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1.  Cost utility analysis of co-prescribed heroin compared with methadone maintenance treatment in heroin addicts in two randomised trials 
BMJ : British Medical Journal  2005;330(7503):1297.
Objective To determine the cost utility of medical co-prescription of heroin compared with methadone maintenance treatment for chronic, treatment resistant heroin addicts.
Design Cost utility analysis of two pooled open label randomised controlled trials.
Setting Methadone maintenance programmes in six cities in the Netherlands.
Participants 430 heroin addicts.
Interventions Inhalable or injectable heroin prescribed over 12 months. Methadone (maximum 150 mg a day) plus heroin (maximum 1000 mg a day) compared with methadone alone (maximum 150 mg a day). Psychosocial treatment was offered throughout.
Main outcome measures One year costs estimated from a societal perspective. Quality adjusted life years (QALYs) based on responses to the EuroQol EQ-5D at baseline and during the treatment period.
Results Co-prescription of heroin was associated with 0.058 more QALYs per patient per year (95% confidence interval 0.016 to 0.099) and a mean saving of €12 793 (£8793, $16 122) (€1083 to €25 229) per patient per year. The higher programme costs (€16 222; lower 95% confidence limit €15 084) were compensated for by lower costs of law enforcement (- €4129; upper 95% confidence limit - €486) and damage to victims of crime (- €25 374; upper 95% confidence limit - €16 625). The results were robust for the use of national EQ-5D tariffs and for the exclusion of the initial implementation costs of heroin treatment. Completion of treatment is essential; having participated in any abstinence treatment in the past is not.
Conclusions Co-prescription of heroin is cost effective compared with treatment with methadone alone for chronic, treatment resistant heroin addicts.
PMCID: PMC558200  PMID: 15933353
2.  Randomised trial of heroin maintenance programme for addicts who fail in conventional drug treatments 
BMJ : British Medical Journal  1998;317(7150):13-18.
Objective: To evaluate an experimental heroin maintenance programme.
Design: Randomised trial.
Setting: Outpatient clinic in Geneva, Switzerland.
Subjects: Heroin addicts recruited from the community who were socially marginalised and in poor health and had failed in at least two previous drug treatments.
Intervention: Patients in the experimental programme (n=27) received intravenous heroin and other health and psychosocial services. Control patients (n=24) received any other conventional drug treatment (usually methadone maintenance).
Main outcome measures: Self reported drug use, health status (SF-36), and social functioning.
Results: 25 experimental patients completed 6 months in the programme, receiving a median of 480 mg of heroin daily. One experimental subject and 10 control subjects still used street heroin daily at follow up (difference 44%; 95% confidence interval 16% to 71%). Health status scores that improved significantly more in experimental subjects were mental health (0.58 SD; 0.07 to 1.10), role limitations due to emotional problems (0.95 SD; 0.11 to 1.79), and social functioning (0.65 SD; 0.03 to 1.26). Experimental subjects also significantly reduced their illegal income and drug expenses and committed fewer drug and property related offences. There were no benefits in terms of work, housing situation, somatic health status, and use of other drugs. Unexpectedly, only nine (38%) control subjects entered the heroin maintenance programme at follow up.
Conclusions: A heroin maintenance programme is a feasible and clinically effective treatment for heroin users who fail in conventional drug treatment programmes. Even in this population, however, another attempt at methadone maintenance may be successful and help the patient to stop using injectable opioids.
Key messages A heroin maintenance programme may be a useful treatment option for patients who do not succeed in conventional drug treatment programmes Patients randomly allocated to the Geneva heroin maintenance programme fared better that patients in conventional drug treatments in terms of street drug use, mental health, social functioning, and illegal activities Results of the trial apply only to a subgroup of severely addicted people who failed repeatedly in conventional drug treatments This evaluation does not distinguish between the effects of heroin itself and the effects of other medical and psychosocial services that were provided as part of the programme There was less demand for the heroin maintenance programme than anticipated and most control subjects declined entry into the programme at the end of the study
PMCID: PMC28595  PMID: 9651260
3.  Heroin and cocaine co-use in a group of injection drug users in Montréal 
To describe the pattern of co-use of heroin and cocaine in individuals who were not receiving methadone maintenance treatment.
Structured interviews.
Community hospital.
Individuals (n = 1111) selected from a cohort of out-of-treatment injection drug users in Montréal, Que.
Outcome measure
Frequency (injections per day) and quantity (number of days of use) of heroin, cocaine and speedball (the simultaneous administration of heroin and cocaine) use reported in the month preceding the interview.
About 50% of the sample reported using only cocaine intravenously (C group), about 8% reported using only heroin (H group) intravenously and about 15% reported using both heroin and cocaine (HC group) intravenously. Reported cocaine consumption was similar in the HC and C groups. Heroin was used on fewer days by the HC than by the H group, but the number of injections per day was similar. Speedball use, which was quantified independently from heroin and cocaine use, was reported almost exclusively by the HC group, and speedball was used less often than either heroin or cocaine alone. Finally, a similar proportion of individuals in the C and the HC groups consumed alcohol in the 24 hours preceding the interview, but a larger proportion of individuals in the HC group reported the use of marijuana.
