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Drug and Alcohol Dependence
j o u r n a l h o m e p a g e :
w w w . e l s e v i e r . c o m / l o c a t e / d r u g a l c d e p
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
aSchool of Population and Public Health, University of British Columbia, 5804 Fairview Ave, Vancouver, BC, Canada V6T 1Z3 bCentre for Health Evaluation & Outcome Sciences, Providence Health Care, 620-1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6 cCentre Hospitalier de l’Université de Montréal, Hôpital Saint-Luc, CHUM Montréal, QC, Canada H2X 3J4
dDepartment of Psychiatry, University of British Columbia, 2255 Wesbrook Mall Vancouver, BC, Canada V6T 2A1 eVancouver Coastal Health & Providence Health Care, 620-1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6 fCentre for Addiction Treatment BC, University of Victoria, 2300 McKenzie Ave, Victoria, BC, Canada V8P 5C2
a r t i c l e i n f o
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
a b s t r a c t
Background:There is consistent evidence showing women access treatment with more severe substance-related 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 avail-able treatments, medically prescribed diacetylmorphine is more effective than oral methadone. Men receiving diacetylmorphine showed more improvements than women.
© 2010 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
comor-bidities, 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, 620-1081 Burrard Street, Vancou-ver, BC, Canada V6Z 1Y6. Tel.: +1 604 682 2344x62973; fax: +1 604 806 8210.
E-mail address:[email protected](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
bio-logical 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-0376-8716/$ – see front matter© 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2010.03.016
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
vul-nerable (
Fattore et al., 2008; Lynch et al., 2002; Roth et al., 2004;
Wetherington, 2007
). This suggests sex and gender affects
treat-ment 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
substance-related 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,
treat-ment 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
ran-domized 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
conclu-sions about gender differences with respect to response to specific
treatments.
In the last decade, six countries have provided evidence
sup-porting the effectiveness of injectable diacetylmorphine (DAM),
the active ingredient in heroin, for the treatment of
long-term, 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
).
How-ever, 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
evalu-ated 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 opi-oid dependent individuals. The study was conducted in Vancouver and Montreal between March 2005 and July 2008. 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.
2.2. Interventions
Participants were randomized to receive oral methadone (n= 111) or injected diacetylmorphine (n= 115). A small subgroup of participants (n= 25) was ran-domized 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.
2.3. 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 inter-val. 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.
2.4. Gender-specific analysis
Comparisons were made using Student’st, Mann–WhitneyUand 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 (Chi-square 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 observa-tion carried forward. All reportedp-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 pre-treatment 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 Equa-tion) 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. 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
par-ticipants. 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
life-time 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
life-time 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.
3.2. 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,
reten-tion 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±7.1 40.1±7.9 35.7±9.1 41.8±8.9 37.3±8.3 40.9±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 11.1±2.6 10.7±1.9 11.2±2.3 10.5±2.2 11.2±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 drugs,n(%)
15 (35.7) 16 (21.9) 10 (21.7) 18 (27.7) 25 (28.4) 34 (24.6)
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±5.7 3.7±6.5 4.7±9.1 3.4±6.3 4.1±7.6 3.6±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 positivea,n(%) 37 (88.1) 47 (64.4) 36 (78.3) 46 (70.8) 73 (83.0) 93 (67.4)*
HIV positivea,n(%) 11 (26.2) 3 (4.1) 10 (21.7) 4 (6.2) 21 (23.9) 7 (5.1)*
Sharing of injection materialb,n(%) 4 (9.5) 6 (8.2) 5 (10.9) 4 (6.2) 9 (10.2) 10 (7.2)
Previous drug treatments 10.0±10.6 14.4±13.7 11.8±15.6 13.8±15.7 10.9±13.4 14.1±14.6
Previous MMT 3.6±2.3 3.0±1.4 3.5±2.1 3.0±2.0 3.5±2.2 3.0±1.7
Past drug usec
Injecting drugs, years 15.68∼1.20 16.29∼0.91 16.88∼1.13 15.89∼0.94 16.25∼0.82 16.14∼0.65
Heroin regular use in life, years 14.68∼1.14 13.23∼0.86 15.58∼1.12 13.02∼0.93 15.07∼0.79 13.18∼0.63
Illicit opioids regular use in life, years 4.71∼1.24 6.38∼0.94 2.37∼0.96 6.08∼0.80 3.69∼0.79 6.11∼0.63*
Cocaine regular use in life, years 13.31∼1.23 11.63∼0.94 11.28∼1.16 10.14∼0.97 12.33∼0.85 10.88∼0.67
Cannabis regular use in life, years 10.43∼1.74 15.16∼1.32 7.12∼1.55 12.50∼1.29 8.95∼1.18 13.75∼0.94*
Current drug use
Heroin use prior monthd, days 27.6±6.7 25.9±7.6 28.1±5.5 27.0±5.9 27.9±6.1 26.4±6.9
Illicit opioids use prior monthd, days 6.8±10.2 11.0±11.9 3.6±7.0 10.2±11.7 5.1±8.8 10.6±11.8*
Cocaine use prior monthe, days 21.6±11.2 14.7±12.8 18.7±12.8 12.9±12.2 20.1±12.1 13.7±12.5*
Cannabis use prior monthf, days 3.1±7.6 7.5±11.4 4.4±8.9 7.9±11.2 3.8±8.2 7.7±11.3*
Money spent in drugs prior month, CND 2912±6256 2107±2078 2832±3385 2037±1809 2870±49367 2074±1949
DAM: diacetylmorphine; MMT: methadone maintenance treatment;±: standard deviation;∼: standard error.
