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 "G UIDELINES 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.

References of excluded studies Albanese AP, Gevirtz C, Oppenheim B, Field JM, Abels I, Eustace JC. Outcome and six month follow up of patients after ultra rapid opiate detoxification (urod). J Addict Dis 2000; 19(2):11-28 Bartu A , Freeman NC, Gawthorne GS, Codde JP, Holman CDA. Mortality in a cohort of opiate and amphetamine users in Perth, Western Australia. Addiction 2004; 99: 53-60 Basu D, Mattoo SK, Malhotra A, Gupta N, Malhotra R. A longitudinal study of male buprenorphine addicts attendine an addiction clinic in India. Addiction 2000; 95:1363-72 Caplehorn JR , Dalton MS, Haldar F, Petrenas AM, Nisbet JG. Methadone maintenance and addicts' risk of fatal heroin overdose. Subst Use Misuse 1996; 31(2):177-96 Cushman, P. Jr . Ten years of methadone maintenance treatment: some clinical observations. Am J Drug Alcohol Abuse 1977; 4(4):543-53 Fugelstad A , Rajs J, Bottiger M, Gerhardsson de Verdier M. Mortality among hiv-infected intravenous drug addicts in Stockholm in relation to methadone treatment. Addiction 1995; 90(5):711-6 Joe GW, Lehman W, Simpson DD. Addict death rates during a four-year posttreatment follow-up. Am J Public Health 1982;72(7):703-9 Lavignasse P, Lowenstein W Batel P, Constant MV, Jourdan JJ, Kopp P, Reynaud-Maurupt C, Riff B, Videau B, Mucchielli A. Economic and social effects of high dose buprenorphine substitution therapy. Ann Med Interne 2002;153:1s20-1s26 Maxwell S, Shinderman MS. Optimizing long term response to methadone maintenance treatment: a 152 week follow up using higher dose methadone. J Addict Dis 2002; 21: 1-12 Miotto K, McCann MJ, Rawson RA, Frosch D, Ling W. Overdose, suicide attemps and death among a cohort of naltrexone treated opioid addicts. Drug Alcohol Depend 1997; 45:131-4 Paxton R, Mullin P, Beattie J. The effects of methadone maintenance with opioid takers. A review and some findings from one british city. British Journal of Psychiatry 1978; 132:473-81 Rehm J, Frick U, Hartwig C, Gutzwiller F, Gschwend P, Uchtenhagen A. Mortality in heroin assisted treatment in Switzerland 1994-2000. Drug Alcohol Depend 2005; 79: 137-143 Schwartz RP , Brooner RK, Montoya ID, Currens M, Hayes M. A 12-year follow-up of a methadone medical maintenance program. Am J Addict 1999; 8(4):293-9 Segest E, Mygind O, Bay H. The influence of prolonged stable methadone maintenance treatment on mortality and employment: an 8 year follow up. The international journal of addiction 1990; 25:53-63 Uchtenhagen A , Gutzwiller F, Dobler-Mikola A, Steffen T. Programme for a medical prescription of narcotics. A synthesis of results. Eur Addict Res 1997;3(4):160-63 van Beek, I. Kimber, J, Dakin, A, Gilmour, S. The sydney medically supervised injecting centre: reducing harm associated with heroin overdose. Crit Public Health 2004;14(4):391-406 Wiepert GD, Bewlwy TH, d’Orban PT. Outcomes for 575 british opiate addicts entering treatment between a968 and 1975. Bulletin of narcotics 1978;30: 21-32

References of included studies Appel PW, Joseph H, Richman B. Causes and rates of death among methadone maintenance patients before and after the onset of the HIV/AIDS epidemic. The Mount Sinaj Journal of medicine 2000; 67: 444-451 Brugal MT, Domingo Salvany A, Puig R, Barrio G, Garcia de Ofalla P, de la Fuente L. Evaluating the impct of metadone maintenance programmes on mortalità due to overdose and AIDS in a cohort of heroin users in Spain. Addiction 2005; 100:981-89 Buster MCA, van Brussel GHA, van den Brink W. An increase in overdose mortality during the first 2 weeks after entering or re-entering methadone treatment in Amsterdam. Addiction 2002,97: 993-1001 Caplehorn JRM, Dalton MSYN, Cluff MC, Petrenas AM. Retention in methadone maintenance and heroin addicts’ risk of death. Addiction 1994; 89: 203-207 Concool B, Smith H, Stimmel B. Mortality rates of persons entering methadone maintenance; a seven year study. Am J Drug Alcohol Abuse 1979;6(3):345-53 Davoli M, Perucci CA, Forastiere F, Doyle P, Rapiti E, Zaccarelli M, Abeni DD. Risk factors for overdose mortality: a case-control study within a cohort of intravenous drug users. International journal of Epidemiology 1993; 22:273-77 Davoli M , Bargagli AM, Perucci CA, Schifano P, Belleudi V, Hickman M, Salamina M, Decidue R, Vigna-Taglianti F, Faggiano F. Drug treatment reduces overdose risk, but detoxification and short term therapies cause more deaths than they prevent: the VEdeTTE Study, a national multisite prospective cohort study. 2006. (Submitted) Di Giusto E, Shakeshaft A, Ritter A, O’Brien S, Mattick RP and the Nepod research group. Serious adverse events in the Australian National Evaluation of pharmacotherapies for opioid dependence. Addiction 2004, 99: 450-460 Esteban J, Gimeno C, Barril J, Aragones A, Climent JM, de la Cruz Pellin M. Survival study of opioid addicts in relation to its adherence to methadone maintenance treatment. Drug Alcohol Depend 2003;70:193-200 Fugelstad A, Agren G, Romelsjo A. Changes in mortality, arrests, and hospitalizations in nonvoluntarily treated heroin addicts in relation to methadone treatment. Subst Use Misuse 1998; 33:2803-2817 Gronbladh L, Ohlund LS, Gunne LM. Mortality in heroin addiction: impact of methadone treatment. Acta Psychiatr Scand 1990; 82:223-227 Hulse GK, Tait RJ, Comer SD, Sullivan MA, Jacobs IG, Arnold-Reed D. Reducing hospital presentations for opioid overdose in patients treated with sustained release naltrexone implants. Drug Alcohol Depend 2005;79: 351-57 Hutchinson SJ , Taylor A, Gruer L, Barr C, Mills C, Elliott L, Goldberg DJ, Scott R, Gilchrist G. One-year follow-up of opiate injectors treated with oral methadone in a gp-centred programme. Addiction 2000;95(7):1055-1068 Langendam MW, van Brussel GHA, Coutinho RA, van Ameijden EJC. The impact of harm recuction based methadone treatment on mortality among heroin users. Am J Public health 2001;91:774-80 Stewart D , Gossop M, Marsden J. Reductions in non-fatal overdose after drug misuse treatment: results from the national treatment outcome research study (ntors). J Substance Abuse Treat 2002;22(1):1-9 Van Ameijden EJC, Langedam MW, Coutinho RA. Dose effect relationship between overdose mortality and prescribed methadone dosage in low threshold maintenance programs. Addict Behav 1999; 24: 559-63 Watterson O, Simpson DD, Sells SB, Death rates and causes of death among opioid addicts in community drug treatment programs during 1970-1973. Am J Drug Alcohol Abuse 1975;2:99.111 Zanis DA, Woody GE. One year mortality rates following methadone treatment discharge. Drug Alcohol Depend 1998; 52:257-260

