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Differential long-term outcomes for voluntary and involuntary transition from injection to oral opioid… Oviedo-Joekes, Eugenia; Guh, Daphne; Marchand, Kirsten; Marsh, David C; Lock, Kurt; Brissette, Suzanne; Anis, Aslam H; Schechter, Martin T Jun 8, 2014

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SHORT REPORT Open AccessDifferential long-term outcomes for voluntary andinvoluntary transition from injection to oralopioid maintenance treatmentEugenia Oviedo-Joekes1,2*, Daphne Guh1, Kirsten Marchand1,2, David C Marsh4,5, Kurt Lock1, Suzanne Brissette3,Aslam H Anis1,2 and Martin T Schechter1,2AbstractBackground: The most widely used maintenance treatment for opioid dependency is substitution with long-actingoral opioids. Treatment with injectable diacetylmorphine provides an opportunity for patients to stabilize andpossibly transition to oral treatment, if clinically indicated. The aim of this study was to explore outcomes ofindividuals that received injectable diacetylmorphine and voluntarily transitioned to oral methadone.Design and methods: The North American Opiate Medication Initiative was a randomized controlled trial thatcompared the effectiveness of injectable diacetylmorphine (or hydromorphone) to oral methadone for long-termopioid-dependency. Treatment was provided for 12-months with an additional 3 months for transition and weaning.Participants were followed until 24-months from randomization. Among the participants randomized to injectabletreatments, a sub-group voluntarily chose to transition to oral methadone (n = 16) during the treatment period. Illicitheroin use and treatment retention were assessed at 24-months for those voluntarily and involuntarily transitioning(n = 95) to oral methadone.Results: At 24-months, the group that voluntarily transitioned to oral methadone had higher odds of treatmentretention (adjusted odds ratio = 5.55; 95% confidence interval [CI] = 1.11, 27.81; Chi-square = 4.33, df = 1, p-value = 0.037)than the involuntary transition group. At 24-months, the adjusted mean difference in prior 30 days of illicit heroinuse for the voluntary, compared to the involuntary group was −5.58 (95% CI = −11.62, 0.47; t-value = −1.83, df = 97.4,p-value = 0.070).Conclusions: Although the results of this study were based on small groups of self-selected (i.e., non-randomized)participants, our data underlines the critical importance of voluntary and patient-centered decision making. If we hadcontinued offering treatment with diacetylmorphine, those retained to injectable medication may have sustained theachieved improvements in the first 12 months. Diversified opioid treatment should be available so patients andphysicians can flexibly choose the best treatment at the time.Trial registration: Clinical Trial Registration: NCT00175357Keywords: Opioid dependency, Diacetylmorphine, Injectable, Oral methadone, Opioid maintenance treatment* Correspondence: eugenia@cheos.ubc.ca1Centre for Health Evaluation & Outcome Sciences, Providence Health Care,St. Paul’s Hospital, 575- 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada2School of Population and Public Health, University of British Columbia, 2206East Mall, Vancouver, BC V6T 1Z3, CanadaFull list of author information is available at the end of the article© 2014 Oviedo-Joekes et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of theCreative Commons Attribution License (, which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons PublicDomain Dedication waiver ( applies to the data made available in thisarticle, unless otherwise stated.Oviedo-Joekes et al. Substance Abuse Treatment, Prevention, and Policy 2014, 9:23 on heroin and other opioids is a chronic re-lapsing disease and continues to be a major public healthconcern. Individuals injecting street opioids are vulner-able to blood borne diseases, overdoses, premature deathand involvement in criminal activities to sustain theirdrug use [1-3]. Currently, the most widely used andstudied maintenance treatment for opioid dependency issubstitution with methadone [4]. Methadone mainten-ance treatment (MMT) is effective at reducing the aboveharms associated with illicit opioid use [5]. For those forwhom