Drug and Alcohol Dependence

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1 Drug and Alcohol Dependence 111 (2010) Contents lists available at ScienceDirect Drug and Alcohol Dependence journal homepage: Effectiveness of diacetylmorphine versus methadone for the treatment of opioid dependence in women Eugenia Oviedo-Joekes a,b,, Daphne Guh b, Suzanne Brissette c, Kirsten Marchand b, David Marsh a,b,d,e,f, Jill Chettiar b, Bohdan Nosyk b, Michael Krausz b,d, Aslam Anis a,b, Martin T. Schechter a,b a School of Population and Public Health, University of British Columbia, 5804 Fairview Ave, Vancouver, BC, Canada V6T 1Z3 b Centre for Health Evaluation & Outcome Sciences, Providence Health Care, Burrard Street, Vancouver, BC, Canada V6Z 1Y6 c Centre Hospitalier de l Université de Montréal, Hôpital Saint-Luc, CHUM Montréal, QC, Canada H2X 3J4 d Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall Vancouver, BC, Canada V6T 2A1 e Vancouver Coastal Health & Providence Health Care, Burrard Street, Vancouver, BC, Canada V6Z 1Y6 f Centre for Addiction Treatment BC, University of Victoria, 2300 McKenzie Ave, Victoria, BC, Canada V8P 5C2 article info abstract Article history: Received 22 October 2009 Received in revised form 16 March 2010 Accepted 16 March 2010 Available online 26 May 2010 Keywords: Gender Opioid dependence Substitution treatment Diacetylmorphine Injectable Methadone Oral Treatment outcome Background: There is consistent evidence showing women access treatment with more severe substancerelated profiles relative to men; however, treatment outcome evaluation shows inconclusive results regarding gender differences. Furthermore, few studies evaluate response by gender. Methods: The present analyses were performed using data from the NAOMI study, an open-label, phase III randomized controlled trial, carried out between 2005 and 2008 in Vancouver and Montreal, Canada. A total of 226 long-term treatment-refractory opioid dependent individuals were randomized to receive injectable diacetylmorphine or oral methadone for 12 months. Patients in both treatment groups were offered psychosocial and primary care services. Main outcomes were retention in addiction treatment at 12 months. Drug use, health, psychosocial adjustment and health-related quality of life were examined at baseline and during treatment, using the European Addiction Severity Index, Maudsley Addiction Profile, SF-6D and EuroQol EQ-5D. Results: A total of 88 (38.9%) females and 138 (61.1%) males were included in the present analysis. Retention rates among female participants in the diacetylmorphine group were significantly higher than oral methadone (83.3% vs. 47.8%). Males receiving diacetylmorphine improved significantly more than females in physical health, health-related quality of life, and family relations but female participants in the diacetylmorphine group had significantly greater improvements in illicit drug use scores and psychological health compared to females allocated to oral methadone. Conclusions: Among long-term opioid dependent women who have not benefited sufficiently from available treatments, medically prescribed diacetylmorphine is more effective than oral methadone. Men receiving diacetylmorphine showed more improvements than women Elsevier Ireland Ltd. All rights reserved. 1. Introduction There is considerable substance abuse research showing that men and women have different drug use patterns and comorbidities, even within the same sub-populations (Bennett et al., 2000; Covington, 2008; Grella et al., 2009; Powis et al., 1996; Tetrault et al., 2008; Van Etten et al., 1999; Wechsberg et al., 1998; Zilberman et al., 2003, 2007). Although female gender has been associated with later onset of drug use, women may face more risk factors than men, such as physical and sexual abuse (Brady Corresponding author at: St. Paul s Hospital, Burrard Street, Vancouver, BC, Canada V6Z 1Y6. Tel.: x62973; fax: address: eugenia@mail.cheos.ubc.ca (E. Oviedo-Joekes). and Randall, 1999; Brewer et al., 1998; Charney et al., 2007) and greater stigma (Erickson et al., 2000). For example, among opioid dependent individuals in treatment, women were more likely to have been molested as a child and raped as an adult (Hartel et al., 2006), and had higher levels of post-traumatic stress disorder (De Wilde et al., 2007). Also, female heroin users are more frequently HIV positive and have poorer general health (Des Jarlais et al., 2007; Puigdollers et al., 2004). Central nervous system impairment has also shown gender differences; for example, symptoms remitted after 3 months of abstinence in heroin dependent males but not in females (Liu et al., 2006). Considerable research shows sex and gender differences in biological effects, addictive behaviors and progression of addiction (Heading, 2008; Weiss et al., 2003; Wetherington, 2007; Zilberman et al., 2003). In human and animal studies of sex and ovarian hor /$ see front matter 2010 Elsevier Ireland Ltd. All rights reserved. doi: /j.drugalcdep