References of studies awaiting assessment Blix O, Bruvik S, Waal H. [The oslo methadone project]. [Norwegian]. Tidsskrift for Den Norske Laegeforening 1999;119(2):242-6 Chappel JN, Mays VM, Senay EC. Death and the treatment of drug addiction: a five year study of deaths occurring to members of the illinois drug abuse program. Proceedings - National Conference on Methadone Treatment 1973;1:530-7 Dore G M, Walker JD, Paice JR, Clarkson S. Methadone maintenance treatment: outcomes from the otago methadone programme. N Z Medical J 1999;112(1100):442-5 Elias H. [Substitute drug-assisted treatment of drug dependent patients in general practice]. [German]. Fortschritte Der Medizin. 1990;108(13):256-8 Segest E, Mygind O, Bay H. The allocation of drug addicts to different types of treatment. An evaluation and a two-year follow-up. Am J Drug Alcohol Abuse 1989;15(1):41-53 Servais D, Erkens M. Methadone-related deaths in the area of aachen, germany (1994-1998). Rechtsmedizin 2000;(2):65-70 Stenbacka M, Leifman A, Romelsjo A. The impact of methadone on consumption of inpatient care and mortality, with special reference to hiv status. Subst Use Misuse 1998;33(14):2819-34 Webster I W, Waddy N, Jenkins LV, Lai LY. Health status of a group of narcotic addicts in a methadone treatment programme. M J Aust 1977;2(15):485-91

Other References Bargagli AM , Sperati A, Davoli M, Forastiere F, Perucci CA. Mortality among problem drug users in Rome. An 18-year follow-up study 1980-97. Addiction 2001; 96:1455-63 Bargagli AM , Faggiano F, Amato L, Salamina G, Davoli M, Mathis F, Cuomo L, Schifano P, Burroni P, Perucci CA. VEdeTTE, a longitudinal study on effectiveness of treatments for heroin addiction in Italy: study protocol and characteristic of study population. Subs Use Misuse, 2005 in press Black N . Why we need observational studies to evaluate effectiveness of health care. BMJ 1996; 312:1215-18 Darke S, Hall W. Heroin overdose: research and evidence-based intervention. J Urban Health 2003; 80: 189-200 Digiusto E , Shakeshaft, Ritter A, O’Brien S, Mattick RP and the NEPOD Research Group. Serious adverse events in the Australian National Evaluation of pharmacotherapies for Opioid Dependence (NEPOD). Addiction 2004; 99:450-60 Frischer M , Goldberg D, Rahaman M, Berney L. Mortality and survival among a cohort of drug injectors in Glasgow, 1982-1994. Addiction 1997; 92:419-27 Hulse GK , English DR, Milne E, Holman CD. The quantification of mortality resulting from the regular use of illicit opiates. Addiction 1999; 94: 221-29 Ritter AJ . Naltrexone in the treatment of heroin dependence: relationship with depression and risk of overdose. Aust N Z J Psychiatry 2002; 36:224 Schifano P , Bargagli AM, Belleudi V, Amato L, Davoli M, Decidue R, Versino E, Vigna-Taglianti F, Faggiano F, Perucci CA for the VEdeTTE Study Group. Methadone treatment in clinical practice in Italy: need for improvement. Eur Addict Res 2006; 12: 121-27 Sporer KA . Acute heroin overdose. Annals of Internal Medicine 1999; 130:584-590 Wells GA , Shea B, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. [Newcastle-Ottawa Scale]. http://www.lri.ca/programs/ceu/oxford.htm

Table 1. Quality assessment scheme for cohort studies (Newcastle-Ottawa Scale) Study (author and year):

Selection Comparability Outcome Representativeness of the Selection of the Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort non exposed of exposure that outcome cohorts on the basis of of outcome follow up of cohort of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure record a) yes


a) Most important a)Independent a) complete average opioid dependent same community as (eg clinical factors of adjustment


blind follow up - all people receiving any the exposed cohort records)


b) no (route, frequency and assessment


subjects pharmacological treatment in


length of use, health accounted for the community


b) structured status - hiv status, b) record


b) drawn from a interview


psychiatric linkage


b) somewhat representative different source comorbidity, previous b) subjects lost of the average opioid c) written self episodes of overdose -, c) self report to follow up dependent people receiving c) no description of report age, gender) (for side unlikely to any pharmacological the derivation of effects) introduce bias treatment in the community the non exposed d) no b) any additional factor: (lost to follow-


cohort description (educational level, d) no up ≤ 5%)


living status, history of description c) selected group of opioid imprisonment, previous c) subjects lost dependent people eg subjects treatment episodes) to follow up > in prison, parolees 5% and description d) no description of the provided of derivation of the cohort 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 Representativeness Selection of Definition Comparability of cases and Ascertainment of Same method of Non-Response definition of the cases controls of Controls controls on the basis of the exposure ascertainment for rate adequate? design or analysis cases and controls

a) yes, with a) consecutive or a) a) no dead a) Most important factors of a) secure record (eg a) yes


a) same rate for independent obviously community from adjustment


clinical records)


both groups


validation


representative series controls


overdose


(route, frequency and length of cases


of use, health status - hiv b) structured interview b) no b) non b) yes, eg b) hospital b) no status, psychiatric (peer, relatives, friends) respondents record linkage b) potential for controls description comorbidity, previous where blind to described selection biases or of source episodes of overdose -, age, case/control status


c) no not stated c) no gender) c) rate different description description c) interview (peer, and no b) any additional factor: relatives, friends) not designation (educational level, living blinded to case/control status, history of status imprisonment, previous treatment episodes)


e) no description

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 Participants Enrolment Length of Person-years Interventions Outcomes Quality study and setting period follow-up

Appel Cohort 1544 1966-1976 10 years Total 8476,3 py Intervention:MMT 1 Deaths for any Selection: ** 2000, USA Retrospective outpatient In MMT 6118,40 person- Control: Discharged form cause, comparability:* years; Not MMT: 2357,90 MMT Duration of outcome:* person-years MMT for (months): Brugal Cohort 5049 1992-1999 7 years Total 23048 py Intervention: MMT Deaths for any Selection ***; 2005, Spain Prospective outpatient In MMT 5399.5 person- Control: Discharged form cause comparability * years; Not MMT: 17648.6 MMT outcome * person-years

Buster Cohort 5200 1986-1998 12 years Total: 29.729 Intervention: MMT Fatal overdoses Selection ***; 2002, Prospective outpatient Treatment: 18.747; After Control: Discontinuation comparability * Netherlands treatment: 10.983 from MMT outcome *

Caplehorn Cohort 307 1970-1991 21 years Total. 4253 person-years Intervention: MMT Deaths for any Selection: ***; 1994, Prospective outpatient In MMT: 1975 person- Control: Discharged form cause comparability 0 Australia years; Not MMT 2279 MMT outcome * person-years

Concool Cohort 1156 1969-1976 7 years Not reported Intervention: MMT Deaths for any Selection *** 1979, USA Prospective outpatient Control: Discharged form cause comparability 0 MMT outcome *

Davoli Case-control Cases: 81; 1980-1988 Intervention: MMT; Selection: ***; 1993 Italy control: 324 Control: No MMT comparability** exposure ***

Author Type of Participants Enrolment Length of Person-years Interventions Outcomes Quality study and setting period follow-up

Davoli Cohort 10,258 1998-2001 2.5 years Total: 13,538.2 Intervention: MMT, TC 4, Overdose Selection *** 2006, Italy Prospective outpatient In treatment: 10,208 methadone detoxification, mortality comparability** Out of treatment: 2914 other pharmacological, outcome ** In MMT: 5751.3 psychosocial treatments In TC: 1188.9 Control: in any treatment, In Methadone detox: out of treatment 1495.7 Other pharmacological: 422.6 Psychosocial : 1349.2 Di Giusto Cohort 1244; (MMT Not reported > 6 months Total 394 person-years Intervention: MMT; Serious adverse Selection *** 2004, Prospective 403, BMT 2 NTX in treatment: BMT; NTX; Control: events comparability 0 Australia 402, LAAM 44.4py, out of treatment: Patients out of treatment outcome* 115, NTX 3 62.2py; Agonist in 324) treatment: 267py, out of outpatient treatment: 19.7py

Esteban Cohort 1487, 1990-1997 7 years Not reported Intervention: MMT; Deaths for any Selection *** 2003, Spain Retrospective outpatient Control: Discharged form cause comparability * MMT outcome ** Fugelstad Cohort 101 1986-1993 8 years Total: 503.7 For all Compulsory Deaths for any Selection ** 1998, Prospective inpatients 2-6 MMT: 177.3. Involuntary residential treatment for cause comparability* Sweden months, then discharged: 57.3. No 2-6 months, then outcome ** outpatients MMT: 272.8. Intervention: no MMT; voluntary MMT; Control: involuntary discharged due to disrespect to the rules of treatment.

