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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
Anna Maria Bargagli, Marina Davoli, Silvia Minozzi, Simona Vecchi, and Carlo A Perucci
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
Anna Maria Bargagli, Marina Davoli, Silvia Minozzi, Simona Vecchi, and Carlo A Perucci
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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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
Interventions (type, length, dosages, frequency and duration of sessions
Control interventions (no treatment, type of treatment)
Confounding factors controlled for
Crude OR
Adjusted OR
Proportion (i.e. side effects) Other
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
Control: Discharged form 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
Control: Discharged form MMT
Deaths for any cause
Selection: ***; comparability 0 outcome *
Concool 1979, USA
Cohort Prospective
1156 outpatient
1969-1976 7 years Not reported Intervention: MMT
Control: Discharged form MMT
Deaths for any cause
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
Person-years Interventions
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
Cohort Retrospective
1487, outpatient
1990-1997 7 years Not reported Intervention: MMT; Control: Discharged form MMT
Deaths for any cause
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.
Deaths for any cause
Selection ** comparability* outcome **
Gronbladh 1990, Sweden
Cohort Retrospective
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
Deaths for any cause
Selection *** comparability 0 outcome **
Author Type of
study
Participants
and setting
Enrolment
period
Length of
follow-up
Person-years Interventions
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
Cohort Retrospective
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
Control: Discharged form MMT
Deaths for any cause
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
Deaths for any cause
Selection *** comparability ** outcome *
Author Type of
study
Participants
and setting
Enrolment
period
Length of
follow-up
Person-years Interventions
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
Deaths for any cause
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
Deaths for any cause
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)
Crude RR/OR Adjusted
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)
Crude RR/OR Adjusted
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)
Crude RR/OR Adjusted
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
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)
Crude RR/OR Adjusted
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)
Crude RR/OR Adjusted RR/OR
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)
Crude RR/OR Adjusted RR/OR
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)
Not calculated Not calculated Not calculated
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)
Crude RR/OR Adjusted RR/OR
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
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
Selection: ��������
Comparability: ����
Outcome: ����
Cohort study
Study (author and year) Brugal 2005
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
Selection: ������������
Comparability: ����
Outcome: ����
Cohort study
Study (author and year): Buster 2002
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
Selection: ������������ Comparability: ����
Outcome: ����
Cohort study
Study (author and year): Caplehorn 1994
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
Selection: ������������
Comparability: - Outcome: ����
Cohort study
Study (author and year): Concool 1979
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
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
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
Selection: ������������
Comparability: ��������
Exposure: ������������
Cohort study
Study (author and year): Davoli 2006
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
Selection: ������������
Comparability: �������� Outcome: ��������
Cohort study
Study (author and year): Di Giusto 2004
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
Selection: ������������
Comparability: - Outcome: ����
Cohort study
Study (author and year): Esteban 2003
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
Selection: ������������
Comparability: ����
Outcome: ��������
Cohort study
Study (author and year): Fugelstad 1998
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
Selection: ��������
Comparability: ����
Outcome: ��������
Cohort study
Study (author and year): Gronbladh 1990
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
Selection: ������������
Comparability: - Outcome: ��������
Cohort study
Study (author and year) Hulse 2005
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
Selection: ������������
Comparability: ����
Outcome: ����
Cohort study
Study (author and year): Hutchinson 2000
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
Selection: ������������
Comparability: - Outcome: -
Cohort study
Study (author and year): Langedam 2001
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
Selection: ������������
Comparability: ��������
Outcome: ����
Cohort study
Study (author and year): Stewart 2002
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
Selection: ������������
Comparability: ����
Outcome: -
Cohort study
Study (author and year): van Amejiden 1999
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
Selection: ������������
Comparability: �������� Outcome: ����
Cohort study
Study (author and year): Watterson 1975
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