2 E. Oviedo-Joekes et al. / Drug and Alcohol Dependence 111 (2010) monal influences on drug abuse, differences in subjective effect, patterns of use and relapse have been found, particularly for stimulants and nicotine, where females appeared to be more vulnerable (Fattore et al., 2008; Lynch et al., 2002; Roth et al., 2004; Wetherington, 2007). This suggests sex and gender affects treatment outcomes; however, the underlying mechanisms are not yet understood and empirical data are lacking (Fattore et al., 2008; Grella, 2008; Lynch et al., 2002; Roth et al., 2004). There is consistent evidence showing women are less likely to seek treatment, but they tend to access treatment earlier and with more severe substancerelated profiles than men (Fattore et al., 2008; Grella, 2008; Weiss et al., 2003); however, studies show inconclusive results regarding gender differences in treatment outcomes (Greenfield et al., 2007; Grella, 2008). A large national study (Acharyya and Zhang, 2003) found women were more likely than men to be younger, unemployed, living with a partner, and have previously accessed methadone maintenance treatment (MMT) at intake. Women were more likely to use stimulants, opioids and sedatives, whereas males reported more alcohol, and marijuana use. Despite these differences, treatment was equally effective for men and women (Acharyya and Zhang, 2003). Likewise, in another national study, Stewart et al. (2003) found similar differences at treatment entry and no gender differences in treatment outcomes. In two large studies of MMT, gender was not a predictor of treatment response (Chatham et al., 1999; Mulvaney et al., 1999). On the other hand, some studies have demonstrated gender differences in treatment retention (Hser et al., 2004), and Arfken et al. (2001) found that females were less likely to be retained in treatment and showed less improvements over time. It is difficult to test whether such gender differences exist in the context of addiction treatment studies because the proportion of women is often low (usually around 20%). Moreover, few randomized controlled trials (RCT) report gender-specific treatment effects and miss the opportunity to draw conclusions about gender differences. Thus, it is not surprising that a recent review reported a lack of evidence about gender differences in addiction treatment response (Greenfield et al., 2007). However, the paucity of data from RCTs, the diversity of treatments, and the different substances of abuse included in the latter review make it difficult to draw conclusions about gender differences with respect to response to specific treatments. In the last decade, six countries have provided evidence supporting the effectiveness of injectable diacetylmorphine (DAM), the active ingredient in heroin, for the treatment of longterm, treatment-refractory opioid dependent individuals. Patients receiving injectable DAM under supervision decreased the use of illicit opioids, improved their health and psychosocial status, and reduced HIV risk behavior and criminal activities (Haasen et al., 2007; March et al., 2006; Metrebian et al., 2001; Oviedo-Joekes et al., 2009a; Rehm et al., 2001; van den Brink et al., 2003). However, limited data are available regarding the profile and treatment response among women receiving DAM (Haasen et al., 2006; Rehm et al., 2005; Ribeaud, 2004). The North American Opiate Medication Initiative (NAOMI) was an RCT comparing injectable DAM versus oral methadone maintenance in the treatment of long-term, treatment-refractory opioid dependent individuals in two Canadian cities. After 12 months of treatment, participants randomized to the DAM group showed significantly higher treatment retention and clinical response rates compared to those randomized to the MMT group (Oviedo-Joekes et al., 2009a). The present study evaluated whether there were gender differences in treatment effect. We expected females to derive greater benefit from DAM than MMT but the treatment effect may have differed in men and women. 