Gronbladh Cohort 166, voluntary 1967-1988 20 y treated, Not reported Intervention: MMT; Deaths for any Selection *** 1990, Retrospective discharged 34, treated, voluntary and Control: waiting list, cause comparability 0 Sweden involuntary voluntary and involuntary untreated outcome ** discharged: 53, involuntary discharged untreated and discharged 5-8y untreated, waiting list: 1979-1988 waiting list 115 untreated, waiting list

Author Type of Participants Enrolment Length of Person-years Interventions Outcomes Quality study and setting period follow-up

Hulse 2005, Pre-post 361 2001-2002 For each Not reported Intervention: Naltrexone Non fatal Selection *** Australia design, data outpatient patients: 6 implant with rapid opioid overdoses comparability* prospectively months before detoxification (ROD); outcome* collected and after Control: Same patients treatment with a before naltrexone sustained implants release naltrexone implant Pre-treatment: mean 490 days (SD 183) Post-treatment: mean 603 days (SD 183)

Hutchinson Cohort 204 February- 6 - 12 months Not reported Intervention: MMT a) Non fatal Selection*** 2000, UK Retrospective outpatient December continuous, b) non overdoses comparability 0 1996 continuous; Control: outcome 0 Before starting treatment and MMT a) continuous, b) non continuous; Langedam Cohort 827 1985-1996 11 years Total 4961 person-years Intervention:MMT Deaths for any Selection *** 2001, Prospective outpatient Control: Discharged form cause comparability ** Netherlands MMT outcome * Stewart Cohort 913, March-July 1 year Not reported Intervention: Residential Non fatal Selection *** 2002, UK Prospective Inpatients and 1995 treatments, Community overdoses comparability * outpatients treatments; Control: not in outcome 0 treatment and all the treatments above van Cohort 498, outpatient 1989-1995 6 years 1968 person-years Intervention: MMT; Deaths for any Selection *** Ameijden Prospective Methadone Maintenance Control: Discharged form cause comparability ** 1999, Treatment (MMT): 155 MMT outcome * Netherlands person-years Not MMT: 466 person- years

Author Type of Participants Enrolment Length of Person-years Interventions Outcomes Quality study and setting period follow-up

Watterson Cohort 1970-71: 9276 3 cohorts 1 year Total 1970-71: Intervention: MMT, Deaths for any Selection *** 1975, USA Prospective 1071-72:17684 1970-71 3287person-years Therapeutic Community, cause comparability 0 1972-73:23529 1971-72, Total 1071-72: 7400 Other drug free, outcome * 1972-73 person-years Withdrawal only (WD); Total 1972-73: 10121 Control: No treatment person-years

Zanis 1998, Cohort 507, MMT: 1993-1994 1 year Not reported Intervention: MMT; Deaths for any Selection *** USA Prospective 397, Control: Discharged from cause comparability 0 Discharged MMT outcome ** from MMT: 110

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 Subjects Confounding Crude Rate Standardised rate Crude RR/OR Adjusted follow-up experiencing the factors controlled (1000 p-y) (1000 p-y) RR/OR N (%) outcome for Crude OR (N)

Appel 2000 Not Death for any Age, gender, Death for any cause Age 18-24 Discharged vs in Not calculated reported cause : 176 ethnicity In MMT: 15.2 In MMT: 8.3 MMT In MMT 1: 93 Discharged from MMT: Discharged from MMT: 10.8 Death for any Discharged from 35.2 Age 25-44 cause: 2.3 MMT: 83 In MMT:15.7 Opiate-related death Discharged from MMT:38.6 Opiate-related Opiate-related In MMT: 0.3 Age 45-64 death: 51 death : 38 Discharged from MMT: In MMT: 18.9 In MMT 1: 2 15.3 Discharged from MMT: 58.4 Discharged from Gender MMT: 36 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 Brugal 2005 353 (7) Death for any Gender, age, years Overdose death Not calculated Overdose death Overdose death cause: 1005 of consumption, In MMT: 0.2 Out MMT vs in Out MMT vs in Death for : HIV status, drugs Out MMT: 1.9 MMT: MMT: AIDS: 386 injection, calendar 9.4 (95% CI 5.1- 7.1 (95% CI 3.8- Overdose : 349 year 17.1) 13.4) Other causes: 270 Author Lost to Subjects Confounding Crude Rate Standardised rate Crude RR/OR Adjusted follow-up experiencing the factors controlled (1000 p-y) (1000 p-y) RR/OR N (%) outcome for Crude OR (N)

Buster 2002 Not Overdose death : Sex, born in the MMT: 2.2 Not calculated First two weeks First two weeks reported 68 Netherlands, time Discontinuation MMT: 2.4 Very low baseline rate, heroin after (re)entering after (re)entering In MMT: 42 since first First 2 weeks after inhaling treatment vs not treatment: 2.86 Discontinuation treatment, (re)entering MMT: 6.0 during the first 2 95% CI 1.42- from MMT: 22 treatment modality, (95% CI 1.4-5.) weeks: 2.82 5.78) first two weeks > week 10: 2.1 (95% CI 1.4- (95% CI 1.39- after (re)entering 3.1) 5.70) treatment Very low rates in and out of treatment (no difference) Caplehorn Not Death for any None Death for any cause Not calculated Death for any Not calculated 1994 reported cause . 47 In MMT: 5.6 cause in MMT In MMT:11 Out MMT: 15.8 vs out Out MMT: 36 0.35 (95% CI: 0.18-0.69) Concool 102 (8.8) Death for any Age Death for any cause Death for any cause Not calculated In MMT vs 1979 cause : 45 In MMT: 20 All patients: 39 overall: 0.26 In MMT: 23 After discharge: 19 In MMT: 10.2 After discharge: 22 Davoli 1993 4 Overdose death Calendar year of MMT vs no MMT: 3.55 - - 1-12 months out 81 first treatment, (95% CI 1.82- 6.90) of treatment vs duration of in treatment:: treatment, age at 1-12 months out of 10.35 (95% CI first drug use, treatment vs in treatment: 3.32-32.2 marital status, time 7.98 (95% CI 3.40-18.73) since last > 12 months out treatment, age, > 12 months out of of treatment vs gender treatment vs in treatment: in treatment: 2.54 (95% CI 1.25-5.15) 2.91 (95% CI 1.00-8.49)

Author Lost to Subjects Confounding Crude Rate Standardised rate Crude RR/OR Adjusted RR/OR follow-up experiencing the factors controlled (1000 p-y) (1000 p-y) N (%) outcome for Crude OR (N)

Davoli 2006 379 Overdose death Type of treatment, In treatment: 0.98 Not calculated In treatment vs out of In treatment vs out of (3.7%) Total 41; 31 out of age, gender, Out treatment: 10.6 treatment: 0.09 treatment: 0.09 (95% treatment, 10 in cocaine use, HIV In MMT: 1.22 In MMT vs out of CI 0.04-0.19) treatment status, psychiatric Out MMT: 9.0 treatment: 0.11 In MMT vs out of In MMT: 7; out diagnoses, route of Out TC: 21.6 In methadone detox vs treatment: 0.10 (95% MMT: 9 administration, age In methadone detox: 0.67 out of treatment: 0.06 CI 0.04-0.24) In TC: 0; out TC: 5 at first heroin use, Out methadone detox: 8.6 In other pharmacol vs In methadone detox In methadone previous overdose, In other pharmacol: 2.4 out of treatment: 0.22 vs out of treatment: detox: 1; out imprisonment, Out other pharmacol: 11.4 In psychosocial vs out 0.07 (95% CI 0.01- methadone detox: 7 educational level, In psychosocial: 0.7 of treatment: 0.07 0.50) In other pharmacol: living situation, Out psychosocial: 12.0 In other pharmacol vs 1; out other employment status Out of treatment vs in out of treatment: 0.37 pharmacol: 7 treatment: 10.9 (95% CI 0.05-2.76) In psychosocial: 1; Out of MMT vs in In psychosocial vs out psychosocial: 3 treatment: 9.2 out of treatment: 0.07 Out of TC vs in (95% CI 0.01-0.55) treatment: 22.0 Out of methadone detox Out of treatment vs in vs in treatment: 8.8 treatment: 11.1 (95% Out other pharmacol vs CI 5.29-23.3) in treatment: 11.7 Out of MMT vs in Out psychosocial vs in treatment: 8.2 (95% treatment: 12.2 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 Subjects Confounding Crude Rate Standardised rate Crude RR/OR Adjusted follow-up experiencing the factors controlled (1000 p-y) (1000 p-y) RR/OR N (%) outcome for Crude OR (N)

