Background
Since 1996, two opioid maintenance treatments (OMT) have been marketed in France for opioid dependence: methadone and buprenorphine. It is acknowledged that recommended doses of buprenorphine are less effective than methadone in retaining patients in treatment
Despite the lack of official clinical guidelines about the specific drug(s) to be prescribed in first-line treatment, buprenorphine is prescribed more often and is more widely available in France through primary care. This is due to its safety profile. While the effectiveness of the two treatments at adequate doses (for buprenorphine, this means doses which are higher than those recommended) is comparable, the risk of overdose is lower in buprenorphine patients
Methods/Design
Pre-trial phase
The study was designed in response to a request by the French Ministry of Health which asked the AIDS agency (ANRS) to develop an experimental study which would evaluate the effectiveness of methadone in primary care.
The research unit responsible for conducting the study is the unit U912 of the National Institute of Health and Medical Research (INSERM) in Marseilles, under the scientific responsibility of Patrizia Carrieri.
Before designing the trial, a multidisciplinary working group which also included members of patients’ associations was set up by the ANRS.
One of the major points to decide upon was the identification of a model for primary care which could maximize access while minimizing the risk of overdose. This model was designed from previous experiences of methadone provision in primary care
Several subgroups were charged with, respectively, preparing the guidelines for methadone prescription, updating the methadone drug-drug interactions manual and designing an information booklet for the patient.
Participants
From January 2009 to January 2010, we recruited 195 men and women in 10 cities (Avignon, Bayonne, Besancon, Bordeaux, Boulogne, Le Havre, Marseille, Metz, Rouen, Strasbourg) who were all over 18 and less than 70 years old, opioid-dependent in accordance with the DSM-IV criteria, and with an indication for methadone treatment (patients seeking care for opioid dependence and methadone prescription naive for at least one month or patients receiving buprenorphine but needing to switch to methadone treatment for medical reasons). The only difference between this trial and some previous trials
Research design
This study is a multi-site, open-label, randomized controlled non-inferiority trial, comparing methadone induction in France in a CSAPA or with primary care physicians with an allocation ratio of 1 :2. The randomization procedure allocated patients to the two different types of prescriber for methadone induction, lasting approximately 14 days for both prescribers).
A pilot phase was first carried out at one site (Avignon CSAPA and local primary care physicians) at a “slowed” recruitment rate in order to identify and prevent possible future problems when the trial was extended to the other sites.
Physician recruitment and training
A one-day training session was provided to all physicians involved in the study to standardize how to initiate methadone treatment (as set down by the trial’s guidelines) and to become acquainted with the design of the trial. This training session also provided the opportunity to collect data about the physicians’ own socio-demographic characteristics and their history of care with opioid-dependent individuals.
We trained 57 prescribers and each site was characterized by a group of trained primary care physicians and a group of trained physicians from a CSAPA. Primary care and CSAPA physicians collaborated closely together to make the randomization process possible and to ensure effective patient follow-up. Concerning patient selection, the Mini-International Neuropsychiatric Interview (MINI) was used to ascertain DSM-IV diagnosis
Pharmacist involvement
We also enrolled primary care pharmacists who agreed to deliver methadone and supervise dose taking during the 2-week induction phase (except during weekends, in most cases) for all the trial’s participants. Pharmacists were asked to complete a self-administered questionnaire before and after the trial and also to register all stock entries and exits for methadone doses.
Remuneration
Physicians who accepted to participate in the trial were remunerated for the one-day initial training session and for each medical visit during the induction phase. Participants were covered for all health costs related to their methadone induction.
Intervention
Patient screening
The first visit took place when a patient willing to be treated for his/her opioid dependence came to a Methaville physician, either in primary care or in a CSAPA (see Figure
This study was approved by the Ethics Committee of Persons Protection in Paris, France.
The screening physician, whether in a CSAPA or in a primary care setting, provided the randomization setting to the patient: if the patient was randomized into the same type of setting at that where initial screening took place, he/she could initiate methadone where he/she was screened. Otherwise he/she had to go to the other type of setting.