In a cohort of injection drug users in Montréal, cocaine was the most prevalent illicit drug. Furthermore, about 70% of the heroin users also injected cocaine, but not in the form of speedball. Thus, the sequential co-use of heroin and cocaine is highly prevalent in Montréal and deserves particular clinical attention.
PMCID: PMC305269  PMID: 14719049
cocaine; heroin; substance abuse, intravenous
4.  The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) Prisons Project Study: protocol for a randomised controlled trial comparing methadone and buprenorphine for opiate detoxification 
Trials  2009;10:53.
In the United Kingdom (UK), there is an extensive market for the class 'A' drug heroin and many heroin users spend time in prison. People addicted to heroin often require prescribed medication when attempting to cease their drug use. The most commonly used detoxification agents in UK prisons are currently buprenorphine and methadone, both are recommended by national clinical guidelines. However, these agents have never been compared for opiate detoxification in the prison estate and there is a general paucity of research evaluating the most effective treatment for opiate detoxification in prisons. This study seeks to address this paucity by evaluating the most routinely used interventions amongst drug users within UK prisons.
This study uses randomised controlled trial methodology to compare the open use of buprenorphine and methadone for opiate detoxification, given in the context of routine care, within three UK prisons. Prisoners who are eligible and give informed consent will be entered into the trial. The primary outcome will be abstinence status eight days after detoxification, as determined by a urine test. Secondary outcomes will be recorded during the detoxification and then at one, three and six months post-detoxification.
Trial registration
Current Controlled Trials ISRCTN58823759
PMCID: PMC2715402  PMID: 19602218
5.  Randomized Trial of Standard Methadone Treatment Compared to Initiating Methadone without Counseling: 12-month Findings 
Addiction (Abingdon, England)  2012;107(5):943-952.
This study aimed to determine the relative effectiveness of 12-months of Interim Methadone (IM; supervised methadone with emergency counseling only for the first 4 months of treatment), Standard Methadone treatment (SM; with routine counseling) and Restored Methadone treatment (RM: routine counseling with smaller caseloads).
A randomized controlled trial was conducted comparing: IM, SM, and RM treatment. IM lasted for 4 months after which participants were transferred to SM.
The study was conducted in two methadone treatment programs in Baltimore, MD, USA.
The study included 230 adult methadone patients newly-admitted through waiting lists.
We administered the Addiction Severity Index and a supplemental questionnaire at baseline, 4-, and 12-months post- baseline.
Measurements included retention in treatment, self-reported days of heroin and cocaine use, criminal behavior and arrests, and urine tests for heroin and cocaine metabolites.
At 12 months, on an intent-to-treat basis, there were no significant differences in retention in treatment among the IM, SM and RM groups (60.6%, 54.8% and 37.8%, respectively). Positive urine tests for the three groups declined significantly from baseline (ps<0.001 and 0.003, for heroin and cocaine metabolistes respectively) but there were no significant Group x Time interactions for these measures. Thirty-one percent of the sample reported at least one arrest during the year, but there were no significant between-group effects.
Limited availability of drug counseling services should not be a barrier to providing supervised methadone to adults dependent on heroin - at least for the first 4 months of treatment.
PMCID: PMC3319854  PMID: 22029398
Interim methadone; methadone treatment; counseling; heroin addiction treatment
6.  Heroin Dependence Treatment in Malaysia: A randomized, double-blind placebo-controlled comparison of buprenorphine and naltrexone maintenance treatment 
Lancet  2008;371(9631):2192-2200.
Expanding access to effective treatments for heroin dependence is a global health priority that will also reduce HIV transmission. This study compares the efficacy for maintaining heroin abstinence, preventing relapse, and reducing HIV risk behaviors of three common treatments: detoxification followed by drug counseling only or drug counseling combined with opioid antagonist (naltrexone) or agonist (buprenorphine) maintenance treatment.
126 detoxified heroin dependent patients in Malaysia were randomly assigned to 24 weeks of medication maintenance with naltrexone, buprenorphine, or placebo, provided double-blind and double-dummy. All patients received manual-guided drug counseling. Primary outcomes, assessed by three times per week urine testing, were days to first heroin use, days to heroin relapse (3 consecutive opioid-positive urine tests), maximum consecutive days heroin abstinence, and, assessed by self-report at baseline, 3- and 6-months, reductions in HIV risk behaviors. The study was terminated after 22 months of enrolment, based on findings of superior buprenorphine efficacy in an interim safety analysis and the recommendation of the Data and Safety Monitoring Board. This study is registered with, with the number NCT00383045.
We observed consistent, significant linear contrasts in days to first heroin use (p<0.001), days to heroin relapse (p<0.001), maximum consecutive days heroin abstinence (p<0.01), and retention (p<0.001), with all results best for buprenorphine, intermediate for naltrexone, and worst for placebo. Buprenorphine was associated with significantly greater time to first heroin use and retention compared to naltrexone (p<0.01 for both measures) or placebo (p<0.001 for both measures) and also significantly greater time to heroin relapse (p<0.01) and maximum consecutive weeks abstinent (p<0.01) compared to placebo. There were no significant differences between naltrexone and placebo on these measures. HIV risk behaviors were significantly reduced from baseline across all 3 treatments (p<0.001), but the reductions did not differ significantly among the 3 treatments.