Esteban None Death for any Gender, HIV status In MMT: 113/966 Not calculated Not calculated Not receiving vs 2003 cause : 160 Discharged from MMT: receiving MMT: In MMT: 113 47/521 3.2 (1.5-7.1) Discharged form MMT: 47 Retained vs drop out: 0.5 (95% CI 0.2-1.1) Fugelstad None Death for any Gender, HIV status Not reported Not calculated Not reported MMT vs no 1998 cause : 40 MMT In MMT: 7 Male HIV +: 0.8 Involuntary (95% CI 0.2-2.3) discharged: 4 female HIV +: 0.2 No MMT: 27 (95% CI 0.004- In MMT male 1.3) HIV +: 6; Discharged vs no HIV - 1 MMT In MMT female Male HIV +: 0.6 HIV+:1; HIV -: 0 (95% CI 0.1- Involuntary 2.3); female discharged male HIV +: 1.2 (95% HIV +: 3; HIV -: 0; CI 0.3-9.7) female HIV + 1; HIV -:0 No MMT male HIV +: 9; HIV -:8 female HIV +: 6, HIV - :6 Gronbladh None Death for any None In MMT: 0.14 per treatment Not calculated Not calculated Not calculated 1990 cause year In MMT: 16 Voluntary Survival of treated vs discharged: 6 untreated higher (p<0.0001) Involuntary discharged: 26 Untreated and waiting list: 48

Author Lost to Subjects Confounding Crude Rate Standardised rate Crude RR/OR Adjusted follow-up experiencing the factors controlled (1000 p-y) (1000 p-y) RR/OR N (%) outcome for Crude OR (N)

Langedam 53 (6) Death for any Gender, age, Death for any cause: 30.2 Not calculated Not calculated Death for 2001 cause: 150 calendar year, Natural cause : 17.9 Natural cause : Death for natural nationality, Overdose death : 6.3 not current cause (AIDS, ethnicity, receiving vs pneumonia, liver homelessness, HIV receiving: failure, status, body mass methadone: 2.38 cerebral/neural): 89 index, years since (95% CI 1.28- Overdose death : first drug use, 4.55) 39 current use Overdose Injectors not current receiving vs receiving methadone: 4.55 (95%CI 1.89- 10.0)

Watterson Not Death for any Total 1970-71: 15 Not calculated Not calculated Not calculated 1975 reported cause Total 1071-72: 12 1970-71: 50 Total 1972-73: 13 1971-72: 91 MMT: 15 1972-73: 134 TC 4: 2 DF 5: 18 NINT 6: 13

Author Lost to Subjects Confounding Crude Rate Standardised rate Crude RR/OR Adjusted follow-up experiencing the factors controlled (1000 p-y) (1000 p-y) RR/OR N (%) outcome for Crude OR (N)

Van Not Death for any Age gender, All causes:: 22.4 Not calculated Overdose death: All cause Ameijden reported cause : 44 (15 prostitution, stable Overdose: 7.6 0.35 vs in MMT In MMT vs not 1999 overdose, 7 housing, duration Overdose not MMT: 1.5 vs not in MMT MMT: 0.83 suicide, 12 medical of dependence, Overdose in MMT: 0.53 Overdose cause, 4 accident, 6 poli-drug use In MMT vs not other) in MMT 5-55 mg: 0.35 Overdose death in (95% CI: 0.11- MMT: 8 1.08) not in MMT: 7 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) Death for any None In MMT: 1.0% Not calculated In MMT vs Not calculated among cause Discharged: 8.1% discharged: 0.12 discharged In MMT: 4 Discharged: 9

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 Subjects Confounding Crude Rate Standardised Crude RR/OR Adjusted RR/OR follow-up experiencing the factors controlled (1000 p-y) rate N (%) outcome for Crude OR (1000 p-y) (N)

Digiusto Not Total Serious None NTX 2: Not calculated Overdose : Not calculated 2004 reported Adverse effects Total SAE: 20/100 p-y out of NTX (SAEs ): 96 Overdose in: 6.8/ p-y treatment vs in Heroin overdose: Overdose out: 38.6/100 p-y NTX: 5.7 (95% CI 32 Other SAE in: 13.5/100 p-y 1.7-29.6) Fatal SAE: 5 Other SAE out: 11.3/100 p-y out of agonist vs Agonist 3: in agonist Total SAE: 14/100 p-y Overdose in: 1.9/100 p-y treatment 0.0 (95% Overdose out: 0 CI 0.0-14.8) Other SAE in: 11.2/100 p-t Other SAE out: 20.3/100 p-y Other SAE In any treatment: out of NTX Total SAE: 14.4/100 p-y treatment vs in Out of any treatment: NTX: 0.8 (95% CI Total SAE: 42.7/100 p-y 0.2-3.0) Fatal SAE: 1.3/100 p-y 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)

Author Lost to Subjects Confounding Crude Rate Standardised Crude RR/OR Adjusted RR/OR follow-up experiencing the factors (1000 p-y) rate N (%) outcome controlled for Crude OR (1000 p-y) (N)

Hulse 2005 Not Non fatal Measures on the Opioid overdose Not calculated Not calculated Not calculated reported overdose same subjects 5.5% in the 6 months pre NTX implant vs (20 people) in the 0 post treatment 6 months pre- Sedative overdose treatment: 21 1.9% pre treatment vs 4.4% post NTX Opioid overdose implant (p=.004) in the 6 months post-treatment: 0

Hutchinson After Non fatal Adjustment for Non fatal overdose Not calculated At 6 months Not calculated 2000 treatment overdose the lost to follow- Continuous MMT group before after starting 6 months: Continuous MMT up bias (assuming starting treatment 24% treatment vs 55 (27) group before that individuals 12-months after starting treatment 2% before starting 12 starting treatment: not followed-up Non-continuous MMT group treatment= 0.55 months: 12 made non before starting treatment 28% At 12 months 82 (58.3) 6-months after improvement) 6-months after starting treatment 19% after starting 6 and 12 starting treatment: 12-months after starting treatment 7% treatment vs months: 0 before starting 83 (41) 12-months after treatment= 0.55 starting treatment: Continuous 1 MMT group vs Non-continuous non-continuous MMT group at 12 months= before starting 0.28 treatment: 16 6-months after starting treatment: 11 12-months after starting treatment: 4

Author Lost to Subjects Confounding Crude Rate Standardised Crude RR/OR Adjusted RR/OR follow-up experiencing the factors (1000 p-y) rate N (%) outcome controlled for Crude OR (1000 p-y) (N)

Stewart 322 (30) Non fatal None Before starting treatment: 15% Not calculated After entering Not calculated 2002 overdose before One year after treatment entry: 5.7% treatment vs starting treatment: No difference in the rate of overdose for before starting 112 clients treated in residential or community treatment: 0.38 Non fatal setting overdose 1 years after starting treatment: 43

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: any cause mortality Comparison: in methad one 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] 11/5400 338/17649 21.30 0.11 [0.06, 0.19] Brugal, Spain1992-1999 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 Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome follow up of of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure record a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as (eg clinical of adjustment


blind follow up - all people receiving any the exposed cohort


records)


b) no (route, frequency and assessment


subjects pharmacological treatment in length of use, health accounted for


the community


b) drawn from a b) structured status - hiv status, b) record different source interview


psychiatric comorbidity, linkage


b) subjects lost to b) somewhat representative of previous episodes of follow up the average opioid dependent c) no description of c) written self overdose -, age, gender) c) self report unlikely to people receiving any the derivation of the report (for side introduce bias pharmacological treatment in non exposed cohort b) any additional effects) (lost to follow-up the community


d) no factor


: ≤ 5%)


description (educational level, living d) no c) selected group of opioid status, history of description c) subjects lost to dependent people eg subjects imprisonment, previous follow up > 5% in prison, parolees treatment episodes) and description provided of those d) no description of the lost derivation of the cohort d) no statement