oral methadone is not effective, despite repeatedattempts in the past, studies in Europe and Canada havedemonstrated that medically supervised treatment withinjectable diacetylmorphine (DAM) is effective [6,7].Supervised injectable DAM is associated with increasedretention in addiction treatment and decreased use ofillicit substances, involvement in criminal activity andincarceration, and possibly reduced mortality [6,7]. Also,this treatment model provides an opportunity for indi-viduals using illicit opioids to connect and engage withthe addiction treatment system. Moreover, after startingtreatment with DAM, some patients may choose totransfer to MMT. European studies suggest that amongthose who stopped treatment with injectable diacetyl-morphine, approximately 30% per year transitioned toMMT [8,9]. The supervised model requires clinic visitstwo to three times per day, which has been suggested itcould affect individuals’ psychosocial functioning [10].Therefore, if clinically indicated and in consultation withthe patient, transitions to other forms of treatments, inparticular long acting oral opioids, might be a favourableoutcome. The present study sought to determine out-comes of participants receiving injectable DAM in aCanadian trial who voluntarily transitioned to oralmethadone during the study period compared to thosewhose treatment was discontinued as the study ended.MethodsStudy design, setting, participants and proceduresThe North American Opiate Medication Initiative (NAOMI)study was a phase III, open-label randomized controlledtrial that compared the effectiveness of injectable diacetyl-morphine to oral methadone for treatment-refractoryopioid-dependence. The study was conducted in Vancou-ver and Montreal, Canada, between March 2005 and July2008. Study results, methodology and patients’ profileshave been published elsewhere [11-13]. Inclusion criteriawere opioid dependence [14]; daily opioid injection; atleast 5 years of opioid use; a minimum age of 25; a mini-mum of two previous treatments for opioid dependenceincluding at least one attempt at MMT (in which 60 milli-grams or more of methadone was received daily for atleast 30 days within a 40 day period); and no enrolment inMMT within the prior 6 months. Participants were ran-domly assigned to receive oral methadone (n = 111),injectable diacetylmorphine (n = 115) or injectable hydro-morphone (n = 25) for a period of 12 months. At the endof the 12-month study treatment period, participants’ stillreceiving injectable medications had three months to tran-sition to other treatments available in the community(most likely oral methadone, as injectable medicationswere not available post-trial). All participants providedwritten informed consent. The trial received approval bythe ethics review boards in each study site.MeasuresResearch evaluations were conducted at a separate re-search office by a team not involved in participants' treat-ment. This analysis presents data from the EuropeanAddiction Severity Index (EuropASI) [15], MaudsleyAddiction Profile (MAP) [16] and EuroQol (EQ5D) [17],administered prior to randomization and at 12 and 24-months follow-up. A total of five participants withdrewtheir consent in the methadone group and one in the in-jectable diacetylmorphine group. The follow-up rates at 12(end of treatment) and 24-months were 95.6% and 82.9%,respectively. To be considered retained to treatment, aparticipant must have been abstinent of opioids or con-firmed to be receiving their study medication or any otheraddiction treatment during at least 10 of the 14 days priorto the 12-month assessment or 20 of the 30 days prior tothe 24-month assessment.Statistical analysesData from participants randomized to either injectablediacetylmorphine or hydromorphone were combined,based on similar outcomes during the active treatmentstudy period [18]. These participants were then dividedinto three groups: 1) ‘voluntary transition’ (n = 16) werethose who voluntarily stopped receiving injectable medica-tions and transitioned to oral methadone before the12 month time-point; 2) ‘involuntary transition’ (n = 95)were those who were still receiving injectables at 12 monthsbut were discontinued and offered other treatments be-cause their study