The effectiveness of buprenorphine for maintaining prolonged periods of abstinence, delaying the time to resumption of heroin use or relapse, and retaining patients in treatment supports widespread dissemination of opioid agonist maintenance treatment.
PMCID: PMC4041792  PMID: 18586174
Heroin Dependence; Buprenorphine; Naltrexone; Randomized Clinical Trial; HIV/AIDS
7.  The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) prisons project pilot study: protocol for a randomised controlled trial comparing dihydrocodeine and buprenorphine for opiate detoxification 
Trials  2007;8:1.
In the United Kingdom (UK), there is an extensive market for the class 'A' drug heroin. Many heroin users spend time in prison. People addicted to heroin often require prescribed medication when attempting to cease their drug use. The most commonly used detoxification agents in UK prisons are buprenorphine, dihydrocodeine and methadone. However, national guidelines do not state a detoxification drug of choice. Indeed, there is a paucity of research evaluating the most effective treatment for opiate detoxification in prisons. This study seeks to address the paucity by evaluating routinely used interventions amongst drug using prisoners within UK prisons.
The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) Prisons Pilot Study will use randomised controlled trial methodology to compare the open use of buprenorphine and dihydrocodeine for opiate detoxification, given in the context of routine care, within HMP Leeds. Prisoners who are eligible and give informed consent will be entered into the trial. The primary outcome measure will be abstinence status at five days post detoxification, as determined by a urine test. Secondary outcomes during the detoxification and then at one, three and six months post detoxification will be recorded.
PMCID: PMC1780064  PMID: 17210080
8.  When higher doses in opioid replacement treatment are still inadequate – association to multidimensional illness severity: a cohort study 
Opioid replacement treatment (ORT) with methadone is regarded as gold standard in the treatment of opioid addiction. Treatment doses of 60 mg methadone per day and above are associated with better treatment retention and reduction in the use of heroin and cocaine. However, an absolute dose level cannot function as parameter for adequate dosing. This study aims to determine dose adequacy in a sample of patients on stable methadone treatment, and to relate dose adequacy to disease severity.
This study was designed as open prospective cohort study over 12 months, with baseline data reported here. Patients on stable substitution treatment with methadone (Eptadone®) were consecutively included. Medical and socio-demographic data were gathered and the instruments Opiate Dosage Adequacy Scale (ODAS), European Addiction Severity Index (EuropASI) and the Derogatis Interview for Sexual Functioning – Self Report (DISF-SR) were applied.
Five hundred and sixteen subjects, who received on average 60.3 (±30.4) mg methadone per day, were included. According to ODAS, 40.6% suffered from an inadequate dosing, and 59.4% had an adequate dose. Patients with an adequate dose received on average 57.8 (±27.5) mg methadone per day, whilst patients with an inadequate dose received on average 70.6 (±33.0) mg per day. The frequencies of patients with methadone doses of less than 60 mg per were 45.4% in the inadequate and 60.6% in the adequate group. The inadequate group suffered from a statistically significant higher burden of addiction related problems in all EuropASI domains. Sexual functioning did not differ by adequacy group, but women suffered from more pronounced sexual dysfunction as compared to men.
A high frequency of inadequate dosing was found in this sample of patients on ORT. Higher disease severity should alert for possible need of even higher methadone doses. The tendency to low methadone doses warrants further research in the treatment system. Higher methadone doses are not related to increased sexual dysfunction. Sexual dysfunction, especially in women, should be considered in treatment.
PMCID: PMC3975916  PMID: 24581310
Opiate dependence; Substitution treatment; Dose adequacy; Illness severity; Sexual functioning
9.  Pilot Trial of a Recovery Management Intervention for Heroin Addicts Released from Compulsory Rehabilitation in China 
China faces the challenge of dual epidemics of drug use and HIV/AIDS. Despite the high relapse rate among heroin addicts released from compulsory rehabilitation facilities, there are few programs available in China to assist these addicts in the community. We pilot-tested in China a Recovery Management Intervention (RMI) program designed to facilitate early detection of relapse and prompt linkage from compulsory rehabilitation to the community and, if participants relapse, to community-based methadone maintenance treatment (MMT) programs. One hundred heroin addicts were randomly assigned to either the Standard Care group (n=50) or the RMI group (n=50). At the end of the 3-month trial, participants in the RMI group, relative to the standard care group, demonstrated positive outcomes in recidivism due to relapse (0 vs. 6%, p=0.08; d=0.354), MMT participation (8% vs. 0, p=0.6; d=0.417), and employment (33% vs. 2%, p<.001; d=0.876), although no difference was found in urine testing results (8.5% vs. 8.7%; d=0.013) among interviewed participants. These pilot study results were based on a small sample size and short-term observation, suggesting the need for more research to further improve and test RMI effectiveness with larger samples over a longer period of time in order to provide evidence in support of RMI as an effective strategy for community reintegration among addicts released from rehabilitation facilities in China.