2. Methods 2.1. Design, setting and participants NAOMI was an open-label, phase III randomized controlled trial comparing supervised injected DAM versus oral MMT in the treatment of long-term opioid dependent individuals. The study was conducted in Vancouver and Montreal between March 2005 and July Participants profile, design and methods have been fully described elsewhere (Oviedo-Joekes et al., 2008, 2009a,b). The study was targeted towards long-term treatment-refractory heroin injectors. The inclusion criteria included the following: opioid dependence (DSM-IV; American Psychiatric Association, 1994); daily opioid injection; at least 5 years of opioid use; a minimum age of 25; a minimum of two previous treatments for opioid dependence including at least one attempt at MMT (in which 60 mg or more of methadone was received daily for at least 30 days within a 40 day period); and no enrolment in MMT within the prior 6 months. The criterion of 25 years or older was proposed by the authorities as a way to assure only long-term users were included Interventions Participants were randomized to receive oral methadone (n = 111) or injected diacetylmorphine (n = 115). A small subgroup of participants (n = 25) was randomized to receive injected hydromorphone only for the purpose of a validation sub-study on self-reported illicit heroin use (Oviedo-Joekes et al., 2010). Oral methadone was dispensed daily; the injection medications were self-administered under supervision in the treatment clinics up to three times daily. Patients in both treatment groups were offered psychosocial and primary care services in keeping with Health Canada Best Practices (Health Canada, 2002). Study treatments were provided for 12 months plus a 3-month period for those still receiving injection drugs, in which they were tapered and transitioned to other treatment modalities (mostly methadone). All participants provided written informed consent. The trial received approval by the review ethics boards in each study site Outcome measures At baseline and follow-up (3, 6, 9 and 12 months), research evaluations were conducted at a separate research office; evaluations were based on the European Addiction Severity Index (EuropASI; Kokkevi and Hartgers, 1995), the Maudsley Addiction Profile (MAP; Marsden et al., 1998) and health-related quality of life (HRQL) instruments: the SF-6D (Brazier et al., 1998) and EQ5D (van der Zanden et al., 2006). Retention in addiction treatment at 12 months was defined as follows: to be considered retained, a patient must have received study medication on at least 10 of the 14 days prior to the 12-month assessment or was confirmed to have been in any other addiction treatment program or abstinent of opioids during this interval. Overall clinical response was defined as an improvement of at least 20% in Drug and/or Legal EuropASI composite scores, with deterioration higher than 10% in no more than one of the remaining composite scores. All participants lost to follow-up were considered non-retained. High-performance liquid chromatography (HPLC) testing was used to detect the presence of morphine and 6-monoacetylmorphine (6-MAM), as evidence of illicit heroin use, in urine samples in the methadone and hydromorphone groups Gender-specific analysis Comparisons were made using Student s t, Mann Whitney U and Kruskal Wallis tests for comparisons of means and Chi-square tests for comparisons of frequencies, depending on variable distribution. Retention and clinical response rates between treatment groups and between males and females were compared using a two-sample test of proportions (Chisquare test). Relative risk (RR) and 95% confidence intervals (95% CI) were calculated. Female and male composite scores obtained at baseline, 3, 6, 9 and 12 months were compared between the treatment groups within each gender, and between genders within each treatment group. For both within-group and between-group analyses, linear models for repeated measures that incorporate correlations for all of the observations arising from the same individual were performed. Missing values for the within-group and between-group analyses were imputed using last observation carried forward. All reported p-values are 2-sided and not adjusted for multiple testing. Potential predictors of clinical response and retention in treatment across and within gender were analyzed using stepwise logistic regression models. Key pretreatment variables (site, gender, ethnicity, housing status, age, previous MMT, days of cocaine use and money from illegal activities, school education, sexual abuse and sex work) were tested for the whole sample, as well as for men and women separately. Logistic regressions on having a positive test by treatment by gender were performed where parameters were estimated by GEE (Generalized Estimating Equation) algorithm so that dependence of observations from the same patient were taken into account. Missing urine samples were considered as having a positive test. p-values were not adjusted for multiple comparisons. Data were analyzed using SAS (version 9.1.3).