period ended; and 3) ‘withdrawal/dropouts’ (n = 28) were those who dropped out or were discon-tinued from the injectable medications before 12 months(various reasons: e.g., attempted to divert the study medi-cations, violent behaviour, etc.). The primary outcomes forthe present analyses were days of illicit heroin use and re-tention to treatment at 12 and 24-months follow-up.Baseline characteristics were compared between thewithdrawal, involuntary and voluntary transition groupsusing analysis of variance for continuous variables andchi-square tests for categorical variables. At 12 and24-months follow-up, the overall mean differences forthe EuropASI, MAP and EQ5D scores were comparedOviedo-Joekes et al. Substance Abuse Treatment, Prevention, and Policy 2014, 9:23 Page 2 of 7 analysis of variance (F-test) and then pairwisecomparisons were done using t-test for variables withthe overall p-value of less than 0.05 in the analysis ofvariance. Multivariate regression models were also usedto analyse each of the primary outcomes at 12 and24- months for the voluntary and involuntary transitiongroups: 1) multivariate logistic regression models for re-tention; and 2) multivariate linear regression models fordays of illicit heroin use. All regression models adjustedfor baseline characteristics, including age, gender, ethni-city, chronic medical problems, years injecting drugs,prior 30 days of illicit heroin use, prior 30 days of illegalactivities, and EuropASI-family sub-scale score. Finally,we also included an intention to treat analysis of theprimary outcomes by the injectable and oral arms ofNAOMI. There were no missing data at 24-months forretention. A multiple imputation technique was used formissing data and the adjusted degrees of freedom wasused for inference [19]. Data were analyzed using SAS®(version 9.3) [20].FindingsTable 1 summarizes group characteristics at baseline.Compared to the involuntary transition group, therewere less women and Aboriginal participants in the vol-untary transition group. This group was also youngerand had been injecting drugs for fewer years. However,statistically significant differences between groups werenot observed for these variables, only for prior monthdays of illegal activities and the EuropASI Family sub-scale score reached statistical significance.Table 2 shows retention and illicit heroin use for the vol-untary and involuntary transition groups at 24 months. Ahigher proportion of voluntarily transitioning participantsTable 1 Baseline characteristics for each transition groupVariable at baseline Injectable DAM or HDM (N = 139)Withdraw/drop out (N = 28) Involuntary transition (N = 95) Voluntary transition (N = 16)Agea 39.7 ± 7.6 40.4 ± 7.9 37.6 ± 7.6Female 9 (32.1%) 37 (38.9%) 4 (25.0%)Aboriginal 9 (39.1%) 22 (29.3%) 1 (12.5%)Chronic medical problem 19 (67.9%) 51 (53.7%) 7 (43.8%)Previous MMT attempts 3.4 ± 1.7 3.1 ± 1.8 2.8 ± 1.0Injecting drugsa 16.7 ± 7.9 16.9 ± 10.2 14.9 ± 8.0Heroin use prior monthb 27.7 ± 5.2 26.3 ± 8.2 26.4 ± 7.0Cocaine use prior monthb 20.8 ± 11.7 15.3 ± 12.6 14.9 ± 12.0Illegal activities prior monthb, c 19.68 ± 11.43 14.60 ± 12.68 8.94 ± 11.66Injecting prior monthb 16.71 ± 7.88 16.91 ± 10.23 14.88 ± 8.02EuropASI-Drugd 0.57 ± 0.14 0.52 ± 0.14 0.55 ± 0.18EuropASI-Legald 0.45 ± 0.18 0.36 ± 0.26 0.27 ± 0.28EuropASI-Medicald 0.43 ± 0.33 0.34 ± 0.35 0.41 ± 0.35EuropASI-Econd 0.88 ± 0.29 0.92 ± 0.23 0.83 ± 0.32EuropASI-Job Satisfactiond 0.19 ± 0.26 0.26 ± 0.33 0.27 ± 0.34EuropASI-Familyd, e 0.11 ± 0.14 0.08 ± 0.19 0.22 ± 0.26EuropASI-Sociald 0.16 ± 0.22 0.10 ± 0.18 0.17 ± 0.23EuropASI-Psychiatricd 0.24 ± 0.19 0.19 ± 0.21 0.26 ± 0.25EQ5D (US weight)f 0.68 ± 0.21 0.72 ± 0.2 0.71 ± 0.22EQ5D (UK weight)g 0.56 ± 0.31 0.62 ± 0.31 0.61 ± 0.34MAP-Physicalh 17.64 ± 7.54 14.74 ± 7.35 15.44 ± 9.65MAP-Psychologicalh 15.5 ± 8.57 13.87 ± 7.78 14.81 ± 11.26Numbers are: Mean ± standard deviation or N (%).(a)Years.(b)Days.(c)Analysis of variance; F-test = 4.00, df = 2, 136, p-value = 0.021.(d)EuropASI (European version of the Addiction Severity Index); sub-scale scores range from 0 to 1; higher scores are indicative of more severe problems.(e)Analysis of variance; F-test = 3.73, df = 2, 136, p-value = 0.026.