PMCID: PMC3404204  PMID: 22520276
Recovery management; compulsory rehabilitation; China
10.  A Randomized Clinical Trial of Methadone Maintenance for Prisoners: Results at One-Month Post- Release 
Drug and alcohol dependence  2007;91(2-3):220-227.
Despite its effectiveness, methadone maintenance is rarely provided in American correctional facilities. This study is the first randomized clinical trial in the US to examine the effectiveness of methadone maintenance treatment provided to prisoners with pre-incarceration heroin addiction.
A three-group randomized controlled trial was conducted between September 2003 and June 2005. Two hundred-eleven Baltimore pre-release inmates who were heroin dependent during the year prior to incarceration were enrolled in this study. Participants were randomly assigned to the following: Counseling Only: counseling in prison, with passive referral to treatment upon release (n = 70); Counseling + Transfer: counseling in prison with transfer to methadone maintenance treatment upon release (n = 70); and Counseling + Methadone: methadone maintenance and counseling in prison, continued in a community-based methadone maintenance program upon release (n = 71).
Two hundred participants were located for follow-up interviews and included in the current analysis. The percentages of participants in each condition that entered community-based treatment were, respectively, Counseling Only 7.8%, Counseling + Transfer 50.0%, and Counseling + Methadone 68.6%, p < .05. All pairwise comparisons were statistically significant, (all ps < .05). The percentage of participants in each condition that tested positive for opioids at one month post-release were, respectively, Counseling Only 62.9%, Counseling + Transfer 41.0%, and Counseling + Methadone 27.6%, p < .05, with the Counseling Only group significantly more likely to test positive than the Counseling + Methadone group.
Methadone maintenance initiated prior to or immediately after release from prison appears to have beneficial short-term impact on community treatment entry and heroin use. This intervention may be able to fill an urgent treatment need for prisoners with heroin addiction histories.
PMCID: PMC2423344  PMID: 17628351
methadone maintenance; drug abuse treatment; prisoners; heroin addiction
11.  Referring heroin users from compulsory detoxification centers to community methadone maintenance treatment: a comparison of three models 
BMC Public Health  2013;13:747.
Both compulsory detoxification treatment and community-based methadone maintenance treatment (MMT) exist for heroin addicts in China. We aim to examine the effectiveness of three intervention models for referring heroin addicts released from compulsory detoxification centers to community methadone maintenance treatment (MMT) clinics in Dehong prefecture, Yunnan province, China.
Using a quasi-experimental study design, three different referral models were assigned to four detoxification centers. Heroin addicts were enrolled based on their fulfillment to eligibility criteria and provision of informed consent. Two months prior to their release, information on demographic characteristics, history of heroin use, and prior participation in intervention programs was collected via a survey, and blood samples were obtained for HIV testing. All subjects were followed for six months after release from detoxification centers. Multi-level logistic regression analysis was used to examine factors predicting successful referrals to MMT clinics.
Of the 226 participants who were released and followed, 9.7% were successfully referred to MMT(16.2% of HIV-positive participants and 7.0% of HIV-negative participants). A higher proportion of successful referrals was observed among participants who received both referral cards and MMT treatment while still in detoxification centers (25.8%) as compared to those who received both referral cards and police-assisted MMT enrollment (5.4%) and those who received referral cards only (0%). Furthermore, those who received referral cards and MMT treatment while still in detoxification had increased odds of successful referral to an MMT clinic (adjusted OR = 1.2, CI = 1.1-1.3). Having participated in an MMT program prior to detention (OR = 1.5, CI = 1.3-1.6) was the only baseline covariate associated with increased odds of successful referral.
Findings suggest that providing MMT within detoxification centers promotes successful referral of heroin addicts to community-based MMT upon their release.
PMCID: PMC3844356  PMID: 23938171
Heroin addiction; Detoxification; Methadone maintenance treatment; HIV; China
12.  A randomized clinical trial of methadone maintenance for prisoners: findings at 6 months post-release 
Addiction (Abingdon, England)  2008;103(8):1333-1342.
This study examined the effectiveness of methadone maintenance initiated prior to or just after release from prison at 6 months post-release.
A three-group randomized controlled trial was conducted between September 2003 and June 2005.
A Baltimore pre-release prison.
Two hundred and eleven adult pre-release inmates who were heroin-dependent during the year prior to incarceration.
Participants were assigned randomly to the following: counseling only: counseling in prison, with passive referral to treatment upon release (n = 70); counseling + transfer: counseling in prison with transfer to methadone maintenance treatment upon release (n = 70); and counseling + methadone: methadone maintenance and counseling in prison, continued in a community-based methadone maintenance program upon release (n = 71).
Addiction Severity Index at study entry and follow-up. Additional assessments at 6 months post-release were treatment record review; urine drug testing for opioids, cocaine and other illicit drugs.