Selection:





Comparability:


Outcome:

Cohort study Study (author and year) Brugal 2005

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome follow up of of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure record a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as (eg clinical of adjustment


blind follow up - all people receiving any the exposed cohort


records)


b) no (route, frequency and assessment


subjects pharmacological treatment in length of use, health accounted for


the community


b) drawn from a b) structured status - hiv status, b) record different source interview


psychiatric comorbidity, linkage


b) subjects lost to b) somewhat representative of previous episodes of follow up the average opioid dependent c) no description of c) written self overdose -, age, gender) c) self report unlikely to people receiving any the derivation of the report (for side introduce bias pharmacological treatment in non exposed cohort b) any additional factor: effects) (lost to follow-up the community


d) no (educational level, living ≤ 5%)


description status, history of d) no c) selected group of opioid imprisonment, previous description c) subjects lost dependent people eg subjects treatment episodes)


to follow up > in prison, parolees 5% and description d) no description of the provided of derivation of the cohort those lost

d) no statement

Selection:


Comparability:


Outcome:

Cohort study Study (author and year): Buster 2002

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome follow up of of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as record (eg of adjustment


blind follow up - all people receiving any the exposed cohort


clinical b) no (route, frequency and assessment


subjects pharmacological treatment in records)


length of use, health accounted for


the community


b) drawn from a status - hiv status, b) record different source b) structured psychiatric linkage


b) subjects lost to b) somewhat representative of interview


comorbidity, previous follow up the average opioid dependent c) no description of c) self report unlikely to episodes of overdose -, people receiving any the derivation of the c) written self (for side introduce bias pharmacological treatment in non exposed cohort report age, gender) effects) (lost to follow-up the community


≤ 5%)


b) any additional factor: d) no d) no (educational level, living c) selected group of opioid description description c) subjects lost to status, history of dependent people eg subjects follow up > 5% imprisonment, previous in prison, parolees and description treatment episodes


) provided of those d) no description of the lost derivation of the cohort d) no statement

Selection:


Comparability:


Outcome:


Cohort study Study (author and year): Caplehorn 1994

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome follow up of of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as record (eg of adjustment


blind follow up - all people receiving any the exposed cohort


clinical b) no (route, frequency and assessment


subjects pharmacological treatment in records)


length of use, health accounted for


the community


b) drawn from a status - hiv status, b) record different source b) structured psychiatric comorbidity, linkage


b) subjects lost to b) somewhat representative of interview


previous episodes of follow up the average opioid dependent c) no description of overdose -, age, gender) c) self report unlikely to people receiving any the derivation of the c) written self (for side introduce bias pharmacological treatment in non exposed cohort report b) any additional factor: effects) (lost to follow-up the community


(educational level, living ≤ 5%)


d) no status, history of d) no c) selected group of opioid description imprisonment, previous description c) subjects lost to dependent people eg subjects treatment episodes)


follow up > 5% in prison, parolees and description provided of those d) no description of the lost derivation of the cohort d) no statement

Selection:


Comparability: - Outcome:

Cohort study Study (author and year): Concool 1979

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome follow up of of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as record (eg of adjustment


blind follow up - all people receiving any the exposed cohort


clinical b) no (route, frequency and assessment


subjects pharmacological treatment in records)


length of use, health accounted for


the community


b) drawn from a status - hiv status, b) record b) structured psychiatric comorbidity, linkage


b) subjects lost to b) somewhat representative of different source interview


previous episodes of follow up the average opioid dependent overdose -, age, gender) c) self report unlikely to people receiving any c) no description of c) written self (for side introduce bias pharmacological treatment in the derivation of the report b) any additional factor: effects) (lost to follow-up the community


non exposed cohort (educational level, living ≤ 5%)


d) no status, history of d) no c) selected group of opioid description imprisonment, previous description c) subjects lost dependent people eg subjects treatment episodes)


to follow up > in prison, parolees 5% and description d) no description of the provided of derivation of the cohort those lost

d) no statement

Selection:


Comparability: - Outcome:

Case-control study Study (author and year) Davoli 1993

Selection Comparability Exposure Is the case Representativeness Selection of Definition Comparability of cases and Ascertainment of Same method of Non-Response definition of the cases controls of Controls controls on the basis of the exposure ascertainment rate adequate? design or analysis for cases and controls a) yes, with a) consecutive or a) a) no dead a) Most important factors of a) secure record (eg a) yes


a) same rate for independent obviously community from adjustment


clinical records)


both groups


validation


representative series controls


overdose


(route, frequency and length of cases


of use, health status - hiv b) structured interview b) no b) non b) yes, eg b) hospital b) no status, psychiatric (peer, relatives, friends) respondents record linkage b) potential for controls description comorbidity, previous where blind to case/control described selection biases or of source episodes of overdose -, age, status


c) no not stated c) no gender) c) rate different description description c) interview (peer, relatives, and no b) any additional factor


: friends) not blinded to designation (educational level, living case/control status status, history of imprisonment, previous e) no description treatment episodes)

Selection:


Comparability:





Exposure:

Cohort study Study (author and year): Davoli 2006

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of cohorts Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome on the basis of the design of outcome follow up of of interest was or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure a) yes


a) Most important factors a)Independ a) complete average opioid dependent same community as record (eg of adjustment


ent blind follow up - all people receiving any the exposed cohort


clinical b) no (route, frequency and assessment subjects pharmacological treatment in records)


length of use, health status


accounted for


the community


b) drawn from a - hiv status, psychiatric different source b) structured comorbidity, previous b) record b) subjects lost to b) somewhat representative of interview


episodes of overdose -, age, linkage


follow up the average opioid dependent c) no description of gender) unlikely to people receiving any the derivation of the c) written self c) self introduce bias pharmacological treatment in non exposed cohort report b) any additional factor: report (for (lost to follow-up the community


(educational level, living side effects) ≤ 5%)


d) no status, history of c) selected group of opioid description imprisonment, previous d) no c) subjects lost to dependent people eg subjects treatment episodes)


description follow up > 5% in prison, parolees and description provided of those d) no description of the lost derivation of the cohort d) no statement

Selection:


Comparability:





Outcome:

Cohort study Study (author and year): Di Giusto 2004

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome follow up of of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as record (eg of adjustment


blind follow up - all people receiving any the exposed cohort


clinical b) no (route, frequency and assessment


subjects pharmacological treatment in records)


length of use, health accounted for


the community


b) drawn from a status - hiv status, b) record different source b) structured psychiatric comorbidity, linkage


b) subjects lost to b) somewhat representative of interview


previous episodes of follow up the average opioid dependent c) no description of overdose -, age, gender) c) self report unlikely to people receiving any the derivation of the c) written self (for side introduce bias pharmacological treatment in non exposed cohort report b) any additional factor: effects) (lost to follow-up the community


(educational level, living ≤ 5%)


d) no status, history of d) no c) selected group of opioid description imprisonment, previous description c) subjects lost to dependent people eg subjects treatment episodes


follow up > 5% in prison, parolees and description provided of those d) no description of the lost derivation of the cohort d) no statement

Selection:


Comparability: - Outcome:


Cohort study Study (author and year): Esteban 2003

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome of interest was the design or analysis follow up of not present at cohorts start of study (for side effects) a) truly representative of the a) drawn from the a) secure a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as record (eg of adjustment


blind follow up - all people receiving any the exposed cohort


clinical b) no (route, frequency and assessment


subjects pharmacological treatment in records)


length of use, health accounted for


the community


b) drawn from a status - hiv status, b) record different source b) structured psychiatric linkage


b) subjects lost to b) somewhat representative of interview


comorbidity, previous follow up the average opioid dependent c) no description of c) self report unlikely to episodes of overdose -, people receiving any the derivation of the c) written self (for side introduce bias pharmacological treatment in non exposed cohort report age, gender) effects) (lost to follow-up the community