3 52 E. Oviedo-Joekes et al. / Drug and Alcohol Dependence 111 (2010) Results 3.1. Female and male profiles before randomization A total of 88 (38.9%) females and 138 (61.1%) males were included in the present analysis. Participants characteristics are shown in Table 1. Female participants were younger than males and reported significantly higher lifetime rates of sexual abuse. More females reported receiving money for sex work in the prior month while more males reported receiving money from employment. No differences were found between male and female participants in housing, education, living arrangements, marital status, current relationship with children, history of criminal charges or illegal activities as a source of income. Human immunodeficiency virus (HIV) and Hepatitis C virus (HCV) positivity rates were significantly higher among female participants. However, both groups did not differ in their reported rate of sharing of injection material or chronic medical conditions that interfere with life. No differences were found in the lifetime number of previous addiction treatment attempts or non-fatal overdose; however, more women reported a history of attempted suicide. There were no statistical differences in years of regular drug injection, heroin or cocaine use. Women reported a shorter lifetime duration and lower recent frequency of cannabis consumption and illicit opioids other than heroin. However, women showed a significantly higher frequency of recent cocaine use compared to men Treatment retention and overall clinical response Overall treatment retention rates were 64.8% and 75.4% for women and men respectively (not significant). Treatment retention in the DAM group for female participants was slightly lower than male participants (Table 2; 83.3% vs. 90.4%). In the MMT group this difference was greater (47.8% vs. 58.5%); however, none of these differences was statistically significant. The comparison between groups by gender indicated that for both males and females, retention rates in DAM were significantly higher than MMT. Overall clinical response rates were 54.5% and 59.4% for women and men respectively (not significant). Clinical response in the DAM group for female participants was lower than male participants (Table 2; 59.5% vs. 71.2%) and similar in the MMT group (50.0% vs. 46.2%); again, none of these differences was statistically signifi- Table 1 Female and male participants profile comparisons at baseline and by treatment group. Patients characteristics DAM MMT Total Female (n = 42) Male (n = 73) Female (n = 46) Male (n = 65) Female (n = 88) Male (n = 138) Socio-demographic Age, years 39.0 ± ± ± ± ± ± 8.4 * First nation, n (%) 12 (36.4) 13 (23.6) 14 (41.2) 14 (27.5) 26 (38.8) 27 (25.5) School education, years 10.2 ± ± ± ± ± ± 2.5 * Precarious housing, n (%) 34 (81.0) 54 (74.0) 31 (67.4) 49 (75.4) 65 (73.9) 103 (74.6) Living with anyone with alcohol problems or using 15 (35.7) 16 (21.9) 10 (21.7) 18 (27.7) 25 (28.4) 34 (24.6) drugs, n (%) Married/common-law, n (%) 7 (16.7) 7 (9.6) 5 (10.9) 11 (16.9) 12 (13.6) 18 (13.0) Have long-lasting relationship with children, n (%) 20 (47.6) 22 (30.1) 14 (30.4) 21 (32.3) 34 (38.6) 43 (31.2) Sexually abused in life, n (%) 14 (33.3) 9 (12.3) 16 (34.8) 5 (7.7) 30 (34.1) 14 (10.1) * Physically abused in life, n (%) 22 (52.4) 32 (43.8) 22 (47.8) 23 (35.4) 44 (50.0) 55 (39.9) Charged in life for any crime, n (%) 41 (97.6) 69 (94.5) 40 (87.0) 63 (96.9) 81 (92.0) 132 (95.7) Money from illegal activities prior month, n (%) 31 (73.8) 55 (75.3) 32 (69.6) 46 (70.8) 63 (71.6) 101 (73.2) Money from prostitution prior month, n (%) 18 (42.9) 1 (1.4) 19 (41.3) 1 (1.5) 37 (42.0) 2 (1.4) * Money from employment prior month, n (%) 0 (0.0) 12 (16.4) 4 (8.7) 13 (20.0) 4 (4.5) 25 (18.1) * Health Chronic medical problem, n (%) 24 (57.1) 40 (54.8) 24 (52.2) 32 (49.2) 48 (54.5) 72 (52.2) Overdoses