Counseling + methadone participants were significantly more likely than both counseling only and counseling + transfer participants to be retained in drug abuse treatment (P = 0.0001) and significantly less likely to have an opioid-positive urine specimen compared to counseling only participants (P = 0.002). Furthermore, counseling + methadone participants reported significantly fewer days of involvement in self-reported heroin use and criminal activity than counseling only participants.
Methadone maintenance, initiated prior to or immediately after release from prison, increases treatment entry and reduces heroin use at 6 months post-release compared to counseling only. This intervention may be able to fill an urgent treatment need for prisoners with heroin addiction histories.
PMCID: PMC2582162  PMID: 18855822
Heroin addiction; methadone maintenance; prisoners; randomized clinical trial; substance abuse treatment
13.  Nerve growth factor beta polypeptide (NGFB) genetic variability: association with the methadone dose required for effective maintenance treatment 
The Pharmacogenomics Journal  2011;12(4):319-327.
Opioid addiction is a chronic disease with high genetic contribution and a large inter-individual variability in therapeutic response. The goal of this study was to identify pharmacodynamic factors that modulate methadone dose requirement. The neurotrophin family is involved in neural plasticity, learning memory and behavior and deregulated neural plasticity may underlie the pathophysiology of drug addiction. BDNF was shown to affect the response to methadone maintenance treatment. This study explores the effects of polymorphisms in the nerve growth factor (beta polypeptide) gene, NGFB, on the methadone doses required for successful maintenance treatment for heroin addiction. Genotypes of 14 NGFB polymorphisms were analyzed for association with the stabilizing methadone dose in 72 former severe heroin addicts with no major co-medications. There was significant difference in methadone doses required by subjects with different genotypes of the NGFB intronic SNP rs2239622 (P = 0.0002). These results may have clinical importance.
PMCID: PMC3130093  PMID: 21358750
methadone; opioid addiction; nerve growth factor; NGFB; heroin addiction
14.  Policy Progress for Physician Treatment of Opiate Addiction 
Medical treatment of heroin addiction with methadone and other pharmacotherapies has important benefits for individuals and society. However, regulatory policies have separated this treatment from the medical care system, limiting access to care and contributing to the social stigma of even effective addiction pharmacotherapy. Increasing problems caused by heroin addiction have added urgency to the search for policies and programs that improve the access to and quality of opiate addiction treatment. Recent initiatives aiming to reintegrate methadone maintenance and other addiction pharmacotherapies into medical practice may promote both expanded treatment capacity and increased physician expertise in addiction medicine. These initiatives include changes in federal oversight of the opiate addiction treatment system, the approval of physician office–based methadone maintenance programs for stabilized patients, and federal legislation that could enable physicians to treat opiate addiction with new medications in regular medical practice.
PMCID: PMC1495048  PMID: 12047733
methadone; heroin addiction
15.  Does Cannabis Use Predict Poor Outcome for Heroin-Dependent Patients on Maintenance Treatment? A Review of Past Findings, and More Evidence Against 
Addiction (Abingdon, England)  2003;98(3):269-279.
To determine whether cannabinoid-positive urine specimens in heroin-dependent outpatients predict other drug use or impairments in psychosocial functioning, and whether such outcomes are better predicted by cannabis-use disorders than by cannabis use itself.
Retrospective analyses of three clinical trials; each included a behavioral intervention (contingency management) for cocaine or heroin use during methadone maintenance. Trials lasted 25–29 weeks; follow-up evaluations occurred 3, 6, and 12 months posttreatment. For the present analyses, data were pooled across trials where appropriate.
Urban outpatient methadone clinic.
408 polydrug abusers meeting methadone-maintenance criteria.
Participants were categorized as nonusers, occasional users, or frequent users of cannabis based on thrice-weekly qualitative urinalyses. Cannabis-use disorders were assessed with the Diagnostic Interview Schedule III-R. Outcome measures included proportion of cocaine- and opiate-positive urines and the Addiction Severity Index (at intake and follow-ups).
Cannabis use was not associated with retention, use of cocaine or heroin, or any other outcome measure during or after treatment. Our analyses had a power of .95 to detect an r2 of .11 between cannabis use and heroin or cocaine use; the r2 we detected was less than .03 and nonsignificant. A previous finding that cannabis use predicted lapse to heroin use in heroin-abstinent patients did not replicate in our sample. However, cannabis-use disorders were weakly associated with psychosocial problems at posttreatment follow-up.
Cannabinoid-positive urines need not be a major focus of clinical attention during treatment for opiate dependence, unless patients report symptoms of cannabis-use disorders.
PMCID: PMC2943839  PMID: 12603227
cannabis; methadone maintenance; treatment outcome
16.  Levo-α-acetylmethadol (LAAM) induced QTc-prolongation - results from a controlled clinical trial 
Due to potential proarrhythmic side-effects levo-α-Acetylmethadol (LAAM) is currently not available in EU countries as maintenance drug in the treatment of opiate addiction. However, recent studies and meta-analyses underline the clinical advantages of LAAM with respect to the reduction of heroin use. Thus a reappraisal of LAAM has been demanded. The aim of the present study was to evaluate the relative impact of LAAM on QTc-interval, as a measure of pro-arrhythmic risk, in comparison to methadone, the current standard in substitution therapy.