(f)EQ5D (Euroquol) US weights: Scores range from −0.11 to 1; higher scores are indicative of better health status.(g)EQ5D (Euroquol) UK weights: Scores range from −0.594 to 1; higher scores are indicative of better health status.(h)MAP (Maudsley Addiction Profile). Scores range from 0 to 40; higher scores are indicative of more symptoms.Oviedo-Joekes et al. Substance Abuse Treatment, Prevention, and Policy 2014, 9:23 Page 3 of 7 retained at 24-months compared to the involuntarygroup. Results from the multivariate logistic regressionmodel revealed that the voluntary transition group had5.55 (95% CI = 1.11, 27.81; Chi-square = 4.33, df = 1,p-value = 0.037) times the adjusted odds of retention at24-months compared to the involuntary transition group.Figure 1 illustrates the trajectory of illicit heroin useover the 24-month study period. All groups reducedtheir use of illicit heroin from baseline to 24-months.From Table 2 it is also evident that the mean prior30 days of illicit heroin use was higher for the involun-tary compared to the voluntary transition group at24-months. The voluntary transition group had anunadjusted mean difference of 8.06 (95% CI = −14.35,−1.76; t-value = −2.53, adjusted df = 104.1, p-value =0.013) days less of illicit heroin use in the prior 30 daysthan the involuntary transition group. The mean differ-ence in days of illicit heroin use between the voluntaryand involuntary transition groups at 24-months in theadjusted model was −5.58 days (95% CI = −11.62, 0.47;t-value = −1.83, df = 97.4, p-value = 0.07). Aside fromillicit heroin use and retention to treatment, the volun-tary and involuntary transition groups were similarin physical and psychological health and psychosocialTable 2 Retention and illicit heroin use for voluntary compared to involuntary transition groupsOutcome Voluntary groupa (n = 16) Involuntary groupa (n = 95) Voluntary vs Involuntary P ValueAdj. odds ratio (95% CI)Retention12 months 16 (100%) 95 (100%) - -24 monthsc 14 (87.5%) 53 (55.8%) 5.55 (1.11, 27.81) 0.037eAdj. mean difference (95% CI)Illicit heroin use12 monthsd 5.66 (1.35, 9.96) 2.68 (1.45, 3.92) 4.02 (0.31, 7.73) 0.034f24 monthsc 2.55 (0, 8.35) 10.61 (8.18, 13.04) −5.58 (−11.62, 0.47) 0.070g(a)Numbers are: Mean (95% Confidence Interval) or N (%).(b)Models adjusted for baseline characteristics: age, gender, ethnicity, chronic medical problem, years injecting drugs, days of heroin use, days of illegal activities,European addiction severity index - family sub-scale score.(c)Adjusted odds ratio from the logistic regression model; not tested at 12 months.(d)Adjusted mean difference from the linear regression model.(e)Wald chi-square test, chi-square value = 4.33, df = 1.(f)t-test, t-value = 2.16, adjusted degrees of freedom for multiple imputation = 76.6.(g)t-test, t-value = −1.83, adjusted degrees of freedom for multiple imputation = 97.4Figure 1 Days of illicit heroin use from baseline to 24-months follow-up for voluntary, involuntary and oral treatment groups.Oviedo-Joekes et al. Substance Abuse Treatment, Prevention, and Policy 2014, 9:23 Page 4 of 7 at 24-months. Although, at 12-months, the vol-untary transition group had a higher EuropASI- Socialfunctioning score compared to the involuntary transitiongroup (t-value = 2.14, adjusted df = 98.3, p-value = 0.034).Table 3 displays ITT analysis of retention and illicitheroin use by randomization arm at 12 and 24-months.At 24 months the oral and injectable groups did notstatistically differ in either retention or illicit heroinuse. Days of illicit heroin use in the injectable groupwas 9.78 mean days (95% CI = 7.71, 11.85) and for thoserandomized to oral methadone was 11.48 mean days (95%CI = 9.1, 13.87). Retention rates were 77 (55.4%) and 60(56.6%) for the injectable and oral group respectively.DiscussionThe present analysis indicates that among individualseligible for 12-months of treatment with injectable di-acetylmorphine or hydromorphone in a clinical trial, asmall sub-group of participants voluntarily transitionedfrom injection medication to oral methadone during thestudy. At the 24-month follow-up evaluation, these par-ticipants had higher retention to addiction treatmentand fewer days of illicit heroin use in the prior 30 days,when compared to participants whose injection