in the past 3.5 ± ± ± ± ± ± 6.4 Ever attempted suicide, n (%) 23 (54.8) 20 (27.4) 15 (32.6) 17 (26.2) 38 (43.2) 37 (26.8) * Hepatitis C positive a, n (%) 37 (88.1) 47 (64.4) 36 (78.3) 46 (70.8) 73 (83.0) 93 (67.4) * HIV positive a, n (%) 11 (26.2) 3 (4.1) 10 (21.7) 4 (6.2) 21 (23.9) 7 (5.1) * Sharing of injection material b, n (%) 4 (9.5) 6 (8.2) 5 (10.9) 4 (6.2) 9 (10.2) 10 (7.2) Previous drug treatments 10.0 ± ± ± ± ± ± 14.6 Previous MMT 3.6 ± ± ± ± ± ± 1.7 Past drug use c Injecting drugs, years Heroin regular use in life, years Illicit opioids regular use in life, years * Cocaine regular use in life, years Cannabis regular use in life, years * Current drug use Heroin use prior month d, days 27.6 ± ± ± ± ± ± 6.9 Illicit opioids use prior month d, days 6.8 ± ± ± ± ± ± 11.8 * Cocaine use prior month e, days 21.6 ± ± ± ± ± ± 12.5 * Cannabis use prior month f, days 3.1 ± ± ± ± ± ± 11.3 * Money spent in drugs prior month, CND 2912 ± ± ± ± ± ± 1949 DAM: diacetylmorphine; MMT: methadone maintenance treatment; ±: standard deviation; : standard error. a Physician assessment. b Past 6 months. c Association of years using drugs and gender was adjusted by age. d More than 95% injected. e 69.5% of the sample used crack cocaine mostly smoked, 45.1% used cocaine powder mostly injected. f More than 95% smoked. * p < 0.05.

4 E. Oviedo-Joekes et al. / Drug and Alcohol Dependence 111 (2010) Table 2 Retention in treatment by group and gender at 12 months. DAM MMT Female (n = 42) Male (n = 73) Female (n = 46) Male (n = 65) (a) Retention in addiction treatment, n (%) 35 (83.3) 66 (90.4) 22 (47.8) 38 (58.5) NAOMI DAM, n (%) 30 (85.7) 47 (71.2) NAOMI MMT, n (%) 5 (14.3) 16 (24.2) 14 (63.6) 31 (81.6) Other MMT, n (%) 2 (3.0) 7 (31.8) 6 (15.8) Other treatments, n (%) Abstinence, n (%) 1 (1.5) 1 (4.6) 1 (2.6) Female vs. male a 0.92 (0.79, 1.08) 0.82 (0.57, 1.18) DAM vs. MMT a Female 1.74 (1.25, 2.43) ** Male 1.55 (1.24, 1.92) ** (b) Clinical response, n (%) 25 (59.5) 52 (71.2) 23 (50.0) 30 (46.2) Drug response alone 10 (23.8) 16 (21.9) 7 (15.2) 8 (12.3) Legal response alone 0 (0.0) 1 (1.4) 2 (4.3) 4 (6.2) Both drug and legal response 15 (35.7) 35 (47.9) 14 (30.4) 18 (27.7) Female vs. male a 0.84 (0.63, 1.12) 1.08 (0.73, 1.60) DAM vs. MMT a Female 1.19 (0.81, 1.74) Male 1.54 (1.14, 2.08) * DAM: diacetylmorphine; MMT: methadone maintenance treatment. a Relative risk; (95% confidence intervals). * p < ** p < cant. DAM response rates were significantly higher than MMT only among males. Stepwise logistic regression did not reveal any significant predictors of treatment retention and clinical response for the whole sample, as well as for men and women separately Treatment outcomes by domain Table 3 shows the scores in the EuropASI subscales, HRQL and MAP at baseline, 3, 6, 9 and 12 months among males and females in both groups, DAM and MMT. The analysis of co-variance within groups shows that both males and females, in each treatment condition, improved from baseline to 12 months in most of the areas evaluated, including drug use, legal situation and health-related quality of life. Only one group, female participants in MMT, showed a decline in the EuropASI psychiatric subscale. Improvements in sub-scores showed differences between males and females in DAM but not in MMT. In the DAM group, males improved significantly more than females in physical health (EuropASI and MAP), Health-related quality of life (EQ5D and SF- 6D), and Family relations (EuropASI). No differences were found in the Drug and Legal scores of the EuropASI between males and females in the DAM group. DAM versus MMT comparisons of mean score changes by gender indicated that, among female participants, those in the DAM group had significantly greater improvements in Drug score and psychological health (EuropASI and MAP) compared to MMT. Male participants in the DAM group also showed