≤ 5%)


d) no b) any additional factor: d) no (educational level, living c) selected group of opioid description description c) subjects lost to dependent people eg subjects status, history of follow up > 5% imprisonment, previous in prison, parolees and description treatment episodes)


provided of those d) no description of the lost derivation of the cohort d) no statement

Selection:


Comparability:


Outcome:

Cohort study Study (author and year): Fugelstad 1998

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome follow up of of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as record (eg of adjustment


blind follow up - all people receiving any the exposed cohort


clinical b) no (route, frequency and assessment


subjects pharmacological treatment in records)


length of use, health accounted for


the community


b) drawn from a status - hiv status, b) record different source b) structured psychiatric linkage


b) subjects lost to b) somewhat representative of interview


comorbidity, previous follow up the average opioid dependent c) no description of c) self report unlikely to episodes of overdose -, people receiving any the derivation of the c) written self (for side introduce bias pharmacological treatment in non exposed cohort report age, gender) effects) (lost to follow-up the community


≤ 5%)


d) no b) any additional factor: d) no (educational level, living c) selected group of opioid description description c) subjects lost to status, history of dependent people eg follow up > 5% imprisonment, previous and description subjects in prison, parolees treatment episodes) provided of those d) no description of the lost derivation of the cohort d) no statement

Selection:





Comparability:


Outcome:





Cohort study Study (author and year): Gronbladh 1990

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome follow up of of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as record (eg of adjustment


blind follow up - all people receiving any the exposed cohort


clinical b) no (route, frequency and assessment


subjects pharmacological treatment in records)


length of use, health accounted for


the community


b) drawn from a status - hiv status, b) record different source b) structured psychiatric comorbidity, linkage


b) subjects lost to b) somewhat representative of interview


previous episodes of follow up the average opioid dependent c) no description of overdose -, age, gender) c) self report unlikely to people receiving any the derivation of the c) written self (for side introduce bias pharmacological treatment in non exposed cohort report b) any additional factor: effects) (lost to follow-up the community


(educational level, living ≤ 5%)


d) no status, history of d) no c) selected group of opioid description imprisonment, previous description c) subjects lost to dependent people eg subjects treatment episodes)


follow up > 5% in prison, parolees and description provided of those d) no description of the lost derivation of the cohort d) no statement

Selection:


Comparability: - Outcome:

Cohort study Study (author and year) Hulse 2005

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome follow up of of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as record (eg of adjustment


blind follow up - all people receiving any the exposed cohort


clinical b) no (route, frequency and assessment


subjects pharmacological treatment in records)


length of use, health accounted for


the community


b) drawn from a status - hiv status, b) record different source b) structured psychiatric linkage


b) subjects lost to b) somewhat representative of interview


comorbidity, previous follow up the average opioid dependent c) no description of c) self report unlikely to episodes of overdose -, people receiving any the derivation of the c) written self (for side introduce bias pharmacological treatment in non exposed cohort report age, gender) effects) (lost to follow-up the community


≤ 5%)


b) any additional d) no d) no factor:


c) selected group of opioid description description c) subjects lost to (educational level, living dependent people eg subjects follow up > 5% status, history of in prison, parolees and description imprisonment, previous provided of those treatment episodes) d) no description of the lost derivation of the cohort d) no statement

Selection:


Comparability:


Outcome:


Cohort study Study (author and year): Hutchinson 2000

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome follow up of of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure record a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as (eg clinical of adjustment


blind follow up - all people receiving any the exposed cohort


records)


b) no (route, frequency and assessment


subjects pharmacological treatment in length of use, health accounted for


the community


b) drawn from a b) structured status - hiv status, b) record different source interview


psychiatric comorbidity, linkage


b) subjects lost to b) somewhat representative of previous episodes of follow up the average opioid dependent c) no description of c) written self overdose -, age, gender ) c) self report unlikely to people receiving any the derivation of the report (for side introduce bias pharmacological treatment in non exposed cohort b) any additional effects) (lost to follow-up the community


d) no factor


: ≤ 5%)


description (educational level, living d) no c) selected group of opioid status, history of description c) subjects lost dependent people eg subjects imprisonment, previous to follow up > in prison, parolees treatment episodes) 5% and description d) no description of the provided of derivation of the cohort those lost

d) no statement

Selection:


Comparability: - Outcome: -

Cohort study Study (author and year): Langedam 2001

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome follow up of of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as record (eg of adjustment


blind follow up - all people receiving any the exposed cohort


clinical b) no (route, frequency and assessment


subjects pharmacological treatment in records)


length of use, health accounted for


the community


b) drawn from a status - hiv status, b) record different source b) structured psychiatric linkage


b) subjects lost to b) somewhat representative of interview


comorbidity, previous follow up the average opioid dependent c) no description of c) self report unlikely to episodes of overdose -, people receiving any the derivation of the c) written self (for side introduce bias pharmacological treatment in non exposed cohort report age, gender) effects) (lost to follow-up the community


≤ 5%)


b) any additional d) no d) no c) selected group of opioid description factor


: description c) subjects lost dependent people eg subjects (educational level, living status, history of to follow up > in prison, parolees 5% and imprisonment, previous treatment episodes) description d) no description of the provided of derivation of the cohort those lost

d) no statement

Selection:


Comparability:





Outcome:

Cohort study Study (author and year): Stewart 2002

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome follow up of of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure record a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as (eg clinical of adjustment


blind follow up - all people receiving any the exposed cohort


records)


b) no (route, frequency and assessment


subjects pharmacological treatment in length of use, health accounted for


the community


b) drawn from a b) structured status - hiv status, b) record different source interview


psychiatric linkage


b) subjects lost to b) somewhat representative of comorbidity, previous follow up the average opioid dependent c) no description of c) written self unlikely to episodes of overdose -, c) self report people receiving any the derivation of the report (for side introduce bias pharmacological treatment in non exposed cohort age, gender) (lost to follow-up effects) the community


d) no ≤ 5%)


b) any additional description factor


: d) no c) selected group of opioid description c) subjects lost dependent people eg subjects (educational level, living status, history of to follow up > in prison, parolees 5% and imprisonment, previous treatment episodes) description d) no description of the provided of derivation of the cohort those lost

d) no statement

Selection:


Comparability:


Outcome: - Cohort study Study (author and year): van Amejiden 1999

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of cohorts Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome on the basis of the design of outcome follow up of of interest was or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure a) yes


a) Most important factors a)Independ a) complete average opioid dependent same community as record (eg of adjustment


ent blind follow up - all people receiving any the exposed cohort


clinical b) no (route, frequency and assessment subjects pharmacological treatment in records)


length of use, health status


accounted for


the community


b) drawn from a - hiv status, psychiatric different source b) structured comorbidity, previous b) record b) subjects lost to b) somewhat representative of interview


episodes of overdose -, age, linkage


follow up the average opioid dependent c) no description of gender) unlikely to people receiving any the derivation of the c) written self c) self introduce bias pharmacological treatment in non exposed cohort report b) any additional factor: report (for (lost to follow-up the community


(educational level, living side effects) ≤ 5%)


d) no status, history of c) selected group of opioid description imprisonment, previous d) no c) subjects lost to dependent people eg subjects treatment episodes)


description follow up > 5% in prison, parolees and description provided of those d) no description of the lost derivation of the cohort d) no statement

Selection:


Comparability:





Outcome:

Cohort study Study (author and year): Watterson 1975

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome follow up of of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as record (eg of adjustment


blind follow up - all people receiving any the exposed cohort


clinical b) no (route, frequency and assessment


subjects pharmacological treatment in records)


length of use, health accounted for


the community


b) drawn from a status - hiv status, b) record different source b) structured psychiatric comorbidity, linkage


b) subjects lost to b) somewhat representative of interview


previous episodes of follow up the average opioid dependent c) no description of overdose -, age, gender) c) self report unlikely to people receiving any the derivation of the c) written self (for side introduce bias pharmacological treatment in non exposed cohort report b) any additional effects) (lost to follow-up the community


factor


: ≤ 5%)


d) no (educational level, living d) no c) selected group of opioid description status, history of description c) subjects lost to dependent people eg subjects imprisonment, previous follow up > 5% in prison, parolees treatment episodes) and description provided of those d) no description of the lost derivation of the cohort d) no statement