ECG recordings were analysed within a randomized, controlled clinical trial evaluating the efficacy and tolerability of maintenance treatment with LAAM compared with racemic methadone. Recordings were done at two points: 1) during a run-in period with all patients on methadone and 2) 24 weeks after randomisation into methadone or LAAM treatment group. These ECG recordings were analysed with respect to QTc-values and QTc-dispersion. Mean values as well as individual changes compared to baseline parameters were evaluated. QTc-intervals were classified according to CPMP-guidelines.
Complete ECG data sets could be obtained in 53 patients (31 LAAM-group, 22 methadone-group). No clinical cardiac complications were observed in either group. After 24 weeks, patients receiving LAAM showed a significant increase in QTc-interval (0.409 s ± 0.022 s versus 0.418 s ± 0.028 s, p = 0.046), whereas no significant changes could be observed in patients remaining on methadone. There was no statistically significant change in QTc-dispersion in either group. More patients with borderline prolonged and prolonged QTc-intervals were observed in the LAAM than in the methadone treatment group (n = 7 vs. n = 1; p = 0.1).
In this controlled trial LAAM induced QTc-prolongation in a higher degree than methadone. Given reports of severe arrhythmic events, careful ECG-monitoring is recommended under LAAM medication.
PMCID: PMC3352205  PMID: 19258204
LAAM; methadone; opiate addiction; cardiac arrhythmia; QTc-interval
17.  Differential long-term outcomes for voluntary and involuntary transition from injection to oral opioid maintenance treatment 
The most widely used maintenance treatment for opioid dependency is substitution with long-acting oral opioids. Treatment with injectable diacetylmorphine provides an opportunity for patients to stabilize and possibly transition to oral treatment, if clinically indicated. The aim of this study was to explore outcomes of individuals that received injectable diacetylmorphine and voluntarily transitioned to oral methadone.
Design and methods
The North American Opiate Medication Initiative was a randomized controlled trial that compared the effectiveness of injectable diacetylmorphine (or hydromorphone) to oral methadone for long-term opioid-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 injectable treatments, a sub-group voluntarily chose to transition to oral methadone (n = 16) during the treatment period. Illicit heroin use and treatment retention were assessed at 24-months for those voluntarily and involuntarily transitioning (n = 95) to oral methadone.
At 24-months, the group that voluntarily transitioned to oral methadone had higher odds of treatment retention (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 heroin use 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).
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 had continued offering treatment with diacetylmorphine, those retained to injectable medication may have sustained the achieved improvements in the first 12 months. Diversified opioid treatment should be available so patients and physicians can flexibly choose the best treatment at the time.
Trial registration
Clinical Trial Registration: NCT00175357
PMCID: PMC4064505  PMID: 24908387
Opioid dependency; Diacetylmorphine, Injectable; Oral methadone; Opioid maintenance treatment
18.  Efficacy of prescribed injectable diacetylmorphine in the Andalusian trial: Bayesian analysis of responders and non-responders according to a multi domain outcome index 
Trials  2009;10:70.
The objective of this research was to evaluate data from a randomized clinical trial that tested injectable diacetylmorphine (DAM) and oral methadone (MMT) for substitution treatment, using a multi-domain dichotomous index, with a Bayesian approach.
Sixty two long-term, socially-excluded heroin injectors, not benefiting from available treatments were randomized to receive either DAM or MMT for 9 months in Granada, Spain. Completers were 44 and data at the end of the study period was obtained for 50. Participants were determined to be responders or non responders using a multi-domain outcome index accounting for their physical and mental health and psychosocial integration, used in a previous trial. Data was analyzed with Bayesian methods, using information from a similar study conducted in The Netherlands to select a priori distributions. On adding the data from the present study to update the a priori information, the distribution of the difference in response rates were obtained and used to build credibility intervals and relevant probability computations.
In the experimental group (n = 27), the rate of responders to treatment was 70.4% (95% CI 53.2-87.6), and in the control group (n = 23), it was 34.8% (95% CI 15.3-54.3). The probability of success in the experimental group using the a posteriori distributions was higher after a proper sensitivity analysis. Almost the whole distribution of the rates difference (the one for diacetylmorphine minus methadone) was located to the right of the zero, indicating the superiority of the experimental treatment.
The present analysis suggests a clinical superiority of injectable diacetylmorphine compared to oral methadone in the treatment of severely affected heroin injectors not benefiting sufficiently from the available treatments.
Trial Registration
Current Controlled Trials ISRCTN52023186
PMCID: PMC2739523  PMID: 19682360
19.  Neuropsychological functioning in opiate-dependent subjects receiving and following methadone maintenance treatment 
Drug and alcohol dependence  2006;84(3):240-247.
An accumulating body of research suggests that former heroin abusers in methadone maintenance therapy (MMT) exhibit deficits in cognitive function. Whether these deficits are present in former methadone maintained patients following discontinuation of MMT is unknown. This study tests the hypothesis that former heroin users who have detoxified from methadone maintenance therapy and are drug-free have less pronounced cognitive impairment than patients continuing long-term MMT.