greater improvement in Drug score and psychological health (EuropASI), physical health (EuropASI and MAP), employment satisfaction (EuropASI) and Health-related quality of life (EQ5D and SF-6D) compared to men in the MMT group Urinalysis The subgroup that received hydromorphone on a double-blind basis allowed a comparison of 6-MAM and morphine positive urine tests with the MMT group. Among women, probabilities of testing positive for 6-MAM were (CI 95% = ) and (CI 95% = ) in the MMT and hydromorphone groups respectively and for morphine, were (CI 95% = ) and (CI 95% = ). Both these differences were statistically significant (p < 0.01). The probabilities of men in the hydromorphone group testing positive were similar to women: (CI 95% = ) for 6-MAM and (CI 95% = ) for morphine. 4. Discussion The present study investigated treatment response and retention by gender in North America s first randomized controlled trial of injectable diacetylmorphine. DAM showed greater effectiveness than MMT with respect to treatment retention and response at 12 months for both men and women, although there were significant treatment differences in more sub-scores for men than women. There were no gender differences in overall clinical response and retention at 12 months in the DAM and MMT groups. While male and female participants both reflected the target population of long-term heroin injectors with severe health and psychosocial problems, women had a worse overall profile including higher rates of reported sexual and physical abuse, HIV and HCV infections, suicide attempts, sex work, cocaine use and less employment, in line with differences found in other studies (De Wilde et al., 2007; Hartel et al., 2006; Petry and Bickel, 2000; Puigdollers et al., 2004; Wechsberg et al., 1998). There was a larger proportion of women in our study than is usually reported in the opioiddependence literature. However, our proportion is consistent with data from studies conducted in the same setting (Anderson and Warren, 2004; Fischer et al., 2006; Kerr et al., 2005; Perreault et al., 2003) suggesting that this is a reflection of the target population (Oviedo-Joekes et al., 2008). No randomized controlled trial comparing DAM versus MMT other than the one conducted in Germany reported treatment efficacy by gender, likely due to sample size and design limitations (Haasen et al., 2006). Female participants in the German trial showed lower response rates than men to DAM treatment in health

5 54 E. Oviedo-Joekes et al. / Drug and Alcohol Dependence 111 (2010) Table 3 Analysis of co-variance by treatment and gender. Evaluations Months EM a Mean score difference M vs. F by Tx b DAM vs. MMT by gender c M F EuropASI d Drug use Legal situation Medical status Psychiatric status Economic status Employment satisfaction Family relations Social relations Alcohol use DAM M * * * DAM F * MMT M * MMT F * DAM M * DAM F * MMT M * MMT F * DAM M * * * DAM F MMT M MMT F DAM M * * * DAM F MMT M MMT F * DAM M DAM F * MMT M MMT F DAM M * * DAM F * MMT M * * MMT F * DAM M * * DAM F MMT M MMT F DAM M * DAM F * MMT M MMT F DAM M DAM F * MMT M MMT F EQ5D e DAM M * * * DAM F * MMT M * MMT F * SF-6D e DAM M * * * DAM F MMT M MMT F * MAP-physical f DAM M * * DAM F * MMT M * MMT F MAP-psychological g DAM M * * DAM F * MMT M * MMT F DAM: diacetylmorphine; MMT: methadone maintenance treatment; M: males; F: females; Tx: treatment group; EQ5D: Euroquol; SF-6D: quality of life; MAP: Maudsley Addiction Profile. a Estimated mean change from baseline to 12 month within groups. Negatives scores indicate improvement. b Difference between males vs. females among each treatment condition, in adjusted mean score. Negative scores indicate higher improvement for male over female participants. c Difference between MMT vs. DAM for males and females, in adjusted mean score. Negative scores indicate higher improvement for DAM over MMT. d EuropASI subscale scores range from 0 to 1; higher scores are indicative of more severe problems. e Scores range from 0 to 1; higher scores are indicative of less severe problems; EQ5D index score with U.S. weights. f Scores range from 0 to 40; higher scores are indicative of more severe problems. * p < 0.05.