Selection:


Comparability: - Outcome:

Cohort study Study (author and year): Zanis 1998

Selection Comparability Outcome Representativeness of the Selection of the non Ascertainment Demonstration Comparability of Assessment Adequacy of exposed cohort exposed cohort of exposure that outcome cohorts on the basis of of outcome follow up of of interest was the design or analysis cohorts not present at start of study (for side effects) a) truly representative of the a) drawn from the a) secure a) yes


a) Most important factors a)Independent a) complete average opioid dependent same community as record (eg of adjustment


blind follow up - all people receiving any the exposed cohort


clinical b) no (route, frequency and assessment


subjects pharmacological treatment in records)


length of use, health accounted for


the community


b) drawn from a status - hiv status, b) record different source b) structured psychiatric comorbidity, linkage


b) subjects lost to b) somewhat representative of interview


previous episodes of follow up the average opioid dependent c) no description of overdose -, age, gender) c) self report unlikely to people receiving any the derivation of the c) written self (for side introduce bias pharmacological treatment in non exposed cohort report b) any additional effects) (lost to follow-up the community


factor:


≤ 5%)


d) no (educational level, living d) no c) selected group of opioid description status, history of description c) subjects lost to dependent people eg subjects imprisonment, previous follow up > 5% in prison, parolees treatment episodes) and description provided of those d) no description of the lost derivation of the cohort 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 Retrospective (prospective/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 Total 8476,3 py treatment typology 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 Methadone Maintenance Treatment (MMT) (type, length, dosages, frequency and duration of sessions Control interventions (no treatment, Discharged form MMT type of treatment) (see above Outcome: Death for any cause, AIDS excluded before the follow up - definition ended in 1976 , before the diffusion of the HIV infection - number of subjects Total: 176 experiencing the outcome 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 MMT: 15.2 /1000 py Crude Rate (specify,i.e mortality,…) 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) Not considered Other 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 (prospective/retrospective) 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 Total 23048 py by treatment typology In MMT 5399.5 person-years Not MMT: 17648.6 person-years Number of lost to follow-up 7% Interventions Methadone Maintenance Treatment (MMT) (type, length, dosages, frequency and duration of sessions

Control interventions (no treatment, Discharged from MMT type of treatment) (see above Outcome: Dead for any cause; AIDS, overdose, other. - definition Total: 1005 (38.4% AIDS, 34.7 %overdose, 27% other) - number of subjects experiencing In MMT: 119 the outcome Not MMT: 887 Confounding factors controlled for Gender, age, years of consumption, HIV status, drugs injection, calendar year Results Overdose: Crude Rate (specify,i.e In MMT: 0.2/1000py mortality,…) 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) Not considered Other 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 (prospective/retrospective) 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 Total: 29.729 by treatment typology Treatment: 18.747 After treatment: 10.983 Number of lost to follow-up Not reported Interventions Methadone Maintenance Treatment (MMT) (type, length, dosages, frequency and duration of sessions

Control interventions (no treatment, Discontinuation from MMT type of treatment) (see above Outcome: Fatal overdose - definition Total: 68 - number of subjects experiencing During MMT: 42 the outcome 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 Total: 2.3/1000 person-years Crude Rate (specify,i.e In MMT: 2.2/1000 person-years mortality,…) 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) Not considered Other Quality Selection ***; comparability *; outcome * (lost at follow up not reported)

COHORT STUDY Study (first author and year) Caplehorn JRM 1994 Type of study Prospective (prospective/retrospective) 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 Total. 4253 person-years and by treatment typology In MMT: 1975 person-years Not MMT 2279 person-years Number of lost to follow-up Not reported Interventions Methadone Maintenance Treatment (MMT) (type, length, dosages, frequency and duration of sessions

Control interventions (no Discharged from MMT treatment, type of treatment) (see above Outcome: Dead for any cause - definition Total. 47 - number of subjects experiencing In MMT:11 the outcome Confounding factors controlled for None Results Overall: 1.11/1000 Crude Rate (specify,i.e In MMT: 0.56 /1000 py mortality,…) 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) Not considered Other 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 (prospective/retrospective) 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 Not reported and by treatment typology Number of lost to follow-up 102 Age, gender, HIV status Not reported Interventions Methadone Maintenance Treatment (MMT) (type, length, dosages, frequency and duration of sessions

Control interventions (no Discharged from MMT treatment, type of treatment) (see above Outcome: Death for any cause, overdose, violent, accident, medical - definition Total: 45 - number of subjects experiencing In MMT: 23 the outcome After discharge: 22 Confounding factors controlled for Age Results Overall: 39/1000 person-years Crude Rate (specify,i.e In MMT: 20/1000 person-years mortality,…) 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) Not considered Other Quality Selection ***, comparability 0, outcome * (more than 5% lost at follow up)

CASE CONTROL STUDY Study (first author and year) Davoli M 1993

Italy - Study site

Sources of cases and controls Cohort of 4200 IVDU attending methadone treatment during 1980- selection 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 Clinical records exposure - Interventions Methadone Maintenance Treatment (MMT) (type, length, dosages, frequency and duration of sessions

- Control interventions (no No MMT treatment, type of treatment)

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) Not considered Other

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

COHORT STUDY Study (first author and year) Davoli M 2006 Type of study Prospective (prospective/retrospective) Study site(s) and setting Italy. Outpatients

Enrolment and follow-up September 1998 – March 2001 periods

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 Total: 13,538.2 and by treatment typology 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 Methadone Maintenance (MMT) (type, length, dosages, Therapeutic community (TC) frequency and duration of Methadone detoxification sessions 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 In any treatment treatment, type of treatment) Out of treatment (see above) Outcome: Death for any cause - definition Total: 100; 63 out of treatment, 37 in treatment - number of subjects experiencing the outcome 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 Type of treatment, age, gender, cocaine use, HIV status, psychiatric for diagnoses, route of administration, age at first heroin use, previous overdose, imprisonment, educational level, living situation, employment status

COHORT STUDY Davoli M 2006 Results Overdose Crude Rate (specify,i.e In treatment: 0.98/1000 person-years mortality,…) 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) Not considered Other Quality Selection ***; comparability **; outcome **

COHORT STUDY Study (first author and year) Di Giusto E 2004 Type of study Prospective (prospective/retrospective) 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 Mean age: 30.4 (range of mean or %) Male: 65% - Number of total person-years Total 394 person-years and by treatment typology 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 Maintenance treatment: methadone, buprenporphine, LAAM, naltrexone (type, length, dosages, frequency and duration of sessions

Control interventions (no Patients out of treatment treatment, type of treatment) (see above 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 - definition defect: heroin overdose, accident, general illness, adverse drug reaction, psychiatric events, pregnancy - number of subjects experiencing related events, admission for inpatients detoxification the outcome 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 Unit of analysis is the event and not the patient Crude Rate (specify,i.e Total SAE naltrexone: 20/100 p-y mortality,…) 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 Retrospective (prospective/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 Not reported and by treatment typology 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 Methadone Maintenance Treatment (MMT) (type, length, dosages, frequency and duration of sessions

Control interventions (no Discharged form MMT treatment, type of treatment) (see above Outcome: Death for any cause - definition Total: 160 - number of subjects experiencing MMT: 113 the outcome Discharged form MMT: 47

Confounding factors controlled gender, HIV status, for Results MMT : 113/966 Crude Rate (specify,i.e Discharged from MMT : 47/521 mortality,…)

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) Not considered Other Quality Selection ***; comparability *; outcome **