A series of neuropsychological tests were administered to three groups of subjects: 29 former heroin addicts receiving methadone maintenance treatment, 27 former heroin addicts withdrawn from all opiates, and 29 healthy controls without a history of drug dependence. Testing included Wechsler Adult Intelligence Scale-Revised Vocabulary Test, the Stroop Color-Word Test, the Controlled Oral Word Association Test, the Benton Visual Retention Test, and a Substance Use Inventory.
Both methadone-maintained and abstinent subject groups performed worse than controls on tasks that measured verbal function, visual-spatial analysis and memory, and resistance to distractibility. Abstinent subjects performed worse than their methadone maintained counterparts on tests measuring visual memory and construct formation. Cognitive impairment did not correlate with any index of drug use.
We confirmed previous findings of neuropsychological impairment in long-term MMT recipients. Both patients receiving MMT and former heroin users in prolonged abstinence exhibited a similar degree of cognitive impairment. Cognitive dysfunction in patients receiving methadone maintenance may not resolve following methadone detoxification.
PMCID: PMC2067988  PMID: 16545923
Methadone; Opiates; Dependence; Abstinence; Neuropsychological; Cognitive
20.  Policy makers ignoring science and scientists ignoring policy: the medical ethical challenges of heroin treatment 
A decade of research in Switzerland, The Netherlands, Germany, and Spain now constitutes a massive body of work supporting the use of heroin treatment for the most difficult patients addicted to opiates. These trials concur on this method's safety and efficacy and are now serving as a prelude to the institution of heroin treatment in clinical practice throughout Europe.
While the different sampling and research protocols for heroin treatment in these studies were important to the academic claims about specific results and conclusions that could be drawn from each study, the overall outcomes were quite clear – and uniformly positive. They all find that the use of prescribed pharmaceutical heroin does exactly what it is intended to do: it reaches a treatment refractory group of addicts by engaging them in a positive healthcare relationship with a physician, it reduces their criminal activity, improves their health status, and increases their social tenure through more stable housing, employment, and contact with family.
The Canadian trial (NAOMI), now underway for over a year, but not yet completed, now faces a dilemma about what to do with its patients who have successfully completed 12 months of heroin and must be withdrawn from heroin and transferred to other treatments in accordance with the research protocol approved by Government of Canada, federal granting body and host institutions. The problem is that the principal criterion for acceptance to NAOMI was their history of repeated failure in these very same treatment programs to which they will now be referred.
The existence of the results from abroad (some of which were not yet available when NAOMI was designed and initiated) now raises a very important question for Canada: is it ethical to continue to prohibit the medical use of heroin treatment that has already been shown to be feasible and effective in numerous medical studies throughout the world? And while this is being worked out, is it acceptable to require patients who have been successfully treated with heroin in Canada, to be forced to move back to less effective treatments (treatments that failed to be efficacious in the past)?
This essay discusses this dilemma and places it in the broader context of ethics, science, and health policy. It makes the case for continuation of the current successful patients in heroin treatment and the institution of heroin treatment to all Canadian patients living with active addictions who qualify.
PMCID: PMC1557662  PMID: 16670010
21.  Uses of diverted methadone and buprenorphine by opioid-addicted individuals in Baltimore, Maryland 
This study examined the uses of diverted methadone and buprenorphine among opiate-addicted individuals recruited from new admissions to methadone programs and from out-of-treatment individuals recruited from the streets. Self-report data regarding diversion were obtained from surveys and semi-structured qualitative interviews. Approximately 16% (n=84) of the total sample (N=515) reported using diverted (street) methadone 2–3 times per week for six months or more, and for an average of 7.8 days (SD=10.3) within the past month. The group reporting lifetime use of diverted methadone as compared to the group that did not report such use was less likely to use heroin and cocaine in the 30 days prior to admission (ps < .01) and had lower ASI Drug Composite scores (p < .05). Participants in our qualitative sub-sample (n=22) indicated that street methadone was more widely used than street buprenorphine and that both drugs were largely used as self-medication for detoxification and withdrawal symptoms. Participants reported using low dosages and no injection of either medication was reported.
PMCID: PMC2771323  PMID: 19874152
methadone; buprenorphine; diversion; mixed-methods
22.  A Randomized Trial of Methadone Initiation Prior to Release from Incarceration 
Substance Abuse  2012;33(1):19-29.
Individuals who use heroin and illicit opioids are at high risk for infection with human immunodeficiency virus (HIV) and other blood-borne pathogens, as well as incarceration. The purpose of the randomized trial reported here is to compare outcomes between participants who initiated methadone maintenance treatment (MMT) prior to release from incarceration, with those who were referred to treatment at the time of release. Participants who initiated MMT prior to release were significantly more likely to enter treatment postrelease (P < .001) and for participants who did enter treatment, those who received MMT prerelease did so within fewer days (P = .03). They also reported less heroin use (P = .008), other opiate use (P = .09), and injection drug use (P = .06) at 6 months. Initiating MMT in the weeks prior to release from incarceration is a feasible and effective way to improve MMT access postrelease and to decrease relapse to opioid use.