treat-ment was discontinued at 12-months due to the end ofthe clinical trial.In NAOMI, the 12-month treatment endpoint was notmandated clinically but was due to the finite nature ofthe clinical trial. Individuals in NAOMI had an averageof 16 years of prior heroin use, a history of MMTattempts and no MMT in the 6-months prior studyinclusion, thus it is not surprising that the majorityrandomized to injectable medications remained on thistreatment for the allocated treatment and transitionperiod. It is noteworthy that a group of participants vol-untarily transitioned to methadone, which they hadpreviously rejected. It could be suggested that treatmentwith injectable diacetylmorphine provided them with anopportunity to stabilize and the participants opted totransition to oral methadone.NAOMI was the only clinical trial with injectable di-acetylmorphine that was unable to provide this treat-ment beyond the 12 month period due to logistical,financial and political reasons [12,21]. Despite differ-ences in design and policies in place among studies, it isnoteworthy that among those who discontinued treat-ment with diacetylmorphine in NAOMI (n = 44), volun-tary transition rates to other treatments (primarily oralmethadone) is similar to other contexts. For example, inthe German study, among those who discontinued treat-ment, 36% of participants receiving treatment with di-acetylmorphine voluntarily switched to other treatments,27% to oral methadone and 9% to abstinence orientedtreatment [8]. In the Swiss program, 2005 to 2010 yearlytransition rates to oral methadone, as a reason to leavethe program, have ranged from 35% to more than 45%among those discontinuing injectable diacetylmorphine[9]. The Swiss transition rates to other treatments de-scribed above do not account for those who were with-drawn or dropped out from diacetylmorphine treatmentfor other reasons (e.g., due to behavioral issues or mov-ing away) and started MMT.The involuntary transition group, despite adjusting forbaseline differences and being retained for the 12-monthtreatment period, experienced an increase in their illicitheroin use at 24-months. Moreover, intention to treatanalysis showed that although at 12 months the inject-able arm had significantly higher retention and less illicitheroin use than the oral arm, at 24 months this differ-ence disappeared. This evidence suggests that with con-tinued provision of injectable medications, participantscould have sustained the achieved positive outcomes andTable 3 Retention and illicit heroin use by randomization armOutcome Injectablec (n = 139) Oral c (n = 106) Injectable vs Oral P ValueRelative risk (95% CI)Retentiona12 months 123 (88.5%) 60 (56.6%) 1.56 (1.31, 1.87) <0.0001d24 months 77 (55.4%) 60 (56.6%) 0.98 (0.78, 1.22) 0.851eMean difference (95% CI)Illicit heroin useb12 months 5.23 (3.43, 7.04) 11.99 (9.91, 14.07) −6.76 (−9.49, −4.02) <0.0001f24 months 9.78 (7.71, 11.85) 11.48 (9.1, 13.87) −1.7 (−4.87, 1.47) 0.291gAll analysis are intention to treat.(a)No missing data.(b)With multiple imputation.(c)Numbers are: Mean (95% Confidence Interval) or N (%).(d)Chi-square test (chi-square value = 32.25, df = 1).(e)Chi-square test (chi-square value = 0.04, df = 1).(f)t-test, t-value = −4.87, adjusted degrees of freedom for multiple imputation = 240.6.(g)t-test, t-value = −1.06, adjusted degrees of freedom for multiple imputation = 159.3.Oviedo-Joekes et al. Substance Abuse Treatment, Prevention, and Policy 2014, 9:23 Page 5 of 7 voluntarily transition to transition to MMT, othertreatments or abstinence. The German study, for ex-ample, found that some psychosocial outcomes might takeas long as 4 years of treatment with injectable diacetyl-morphine before reaching marked improvements [22].Limitations of the NAOMI trial have been discussedelsewhere [11,12]. NAOMI was not designed to deter-mine the outcomes of participants voluntarily transition-ing to oral methadone; thus, the small sample sizes ofthe voluntary and involuntary transition groups impactsthe statistical power of the present analysis and its con-clusions. Motivating factors for transitioning from inject-able treatments were not part of questionnaire data.Although, a qualitative sub-study [23] conducted withparticipants