6 E. Oviedo-Joekes et al. / Drug and Alcohol Dependence 111 (2010) (75.7% vs. 81.1%) and drug use (54.4% vs. 72.8%) (Haasen et al., 2006). Female and male participants showed similar responses to MMT in health (74.3% vs. 73.9%) and drug use (52.5% vs. 55.9%) response rates. As in our study, males showed a higher response rate than females to DAM treatment but not to MMT. However, contrary to the German trial, in our study females in the DAM group showed a significantly higher response in health and drug use than the MMT group. In the Swiss cohort study of DAM (Rehm et al., 2005), women had a higher standardized mortality ratio than men (17.2 vs. 8.4). These data are consistent with our finding that men showed improvements in general health with DAM while women did not. In the Swiss study, males had higher overall pre-treatment rates of criminal involvement than females but this disappeared after program entry, suggesting a greater treatment effect on legal status in men. While in our study women and men did not show differences in the Legal composite score, these overall results suggest males might respond to DAM to a greater degree than women. Retention in treatment is associated with better treatment outcomes (Zhang et al., 2003). In our study, women in DAM showed significantly higher retention than women in MMT and no gender differences were found with either treatment. Unfortunately, there are few data with which to compare our results. In the Swiss study, female and male participants appeared to have similar rates of retention when treated with DAM. However, this can only be inferred from similar male to female ratios entering and leaving treatment during that period (73% vs. 27%; 71% vs. 29%) (Gschwend et al., 2003). Analyses of MMT outcomes by gender showed variable results. In our study there were no differences in retention and response rates between men and women in the MMT group as seen in other studies (Jones et al., 2005; Mulvaney et al., 1999; Rounsaville et al., 1982; Simpson et al., 1997). For example, Mulvaney et al. (1999) did not find gender differences in the ASI subscales scores among MMT patients. However, Chatham et al. (1999) found better health and psychological status among men compared to women after 1 year. There is little support for gender differences in retention rates in MMT (Booth et al., 2004; Joe et al., 1999; Magura et al., 1998; Simpson et al., 1997). Both Chatham et al. (1999) and Peles and Adelson (2006) reported similar retention rates at 1 year among men and women. On the other hand, there is one large study in which women were more likely to remain in MMT compared to men; however, the overall retention rate was extremely low (12%; Hser et al., 2001), making comparisons with other studies difficult. Limitations of the study have been discussed in detail elsewhere (Oviedo-Joekes et al., 2008, 2009a,b). For example, clinical response in the present study was evaluated by self-report. Despite some concerns on relying on self-reported data in addiction treatment, studies have consistently shown validity and reliability of these measures (McLellan et al., 2006). Moreover, self-report has been found to be reliable when obtained by interviewers with no control or power over the treatment process (Darke, 1998) as in the present study. Finally, we confirmed self-reported non-use of illicit heroin by means of urine testing (Oviedo-Joekes et al., 2009a,b). Data indicate that women tend to use the health care system more frequently than men (Green, 2006; Spitzer, 2005; Uphold