COHORT STUDY Study (first author and year) Fugelstad A 1998 Type of study Prospective (prospective/retrospective) 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 Total: 503.7 by treatment typology 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 Compulsory residential treatment for 2-6 months followed by voluntary (type, length, dosages, frequency and MMT duration of sessions Compulsory residential treatment for 2-6 months followed by involuntary discharged due to disrespect to the rules of treatment Control interventions (no treatment, Compulsory residential treatment for 2-6 months followed by no MMT type of treatment) (see above Outcome: Death for any cause - definition Total 40 - number of subjects experiencing MMT :7, involuntary discharged. 4, no MMT: 27 the outcome 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 Not reported Crude Rate (specify,i.e mortality,…)

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) Not considered Other Quality Selection: ** (severe injection heroin users with compulsory treatment). Comparability:*, outcome: **

COHORT STUDY Study (first author and year) Gronbladh 1990 Type of study Retrospective (prospective/retrospective) Study site(s) and setting Sweden

Enrolment and follow-up 1967-1988 treated, voluntary and involuntary discharged periods 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- Not calculated years and by treatment typology Number of lost to follow-up 0 Interventions Methadone Maintenance Treatment (MMT) (type, length, dosages, frequency and duration of sessions

Control interventions (no Waiting list, untreated treatment, type of treatment) (see above Outcome: Death for any cause - definition MMT: 16 - number of subjects Voluntary discharged: 6 experiencing the outcome Involuntary discharged: 26 Untreated and waiting list: 48 Confounding factors None controlled for Results MMT: 1.4% per treatment year Crude Rate (specify,i.e mortality,…)

Standardised rate Not calculated

Crude RR Not calculated

Adjust RR Not calculated

Risk difference Not calculated

Proportion (i.e. side effects) Not considered Other Quality Selection: ***; comparability 0; outcome **

COHORT STUDY Study (first author and year) Hulse GK 2005 Type of study Pre-post design, data prospectively collected (prospective/retrospective) Study site(s) and setting Western Australia, outpatients

Enrolment and follow-up Enrolment period: January 2001 - December 2002 periods 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- Not reported years and by treatment typology Number of lost to follow-up Not reported Interventions Naltrexone implant with rapid opioid detoxification (ROD) (type, length, dosages, frequency and duration of sessions

Control interventions (no The same patients before naltrexone implants treatment, type of treatment) (see above Outcome: Non fatal overdose (identified and grouped using ICD-10 and ICD-9-CM - definition codes) - number of subjects 21 opioid overdose (20 people) in the 6 months pre-treatment experiencing the outcome no opioid overdose in the 6 months post-treatment Confounding factors Measures on the same subjects controlled for Results Pre-treatment overdose: 5% Crude Rate (specify,i.e mortality,…)

Standardised rate Not calculated Crude RR Not calculated Adjust RR Not calculated Risk difference Not calculated Proportion (i.e. side effects) Not considered Other Quality Selection: ***, comparability*, outcome:* (no statement of adequacy of follow up)

COHORT STUDY Study (first author and year) Hutchinson SJ 2000 Type of study Retrospective (prospective/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 Not reported and by treatment typology 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 Methadone Maintenance Treatment (MMT) (type, length, dosages, frequency For the continuous group: dose= 43mg at recruitment and 65mg at 12 months and duration of sessions Control interventions (no Before starting treatment treatment, type of treatment) (see Continuous MMT group N= 50/118 above) Non continuous MMT group N= 57/118 Outcome: Non fatal overdose - definition Continuous MMT group: before starting treatment N= 12 - number of subjects 6-months after starting treatment N= 0 experiencing the outcome 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 Adjustment for the lost to follow-up bias (assuming that individuals not followed- for up made non improvement) Results Continuous MMT group: before starting treatment 24% Crude Rate (specify,i.e 12-months after starting treatment 2% mortality,…) 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) Not considered Other 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 (prospective/retrospective) Study site(s) and setting Amsterdam. Outpatients

Enrolment and follow-up 1985-1996 periods

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- Total 4961 person-years years and by treatment typology Number of lost to follow-up 53 (6%) Interventions Methadone Maintenance Treatment (MMT) (type, length, dosages, frequency and duration of sessions

Control interventions (no Discharged form MMT treatment, type of treatment) (see above Outcome: Death for any cause, natural cause, overdose - definition Any cause: 150 - number of subjects Natural cause: 89 experiencing the outcome Overdose: 39 Confounding factors Gender, age, calendar year, nationality, ethnicity, homelessness, HIV status, controlled for body mass index, years since first drug use, current use Results Total: 30.2/1000 person-years Crude Rate (specify,i.e Natural cause: 17.9/1000 person-years mortality,…) 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) Not considered Other Quality Selection ***; comparability **; outcome * (6%lost at follow up)

COHORT STUDY Study (first author and year) Stewart D 2002 Type of study Prospective (prospective/retrospective) Study site(s) and setting England. In-patients and out-patients

Enrolment and follow-up Enrolment period: March – July 1995 periods 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- Not reported years and by treatment typology Number of lost to follow-up N= 322 (30%) Interventions Residential treatments (inpatients drug units and rehabilitation units) (type, length, dosages, Community treatments (methadone maintenance and frequency and duration of methadone reduction programs) sessions Control interventions (no Not in treatment and all interventions (see above) treatment, type of treatment) (see above Outcome: Non fatal overdose (measured as a single event) before and after starting - definition treatment - number of subjects Non fatal overdose before starting treatment: 112 client experiencing the outcome Non fatal overdose 1 years after treatment entry: 43 clients Confounding factors None controlled for Results Before starting treatment: 15% Crude Rate (specify,i.e One year after treatment entry: 5.7% mortality,…) 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) Not considered Other 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 (prospective/retrospective) Study site(s) and setting Amsterdam. Outpatients

Enrolment and follow-up 1989 – 1995 periods

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- 1968 person-years years and by treatment Methadone Maintenance Treatment (MMT): 155 person-years typology Not MMT: 466 person-years

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

Control interventions (no Discharged from MMT treatment, type of treatment) (see above Outcome: Death for any cause - definition Total: 44 (15 overdose, 7 suicide, 12 medical cause, 4 accident, 6 other) - number of subjects Overdose in MMT: 8 experiencing the outcome Overdose not MMT: 7 Confounding factors Age gender, prostitution, stable housing, duration of dependence, poli-drug use controlled for Results All causes:: 22.4/1000 person-years Crude Rate (specify,i.e Overdose: 7.6/1000 person-years mortality,…) 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) Not considered Other Quality Selection *** comparability **; outcome * (lost at follow up not reported) COHORT STUDY Study (first author and year) Watterson O 1975 Type of study Prospective (prospective/retrospective) Study site(s) and setting USA

Enrolment and follow-up 3 cohorts 1970-71 , 1071-72, 1972-73 periods

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 Total 1970-71: 3287person-years and by treatment typology 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 Methadone Maintenance Treatment (MMT), Therapeutic Community (TC), Other (type, length, dosages, drug free (DF), Withdrawal only (WD) frequency and duration of sessions

Control interventions (no No treatment (NINT) treatment, type of treatment) (see above Outcome: Death for any cause - definition 1970-71: 50 - number of subjects 1971-72: 91 experiencing the outcome 1972-73: 134 Confounding factors controlled None for Results Total 1970-71: 15/1000 person-years Crude Rate (specify,i.e Total 1071-72: 12/1000 person-years mortality,…) 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) Not considered Other 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 (prospective/retrospective) Study site(s) and setting USA. Philadelphia Veteran Affair Medical Centre. Outpatients

Enrolment and follow-up 7/1993 – 6/1994 periods

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- Not reported years and by treatment typology Number of lost to follow-up 5 among discharged people Interventions Methadone Maintenance Treatment (MMT) (type, length, dosages, frequency and duration of sessions Control interventions (no People discharged from MMT. treatment, type of treatment) Discharged because completed treatment: 12% (see above Because transferred to other treatment : 18% Because failed contract: 52% Because dropped out: 18% Outcome: Death for any cause - definition 4 among in MMT - number of subjects 9 among discharged experiencing the outcome Confounding factors None controlled for Results In MMT: 1.0% Crude Rate (specify,i.e Discharged: 8.1% mortality,…) Standardised rate Not calculated

Crude RR 0.12

Adjust RR Not calculated

Risk difference Not calculated

Proportion (i.e. side effects) Not considered Other Quality Selection ***; comparability 0; outcome **