Selection: ������������
Comparability: - Outcome: ����
Cohort study
Study (author and year): Zanis 1998
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
Selection: ������������
Comparability: - Outcome: ��������
ANNEX II
DATA EXTRACTION OF INCLUDED STUDIES
COHORT STUDY
Study (first author and year) Appel PW 2000
Type of study (prospective/retrospective)
Retrospective
Study site(s) and setting
New York, USA. Outpatients
Enrolment and follow-up periods
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)
Control interventions (no treatment, type of treatment) (see above
Discharged form MMT
Outcome: - definition - number of subjects experiencing the outcome
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
Results Crude Rate (specify,i.e mortality,…)
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
Proportion (i.e. side effects) Other
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
Type of study (prospective/retrospective)
Prospective
Study site(s) and setting
Spain, Barcelona. Outpatients
Enrolment and follow-up periods
1992 -1999
Length of follow-up 7 years
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
Methadone Maintenance Treatment (MMT)
Control interventions (no treatment, type of treatment) (see above
Discharged from MMT
Outcome: - definition - number of subjects experiencing the outcome
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
Results Crude Rate (specify,i.e mortality,…)
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
Proportion (i.e. side effects) Other
Not considered
Quality Selection ***; comparability: * outcome * (more than 5%lost at follow up
COHORT STUDY
Study (first author and year) Buster MCA 2002
Type of study (prospective/retrospective)
Prospective
Study site(s) and setting
Netherlands – Amsterdam. Outpatients
Enrolment and follow-up periods
January 1986 – December 1998
Length of follow-up 12 years
Number of subjects
5200
Age, gender, HIV status 71% of the cohort between 30 and 39 years; 77% male
- Number of total person-years and by treatment typology
Total: 29.729 Treatment: 18.747 After treatment: 10.983
Number of lost to follow-up Not reported Interventions (type, length, dosages, frequency and duration of sessions
Methadone Maintenance Treatment (MMT)
Control interventions (no treatment, type of treatment) (see above
Discontinuation from MMT
Outcome: - definition - number of subjects experiencing the outcome
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
Results Crude Rate (specify,i.e mortality,…)
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
Proportion (i.e. side effects) Other
Not considered
Quality Selection ***; comparability *; outcome * (lost at follow up not reported)
COHORT STUDY
Study (first author and year) Caplehorn JRM 1994
Type of study (prospective/retrospective)
Prospective
Study site(s) and setting
Australia, Sidney . Outpatients
Enrolment and follow-up periods
1970 - 1991
Length of follow-up 21 years
Number of subjects
307
Age, gender, HIV status Mean 23.4 (SD 4.3); 72% male;
- Number of total person-years and by treatment typology
Total. 4253 person-years In MMT: 1975 person-years Not MMT 2279 person-years
Number of lost to follow-up Not reported Interventions (type, length, dosages, frequency and duration of sessions
Methadone Maintenance Treatment (MMT)
Control interventions (no treatment, type of treatment) (see above
Discharged from MMT
Outcome: - definition - number of subjects experiencing the outcome
Dead for any cause Total. 47 In MMT:11
Confounding factors controlled for None
Results Crude Rate (specify,i.e mortality,…)
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
Proportion (i.e. side effects) Other
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
Type of study (prospective/retrospective)
Prospective
Study site(s) and setting
USA. Outpatients
Enrolment and follow-up periods
1969-1976
Length of follow-up 7 years
Number of subjects
1156
- Number of total person-years and by treatment typology
Not reported
Number of lost to follow-up 102
Age, gender, HIV status Not reported Interventions (type, length, dosages, frequency and duration of sessions
Methadone Maintenance Treatment (MMT)
Control interventions (no treatment, type of treatment) (see above
Discharged from MMT
Outcome: - definition - number of subjects experiencing the outcome
Death for any cause, overdose, violent, accident, medical Total: 45 In MMT: 23 After discharge: 22
Confounding factors controlled for Age
Results Crude Rate (specify,i.e mortality,…)
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
Proportion (i.e. side effects) Other
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
Methadone Maintenance Treatment (MMT)
- Control interventions (no treatment, type of treatment)
No MMT
Confounding factors controlled for
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)
Proportion (i.e. side effects) Other
Not considered
Quality
Selection: ***; comparability**; exposure ***
COHORT STUDY
Study (first author and year) Davoli M 2006
Type of study (prospective/retrospective)
Prospective
Study site(s) and setting
Italy. Outpatients
Enrolment and follow-up periods
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
- Number of total person-years and by treatment typology
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
Outcome: - definition - number of subjects experiencing the outcome
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
Confounding factors controlled for
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
Proportion (i.e. side effects) Other
Not considered
Quality Selection ***; comparability **; outcome **
COHORT STUDY