and Mkanta, 2005). In our study, no gender differences were found in the use of emergency services and hospitalizations, stratified by treatment allocation (data not shown). However, the utilization of psychosocial and primary services provided by the study clinical team was not formally recorded. It should be noted that our target population consisted of longterm opioid injectors with very poor housing, socioeconomic and medical conditions and a broad experience with the addiction treatment system including MMT. This should be taken into account when generalizing to other populations. No other variable besides treatment allocation predicted retention and response; however, not all interactions could be tested in multivariate models due to sample size. Due to the inclusion of small numbers of women, the results in DAM studies have been based mainly upon the outcomes in male participants. Our study is the first one to show that for the treatment of long-term opioid dependence, injectable diacetylmorphine is more effective than MMT for women as well as for men. It is very difficult to disentangle the various components of DAM treatment in order to explain why it was more effective than MMT among women (and men). Is it the higher attraction due to previous failures of other treatments, is it the access to the opioid which was their drug of choice (Room, 2002), is it the contact with the health care team due to daily visits, or is it the route of administration? Probably these questions would be more appropriately explored with a qualitative approach. Also, in some sub-scores, men in the DAM group showed greater improvement than women whereas at the beginning of the study, women presented more vulnerabilities than men. While the latter did not predict treatment outcome, one hypothesis is that response to DAM treatment could follow a different timeline in men versus women. Certainly, gender differences in DAM treatment require more qualitative and quantitative research attention in order to fully answer these questions as well as to identify opportunities to tailor treatment to men and to women. Role of funding source The study is funded by the Canadian Institutes of Health Research (CIHR). CIHR had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Contributors The authors designed the study and gathered the data. The senior statistician (DG) performed the data analyses. The first author (EOJ) and the last author (MTS) wrote the first draft of the paper and all authors contributed to the final version. The final decision about publishing the paper was made by all the authors. All authors vouch for the accuracy of the data and analysis. Competing interests Nothing to declare. Acknowledgments The NAOMI trial was funded through an operating grant from the Canadian Institutes of Health Research with additional support from the Canada Foundation for Innovation, the Canada Research Chairs Program, the University of British Columbia, Providence Health Care, the University of Montreal, Centre de Recherche et Aide aux Narcomanes, the Government of Quebec, Vancouver Coastal Health Authority and the BC Centre for Disease Control. The authors wish to acknowledge the dedication of N. Laliberté, C. Gartry, K. Sayers, P.A. Guevremont, P. Schneeberger, K. Lock, J. Lawlor, P. Pelletier, S. Maynard, M.I. Turgeon, G. Brunelle, A. Chan, S. MacDonald, T. Corneil, J. Geller, S. Jutha, S. Chai, M. Piacsezna, S. Sizto, the many remaining staff and members of the DSMB (A. Marlatt, N. El-Guebaly, J. Raboud and D. Roy). The authors also wish to recognize the many U.S. and Canadian (J. Rehm and B. Fischer) scientists who contributed to the early design discussions but ultimately were unable to participate in the trial. Most importantly, the authors wish to acknowledge and thank the NAOMI trial participants.

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