in both arms found that participants receiv-ing injectable treatments were disappointed with thestudy ending. These participants discussed that the 12-month period was sufficient to experience many initialbenefits but not long enough for those benefits to befully sustained. Nevertheless, this study allows us to ex-plore outcomes of those who voluntarily transitioned tooral MMT in the context of the Canadian trial.These studies and our data underline the critical import-ance of patient-centered decision making. If injectabletreatments were continued beyond the end of the study,some participants may have sustained the achieved im-provements and some voluntarily transitioned to other al-ternatives in time. To be able to provide patient-centeredcare, an addiction treatment system should offer diversi-fied opioid options for substitution treatment that wouldgrant patients and doctors to choose the most effectivetreatment at a given time, case by case.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsEOJ made substantial contributions to analysis, interpretation and leadpreparation of manuscript; DG carried out analysis; KL made contributionsto the acquisition of NAOMI data and drafting of the manuscript; KMwas involved in revising the manuscript critically; DCM, SB, AA and MTSmade substantial contributions to NAOMI’s conception and design andinterpretation of the present data. All authors read and approved the finalmanuscript and agree to be accountable to the integrity of the work.AcknowledgementsThe NAOMI trial was funded through an operating grant from the CanadianInstitutes of Health Research with additional support from the CanadaFoundation for Innovation, the Canada Research Chairs Program, theUniversity of British Columbia, Providence Health Care, the University ofMontreal, Centre de Recherche et Aide aux Narcomanes, the Government ofQuebec, Vancouver Coastal Health Authority and the BC Centre for DiseaseControl. Dr. Oviedo-Joekes is also funded by the Michael Smith Foundationfor Health Research and the Canadian Institutes of Health Research. Theauthors wish to acknowledge the dedication of N. Laliberté, C. Gartry, K.Sayers, P-A Guevremont, P. Schneeberger, J. Chettiar, J. Lawlor, P. Pelletier,S. Maynard, M-I Turgeon, G. Brunelle, A. Chan, S. MacDonald, T. Corneil, J.Geller, S. Jutha, S. Chai, M. Piaseczny, S. Sizto, and the many remaining staffand members of the DSMB (A. Marlatt, N. El-Guebaly, J. Raboud, D. Roy).Most importantly, the authors wish to acknowledge and thank the NAOMItrial participants.Author details1Centre for Health Evaluation & Outcome Sciences, Providence Health Care,St. Paul’s Hospital, 575- 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada.2School of Population and Public Health, University of British Columbia, 2206East Mall, Vancouver, BC V6T 1Z3, Canada. 3Centre Hospitalier de l’Universitéde Montréal, Hôpital Saint-Luc, CHUM Montréal, Montréal, QC H2X 3 J4,Canada. 4Centre for Addiction Research BC, University of Victoria, 2300McKenzie Ave, Victoria, BC V8P 5C2, Canada. 5Northern Ontario School ofMedicine, 955 Oliver Road, Thunder Bay, ON P7B 5E1, Canada.Received: 26 March 2014 Accepted: 3 June 2014Published: 8 June 2014References1. 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Gartry CC, Oviedo-Joekes E, Laliberte N, Schechter MT: NAOMI: the trialsand tribulations of implementing a heroin assisted treatment study inNorth America. Harm Reduct J 2009, 6:2.22. Verthein U, Schafer I, Degkwitz P: Social integration after 4 years ofheroin-assisted treatment. Rehabilitation (Stuttg) 2013, 52:243–250.23. Trujols J, Iraurgi I, Oviedo-Joekes E, Guardia G: A critical analysis of usersatisfaction surveys in addiction services: opioid maintenance treatmentas a representative case study. Patient Prefer Adherence 2014.doi:10.1186/1747-597X-9-23Cite this article as: Oviedo-Joekes et al.: Differential long-term outcomesfor voluntary and involuntary transition from injection to oral opioidmaintenance treatment. Substance Abuse Treatment, Prevention, and Policy2014 9:23.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at et al. Substance Abuse Treatment, Prevention, and Policy 2014, 9:23 Page 7 of 7


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