Study (first author and year) Di Giusto E 2004
Type of study (prospective/retrospective)
Prospective
Study site(s) and setting
Australia, outpatients
Enrolment and follow-up periods
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%
- Number of total person-years and by treatment typology
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
Interventions (type, length, dosages, frequency and duration of sessions
Maintenance treatment: methadone, buprenporphine, LAAM, naltrexone
Control interventions (no treatment, type of treatment) (see above
Patients out of treatment
Outcome: - definition - number of subjects experiencing the outcome
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
Results Crude Rate (specify,i.e mortality,…)
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
Proportion (i.e. side effects) Other
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
Type of study (prospective/retrospective)
Retrospective
Study site(s) and setting
Spain, Alicante. Outpatients
Enrolment and follow-up periods
1990-1997
Length of follow-up 7 years
Number of subjects
1487
- Number of total person-years and by treatment typology
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
Interventions (type, length, dosages, frequency and duration of sessions
Methadone Maintenance Treatment (MMT)
Control interventions (no treatment, type of treatment) (see above
Discharged form MMT
Outcome: - definition - number of subjects experiencing the outcome
Death for any cause Total: 160 MMT: 113 Discharged form MMT: 47
Confounding factors controlled for
gender, HIV status,
Results Crude Rate (specify,i.e mortality,…)
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
Proportion (i.e. side effects) Other
Not considered
Quality Selection ***; comparability *; outcome **
COHORT STUDY
Study (first author and year) Fugelstad A 1998
Type of study (prospective/retrospective)
Prospective
Study site(s) and setting
Sweden- inpatients 2-6 months, then outpatients
Enrolment and follow-up periods
1986-1993
Length of follow-up 8 years
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%
- Number of total person-years and by treatment typology
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
Control interventions (no treatment, type of treatment) (see above
Compulsory residential treatment for 2-6 months followed by no MMT
Outcome: - definition - number of subjects experiencing the outcome
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
Proportion (i.e. side effects) Other
Not considered
Quality Selection: ** (severe injection heroin users with compulsory treatment). Comparability:*, outcome: **
COHORT STUDY
Study (first author and year) Gronbladh 1990
Type of study (prospective/retrospective)
Retrospective
Study site(s) and setting
Sweden
Enrolment and follow-up periods
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
- Number of total person-years and by treatment typology
Not calculated
Number of lost to follow-up 0
Interventions (type, length, dosages, frequency and duration of sessions
Methadone Maintenance Treatment (MMT)
Control interventions (no treatment, type of treatment) (see above
Waiting list, untreated
Outcome: - definition - number of subjects experiencing the outcome
Death for any cause MMT: 16 Voluntary discharged: 6 Involuntary discharged: 26 Untreated and waiting list: 48
Confounding factors controlled for
None
Results Crude Rate (specify,i.e mortality,…)
MMT: 1.4% per treatment year
Standardised rate
Not calculated
Crude RR
Not calculated
Adjust RR
Not calculated
Risk difference
Not calculated
Proportion (i.e. side effects) Other
Not considered
Quality Selection: ***; comparability 0; outcome **
COHORT STUDY
Study (first author and year) Hulse GK 2005
Type of study (prospective/retrospective)
Pre-post design, data prospectively collected
Study site(s) and setting
Western Australia, outpatients
Enrolment and follow-up periods
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;
- Number of total person-years and by treatment typology
Not reported
Number of lost to follow-up Not reported
Interventions (type, length, dosages, frequency and duration of sessions
Naltrexone implant with rapid opioid detoxification (ROD)
Control interventions (no treatment, type of treatment) (see above
The same patients before naltrexone implants
Outcome: - definition - number of subjects experiencing the outcome
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
Confounding factors controlled for
Measures on the same subjects
Results Crude Rate (specify,i.e mortality,…)
Pre-treatment overdose: 5%
Standardised rate Not calculated
Crude RR Not calculated
Adjust RR Not calculated Risk difference Not calculated
Proportion (i.e. side effects) Other
Not considered
Quality Selection: ***, comparability*, outcome:* (no statement of adequacy of follow up)
COHORT STUDY
Study (first author and year) Hutchinson SJ 2000
Type of study (prospective/retrospective)
Retrospective
Study site(s) and setting
Glasgow. Outpatients (General Practitioners- centred programme)
Enrolment and follow-up periods
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%)
Interventions (type, length, dosages, frequency and duration of sessions
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
Outcome: - definition - number of subjects experiencing the outcome
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
Confounding factors controlled for
Adjustment for the lost to follow-up bias (assuming that individuals not followed-up made non improvement)
Results Crude Rate (specify,i.e mortality,…)
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
Adjust RR Not calculated Risk difference Not calculated
