelessness, HIV status, body mass index, years since first drug use, current use


Total: 30.2/1000 person-years Natural cause: 17.9/1000 person-years Overdose : 6.3/1000 person-years

Standardised rate

Not calculated

Crude RR

Not calculated

Adjust RR

Natural cause: not current receiving methadone: RR 2.38 (95% CI 1.28-4.55) Overdose Injectors not current receiving methadone: RR= 4.55 (95%CI 1.89-10.0) Injectors in methadone treatment but not currently receiving methadone: RR= 2.93 (95% CI 11.4-7.56) Injectors not in methadone treatment: RR= 5.66 (95% CI 1.97-16.28)

Risk difference

Not calculated


Not considered

Quality Selection ***; comparability **; outcome * (6%lost at follow up)

COHORT STUDY

Study (first author and year) Stewart D 2002


Prospective


England. In-patients and out-patients


Enrolment period: March – July 1995

Length of follow-up 1 year

Number of subjects

1075; 85% heroin users 122 from inpatients drug units 286 from rehabilitation units 458 from methadone maintenance clinics 209 from methadone reduction programs

Age, gender, HIV status Mean 29.4 (SD 6.5); 73.6% male


Not reported

Number of lost to follow-up N= 322 (30%)


Residential treatments (inpatients drug units and rehabilitation units) Community treatments (methadone maintenance and methadone reduction programs)


Not in treatment and all interventions (see above)


Non fatal overdose (measured as a single event) before and after starting treatment Non fatal overdose before starting treatment: 112 client Non fatal overdose 1 years after treatment entry: 43 clients


None


Before starting treatment: 15% One year after treatment entry: 5.7% No difference in the rate of overdose for clients treated in residential or community setting

Standardised rate

Not calculated

Crude RR

0.38 ( after entering treatment vs before starting treatment)

Adjust RR

Not calculated

Risk difference

Not calculated


Not considered

Quality Selection ***; comparability *; outcome 0 (subjects lost to follow up > 5%; description provided of those lost)

COHORT STUDY

Study (first author and year) van Ameijden EJC 1999


Prospective


Amsterdam. Outpatients


1989 – 1995


Number of subjects

498; excluded patients with AIDS

Age, sex , HIV status Mean: 32.8 years; 67% male; 29% HIV positive


1968 person-years Methadone Maintenance Treatment (MMT): 155 person-years Not MMT: 466 person-years


MMT


Discharged from MMT


Death for any cause Total: 44 (15 overdose, 7 suicide, 12 medical cause, 4 accident, 6 other) Overdose in MMT: 8 Overdose not MMT: 7


Age gender, prostitution, stable housing, duration of dependence, poli-drug use


All causes:: 22.4/1000 person-years Overdose: 7.6/1000 person-years Overdose not MMT: 1.5/1000 person-years Overdose in MMT: 0.53/1000 person-years

Standardised rate

Not calculated

Crude RR

Overdose death: 0.35 in MMT vs not MMT (CI not reported)

Adjusted RR

All cause in MMT vs not MMT: 0.83 (CI not reported) Overdose in MMT vs not in MMT: 5-55 mg 0.35 (95% CI: 0.11-1.08) 55-70 mg 0.13 (95% CI: 0.02-1.13) >75 mg 0.11 (95% CI: 0.01-0.93)

Risk difference

Not calculated


Not considered

Quality Selection *** comparability **; outcome * (lost at follow up not reported)

COHORT STUDY

Study (first author and year) Watterson O 1975


Prospective


USA


3 cohorts 1970-71 , 1071-72, 1972-73

Length of follow-up 1years

Number of subjects

1970-71: 9276 1971-72: 17684 1972-73: 23529 (not specified if they are in part the same subjects in the three cohort or not)


Total 1970-71: 3287person-years Total 1071-72: 7400 person-years Total 1972-73: 10121 person-years MMT: 14467 person-years TC:1937 person-years DF:2178 person-years WD: 208 person-years Other: 1182 person-years NINT:832 person-years

Age, gender, HIV status Age, proportion of patients aged between 21 and 30: 1970-71: 52% 1971-72: 55% 1972-73: 58% Gender: 1970-71: 81% 1971-72: 79% 1972-73: 77%



Methadone Maintenance Treatment (MMT), Therapeutic Community (TC), Other drug free (DF), Withdrawal only (WD)


No treatment (NINT)


Death for any cause 1970-71: 50 1971-72: 91 1972-73: 134


None


Total 1970-71: 15/1000 person-years Total 1071-72: 12/1000 person-years Total 1972-73: 13/1000 person-years MMT:15/1000 person-years TC: 2/1000 person-years DF: 18/1000 person-years WD: sample too small to calculate death rate Other: 1/1000 person-years NINT: 13/1000 person-years

Standardised rate

Not calculated

Crude RR

Not calculated

Adjusted RR Not calculated Risk difference

Not calculated


Not considered

Quality Selection ***, comparability 0, outcome * (lost at follow up not reported)

COHORT STUDY

Study (first author and year) Zanis DA 1998


Prospective


USA. Philadelphia Veteran Affair Medical Centre. Outpatients


7/1993 – 6/1994

Length of follow-up 1 year

Number of subjects

Total 507 In MMT: 397 Discharged from MMT: 110

Age, gender, HIV status Mean age: Discharged people: 40 years In MMT: 45 years 99% male


Not reported

Number of lost to follow-up 5 among discharged people




People discharged from MMT. Discharged because completed treatment: 12% Because transferred to other treatment : 18% Because failed contract: 52% Because dropped out: 18%


Death for any cause 4 among in MMT 9 among discharged


None


In MMT: 1.0% Discharged: 8.1%

Standardised rate

Not calculated

Crude RR

0.12

Adjust RR

Not calculated

Risk difference

Not calculated


Not considered

Quality Selection ***; comparability 0; outcome **

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