aPhysician assessment. bPast 6 months.
c Association of years using drugs and gender was adjusted by age. dMore than 95% injected.
e69.5% of the sample used crack cocaine mostly smoked, 45.1% used cocaine powder mostly injected. f More than 95% smoked.
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. malea 0.92 (0.79, 1.08) 0.82 (0.57, 1.18) DAM vs. MMTa 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. malea 0.84 (0.63, 1.12) 1.08 (0.73, 1.60)
DAM vs. MMTa
Female 1.19 (0.81, 1.74)
Male 1.54 (1.14, 2.08)*
DAM: diacetylmorphine; MMT: methadone maintenance treatment.
aRelative risk; (95% confidence intervals). *p< 0.05.
**p< 0.01.
cant. DAM response rates were significantly higher than MMT only
among males.
Stepwise logistic regression did not reveal any significant
pre-dictors of treatment retention and clinical response for the whole
sample, as well as for men and women separately.
3.3. 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
con-dition, 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
gen-der 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
improve-ment 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.
3.4. 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 0.435 (CI 95% = 0.341–0.535)
and 0.111 (CI 95% = 0.039–0.279) in the MMT and
hydromor-phone groups respectively and for morphine, were 0.712 (CI
95% = 0.614–0.794) and 0.216 (CI 95% = 0.075–0.482). Both these
differences were statistically significant (
p
< 0.01). The probabilities
of men in the hydromorphone group testing positive were similar
to women: 0.166 (CI 95% = 0.065–0.364) for 6-MAM and 0.125 (CI
95% = 0.044–0.305) for morphine.
4. Discussion
The present study investigated treatment response and
reten-tion 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
includ-ing higher rates of reported sexual and physical abuse, HIV and HCV
infections, suicide attempts, sex work, cocaine use and less
employ-ment, 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
opioid-dependence 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
limita-tions (
Haasen et al., 2006
). Female participants in the German trial
showed lower response rates than men to DAM treatment in health
Table 3
Analysis of co-variance by treatment and gender.
Evaluations Months EMa Mean score difference
0 3 6 9 12 M vs. F by Txb DAM vs. MMT by genderc M F EuropASId Drug use DAM M 0.52 0.27 0.30 0.31 0.25 −0.246* −0.033 −0.072* −0.064* DAM F 0.53 0.32 0.33 0.33 0.29 −0.199* MMT M 0.52 0.38 0.36 0.35 0.30 −0.166* −0.038 MMT F 0.56 0.44 0.42 0.37 0.36 −0.154* Legal situation DAM M 0.38 0.17 0.23 0.24 0.20 −0.194* −0.015 −0.023 −0.044 DAM F 0.34 0.18 0.19 0.19 0.23 −0.145* MMT M 0.36 0.23 0.23 0.22 0.15 −0.129* −0.031 MMT F 0.35 0.26 0.24 0.23 0.22 −0.112* Medical status DAM M 0.38 0.28 0.19 0.23 0.22 −0.137* −0.150* −0.135* 0.053 DAM F 0.38 0.40 0.45 0.39 0.31 0.004 MMT M 0.35 0.37 0.39 0.40 0.28 0.018 0.042 MMT F 0.40 0.35 0.32 0.34 0.32 −0.069 Psychiatric status DAM M 0.20 0.12 0.16 0.17 0.13 −0.051* −0.028 −0.047* −0.081* DAM F 0.22 0.19 0.18 0.16 0.19 −0.046 MMT M 0.16 0.17 0.16 0.18 0.17 0.017 −0.045 MMT F 0.22 0.28 0.27 0.25 0.25 0.042* Economic status DAM M 0.86 0.82 0.80 0.83 0.82 −0.039 −0.046 0.020 0.053 DAM F 1.00 0.96 0.96 0.97 0.97 −0.035* MMT M 0.85 0.78 0.80 0.81 0.80 −0.062 −0.041 MMT F 0.95 0.85 0.87 0.92 0.91 −0.059 Employment satisfaction DAM M 0.24 0.10 0.11 0.07 0.06 −0.164* −0.025 −0.092* 0.013 DAM F 0.27 0.17 0.09 0.08 0.16 −0.163* MMT M 0.27 0.22 0.24 0.19 0.12 −0.108* 0.080* MMT F 0.24 0.11 0.11 0.09 0.08 −0.143* Family relations DAM M 0.08 0.02 0.06 0.03 0.05 −0.044* −0.058* −0.022 0.007 DAM F 0.11 0.12 0.06 0.09 0.10 −0.038 MMT M 0.10 0.08 0.07 0.10 0.04 −0.039 −0.024 MMT F 0.06 0.07 0.08 0.06 0.10 0.004 Social relations DAM M 0.14 0.07 0.11 0.10 0.09 −0.051* 0.025 −0.022 −0.039 DAM F 0.11 0.04 0.08 0.05 0.07 −0.054* MMT M 0.09 0.12 0.10 0.09 0.07 0.004 0.002 MMT F 0.12 0.15 0.10 0.08 0.09 −0.019 Alcohol use DAM M 0.05 0.03 0.04 0.05 0.05 −0.006 0.010 −0.005 −0.013 DAM F 0.01 0.01 0.01 0.01 0.01 −0.004* MMT M 0.02 0.03 0.03 0.03 0.04 0.003 0.001 MMT F 0.07 0.05 0.06 0.06 0.08 −0.005 EQ5De DAM M 0.70 0.83 0.81 0.81 0.86 0.135* 0.054* 0.065* 0.006 DAM F 0.71 0.79 0.77 0.78 0.78 0.065* MMT M 0.70 0.75 0.76 0.79 0.77 0.056* −0.004 MMT F 0.68 0.74 0.76 0.76 0.75 0.089* SF-6De DAM M 0.68 0.75 0.74 0.74 0.75 0.066* 0.050* 0.049* −0.008 DAM F 0.64 0.67 0.68 0.68 0.68 0.035 MMT M 0.69 0.69 0.71 0.71 0.71 0.009 −0.013 MMT F 0.64 0.67 0.69 0.70 0.67 0.045* MAP-physicalf DAM M 13.93 10.88 11.63 11.77 11.59 −2.470* −1.780* −1.148 −0.795 DAM F 18.24 15.79 14.76 15.90 15.46 −2.899* MMT M 14.22 12.33 12.78 13.44 11.70 −1.607* −1.352 MMT F 15.67 15.16 14.50 14.73 15.23 −0.902 MAP-psychologicalg DAM M 13.29 9.14 9.82 10.56 9.22 −3.712* −0.567 −1.081 −2.454* DAM F 16.55 11.79 11.52 11.62 12.17 −4.920* MMT M 12.91 11.19 10.35 10.13 9.70 −2.510* −1.335 MMT F 16.00 14.31 13.20 13.16 15.07 −1.808
DAM: diacetylmorphine; MMT: methadone maintenance treatment; M: males; F: females; Tx: treatment group; EQ5D: Euroquol; SF-6D: quality of life; MAP: Maudsley Addiction Profile.
aEstimated mean change from baseline to 12 month within groups. Negatives scores indicate improvement.
bDifference 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. dEuropASI subscale scores range from 0 to 1; higher scores are indicative of more severe problems.
eScores 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.
(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
improve-ments in general health with DAM while women did not. In the
Swiss study, males had higher overall pre-treatment rates of
crim-inal 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
out-comes (
Zhang et al., 2003
). In our study, women in DAM showed
significantly higher retention than women in MMT and no
gen-der 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
long-term opioid injectors with very poor housing, socioeconomic and
medical conditions and a broad experience with the addiction
treat-ment 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
treat-ment 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
fail-ures 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
differ-ent 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
deci-sion 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.
Mar-latt, 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
ulti-mately were unable to participate in the trial. Most importantly,
the authors wish to acknowledge and thank the NAOMI trial
par-ticipants.
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