PMCID: PMC3278074  PMID: 22263710
HIV prevention; incarceration; medication-assisted treatment; methadone
23.  Promoting Abstinence from Cocaine and Heroin with a Methadone Dose Increase and a Novel Contingency 
Drug and alcohol dependence  2008;101(1-2):92-100.
To test whether a combination of contingency management and methadone dose increase would promote abstinence from heroin and cocaine, we conducted a randomized controlled trial using a 2 X 3 (Dose X Contingency) factorial design in which dose assignment was double-blind. Participants were 252 heroin- and cocaine-abusing outpatients on methadone maintenance. They were randomly assigned to methadone dose (70 or 100 mg/day, double blind) and voucher condition (noncontingent, contingent on cocaine-negative urines, or “split”). The “split” contingency was a novel contingency that reinforced abstinence from either drug while doubly reinforcing simultaneous abstinence from both: the total value of incentives was “split” between drugs to contain costs. The main outcome measures were percentages of urine specimens negative for heroin, cocaine, and both simultaneously; these were monitored during a 5-week baseline of standard treatment (to determine study eligibility), a 12-week intervention, and a 10-week maintenance phase (to examine intervention effects in return-to-baseline conditions). DSM-IV criteria for ongoing drug dependence were assessed at study exit. Urine-screen results showed that the methadone dose increase reduced heroin use but not cocaine use. The Split 100mg group was the only group to achieve a longer duration of simultaneous negatives than its same-dose Noncontingent control group. The frequency of DSM-IV opiate and cocaine dependence diagnoses decreased in the active intervention groups. For a split contingency to promote simultaneous abstinence from cocaine and heroin, a relatively high dose of methadone appears necessary but not sufficient; an increase in overall incentive amount may also be required.
PMCID: PMC2943844  PMID: 19101098
contingency management; polydrug dependence; methadone dose; DSM diagnoses
24.  Behavioral drug and HIV risk reduction counseling (BDRC) in MMT programs in Wuhan, China: A pilot randomized clinical trial 
Drug and alcohol dependence  2010;115(3):237-239.
This pilot clinical trial evaluated whether the efficacy of methadone maintenance treatment (MMT) provided with limited psychosocial services is improved by the addition of manual-guided behavioral drug and HIV risk reduction counseling (BDRC). Heroin dependent individuals (N=37) enrolling in two MMT clinics in Wuhan, China, received standard MMT services, consisting of daily medication at the clinics and infrequent additional services on demand, and were randomly assigned to MMT only (n=17) or MMT with weekly individual BDRC (n=20) for 3 months. Participants were followed for six months from the time of enrollment (3 months active counseling phase and 3 months follow-up while treated with standard MMT). Primary outcome measures included reductions of HIV risk behaviors and illicit opiate use and treatment retention. Participants were 81% male; mean (SD) age 36.7 (7.2) years; there were no significant baseline differences between the two groups. Participants in MMT+BDRC achieved both greater reductions of HIV risk behaviors (p<0.01), as indicated by the scores on a short version of the AIDS Risk Inventory, and of illicit opiate use, as indicated by the proportions of opiate negative test results during the active phase of the study and the follow-up (p< 0.001). 83.3% in the MMT+BDRC group and 76.2% in the standard MMT group were still actively participating in MMT at 6 months. Manual-guided behavioral drug and HIV risk reduction counseling is feasible to deliver by the trained MMT nursing personnel and appears to be a promising approach for improving the efficacy of standard MMT services in China.
PMCID: PMC3076517  PMID: 21159452
Methadone maintenance; drug counseling; HIV risk reduction counseling; China
25.  Increased OPRM1 DNA Methylation in Lymphocytes of Methadone Maintained Former Heroin Addicts 
The μ-opioid receptor is the site of action of opiates and opioids. We examined whether there are differences in CpG dinucleotide methylation in the OPRM1 promoter between former heroin addicts and controls. We analyzed methylation at sixteen CpG dinucleotides in DNA obtained from lymphocytes of 194 Caucasian former severe heroin addicts stabilized in methadone maintenance treatment and 136 Caucasian control subjects. Direct sequencing of bisulfite-treated DNA showed that the percent methylation at two CpG sites was significantly associated with heroin addiction. The level of methylation at the −18 CpG site was 25.4% in the stabilized methadone maintained former heroin addicts and 21.4% in controls (p = 0.0035, generalized estimating equations (GEE); p = 0.0077, t-test; False Discovery Rate (FDR) = 0.048), and the level of methylation at the +84 CpG dinucleotide site was 7.4% in cases and 5.6% in controls (p = 0.0095, GEE; p = 0.0067, t-test; FDR = 0.080). Both the −18 and the +84 CpG sites are located in potential Sp1 transcription factor-binding sites. Methylation of these CpG sites may lead to reduced OPRM1 expression in the lymphocytes of these former heroin addicts.
PMCID: PMC2778040  PMID: 18650805
Methylation; addiction; gene; heroin; methadone; CpG

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