Proportion (i.e. side effects) Other
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
Type of study (prospective/retrospective)
Prospective
Study site(s) and setting
Amsterdam. Outpatients
Enrolment and follow-up periods
1985-1996
Length of follow-up 11 years
Number of subjects
827
Age, gender, HIV status Mean age: 31.0 (SD 6.3, range= 16-57); 60% male; HIV positive: 27%
- Number of total person-years and by treatment typology
Total 4961 person-years
Number of lost to follow-up 53 (6%)
Interventions (type, length, dosages, frequency and duration of sessions
Methadone Maintenance Treatment (MMT)
Control interventions (no treatment, type of treatment) (see above
Discharged form MMT
Outcome: - definition - number of subjects experiencing the outcome
Death for any cause, natural cause, overdose Any cause: 150 Natural cause: 89 Overdose: 39
Confounding factors controlled for
Gender, age, calendar year, nationality, ethnicity, homelessness, HIV status, body mass index, years since first drug use, current use
Results Crude Rate (specify,i.e mortality,…)
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
Proportion (i.e. side effects) Other
Not considered
Quality Selection ***; comparability **; outcome * (6%lost at follow up)
COHORT STUDY
Study (first author and year) Stewart D 2002
Type of study (prospective/retrospective)
Prospective
Study site(s) and setting
England. In-patients and out-patients
Enrolment and follow-up periods
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
- Number of total person-years and by treatment typology
Not reported
Number of lost to follow-up N= 322 (30%)
Interventions (type, length, dosages, frequency and duration of sessions
Residential treatments (inpatients drug units and rehabilitation units) Community treatments (methadone maintenance and methadone reduction programs)
Control interventions (no treatment, type of treatment) (see above
Not in treatment and all interventions (see above)
Outcome: - definition - number of subjects experiencing the outcome
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
Confounding factors controlled for
None
Results Crude Rate (specify,i.e mortality,…)
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
Proportion (i.e. side effects) Other
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
Type of study (prospective/retrospective)
Prospective
Study site(s) and setting
Amsterdam. Outpatients
Enrolment and follow-up periods
1989 – 1995
Length of follow-up 6 years
Number of subjects
498; excluded patients with AIDS
Age, sex , HIV status Mean: 32.8 years; 67% male; 29% HIV positive
- Number of total person-years and by treatment typology
1968 person-years Methadone Maintenance Treatment (MMT): 155 person-years Not MMT: 466 person-years
Number of lost to follow-up Not reported Interventions (type, length, dosages, frequency and duration of sessions
MMT
Control interventions (no treatment, type of treatment) (see above
Discharged from MMT
Outcome: - definition - number of subjects experiencing the outcome
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
Confounding factors controlled for
Age gender, prostitution, stable housing, duration of dependence, poli-drug use
Results Crude Rate (specify,i.e mortality,…)
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
Proportion (i.e. side effects) Other
Not considered
Quality Selection *** comparability **; outcome * (lost at follow up not reported)
COHORT STUDY
Study (first author and year) Watterson O 1975
Type of study (prospective/retrospective)
Prospective
Study site(s) and setting
USA
Enrolment and follow-up periods
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)
- Number of total person-years and by treatment typology
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%
Number of lost to follow-up Not reported
Interventions (type, length, dosages, frequency and duration of sessions
Methadone Maintenance Treatment (MMT), Therapeutic Community (TC), Other drug free (DF), Withdrawal only (WD)
Control interventions (no treatment, type of treatment) (see above
No treatment (NINT)
Outcome: - definition - number of subjects experiencing the outcome
Death for any cause 1970-71: 50 1971-72: 91 1972-73: 134
Confounding factors controlled for
None
Results Crude Rate (specify,i.e mortality,…)
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
Proportion (i.e. side effects) Other
Not considered
Quality Selection ***, comparability 0, outcome * (lost at follow up not reported)
COHORT STUDY
Study (first author and year) Zanis DA 1998
Type of study (prospective/retrospective)
Prospective
Study site(s) and setting
USA. Philadelphia Veteran Affair Medical Centre. Outpatients
Enrolment and follow-up periods
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
- Number of total person-years and by treatment typology
Not reported
Number of lost to follow-up 5 among discharged people
Interventions (type, length, dosages, frequency and duration of sessions
Methadone Maintenance Treatment (MMT)
Control interventions (no treatment, type of treatment) (see above
People discharged from MMT. Discharged because completed treatment: 12% Because transferred to other treatment : 18% Because failed contract: 52% Because dropped out: 18%
Outcome: - definition - number of subjects experiencing the outcome
Death for any cause 4 among in MMT 9 among discharged
Confounding factors controlled for
None
Results Crude Rate (specify,i.e mortality,…)
In MMT: 1.0% Discharged: 8.1%
Standardised rate
Not calculated
Crude RR
0.12
Adjust RR
Not calculated
Risk difference
Not calculated
Proportion (i.e. side effects) Other
Not considered
Quality Selection ***; comparability 0; outcome **