Methadone initiation
During the induction period, the selected physician for the methadone induction had to adjust the methadone dose until stabilization was reached. This induction period was crucial and required a great deal of attention by both the physician and the patient in order to reach a balance between overdose risk reduction and withdrawal symptoms’ alleviation. The initial methadone prescription could not be above 40 mg a day. After writing this first prescription, the physician was required to call the local pharmacist where the patient had chosen to take the methadone. The patient was then given the prescribed dose (in syrup form) at the pharmacy and had a medical visit 2 or 4 hours after that intake in order to assess the tolerance of the first prescribed dose. During the induction period, the patient had to see the physician at least twice a week after the initial prescription consultation. Depending on the severity of opioid dependence, the first dose prescribed could increase by 10 mg every 2 to 4 days with a medical visit 48 hours after each dose increase.
Maintenance phase
After the initial 14 days, the participant could choose to remain in the allocated prescription setting or to change to the other one (i.e. to primary care or CSAPA).
The possible risks for participants were methadone side effects, which are the same as those encountered in standard clinical care: drowsiness, sweating, constipation, sleeping and libido disorder
As there is an increased risk of overdose until stabilization of doses is reached, special guidelines for methadone prescription were drawn up and used, both to train physicians and to have standardized guidelines throughout the course of the trial.
Lost to follow-up
During the induction phase (from day 0 to day 14), the patient had to:
(1) regularly go to the pharmacy (according to the scheduled date of prescription refill) during opening hours to take the treatment. If he/she didn’t appear there for more than 48 hours, the pharmacist had to inform the centre of methodology and management (CMM) which in turn contacted the participant.
(2) see the physician for the scheduled medical visit, every 72 hours on average. If this appointment was not observed, the physician had to call the CMM.
If after 24 hours of investigation, the CMM still could not find the participant in either of these two cases, he/she was considered as “lost to follow-up”. The CMM had to then contact the centre of evaluation and information on drug dependence (CEIP) to check that the participant had not had an overdose.
Safety
An independent data and safety monitoring board periodically reviewed the trial’s efficacy and safety data. This safety committee comprised several experts in the field including addiction psychiatrists, forensic scientists, pharmacologists, methodologists and institutional scientists.
Stopping rules were based on occurrence of overdoses and severe adverse effects.
Objectives
The trial is nearing completion. Its primary objective is to demonstrate the non-inferiority of the proportion of individuals abstinent from street opioids after one year of methadone in patients inducted in primary care with those inducted in CSAPA. Patients who initiated methadone in primary care are expected to have better outcomes compared with those in CSAPA in terms of retention, quality of life and satisfaction after 1 year of methadone treatment.
Outcomes and instruments
Multiple sources were used for data collection at screening (week preceding recruitment and first/seventh day after recruitment), at recruitment (day zero or month zero), induction (from the first to the second week of treatment) and maintenance (third, sixth and twelfth months). Data collection methods (ongoing) include face-to-face interviews, phone interviews using a Computer Assisted Telephone Interview
The Opiate Treatment Index (OTI), a multi-dimensional questionnaire based on patients’ self-report
Sample size
We used the proportion of all patients abstinent from street opioids after 1-year of methadone treatment for the sample size. Many studies have shown that 60% to 80% of opioid-dependent individuals treated with methadone completely stopped using street opioids after one year of treatment
Randomization
For allocation of the participants to a primary care or a CSAPA physician, a computer-generated list of random numbers was used within a secured centralized internet system. Randomization sequencing was not stratified by the CMM, which generated the randomization sequence by computer and provided the number by phone to the prescribing physicians when recruiting a patient into the study.
Blinding
By definition, the arm could not be masked from the prescribing physician but it was masked from all the scientific team involved in the trial. It was obviously unmasked to the logistics team who conducted the interviews and to statisticians and the data managers of the research group, because they had to regularly meet and submit reports to the Independent Committee of the trial. The study will be unmasked at the end of the last M12 interview, during the course of 2012.
Statistical methods
The trial was initially designed as a non-inferiority trial aimed to show the non-inferiority of the proportion of
Secondary outcomes are the occurrence of fatal and non-fatal overdoses and the percentage of retention in both arms. We also investigated the prevalence of other HCV transmission practices and the effectiveness of treatment in terms of adherence, social insertion, addictive behaviours, quality of life, psychiatric comorbidities, social insertion, reduction in criminal acts and cost effectiveness.
When data analysis is completed later in 2012, the computation of the 95% confidence interval for the proportion of patients abstinent from street opioids at M12 in the two arms will be based on Intention To Treat (ITT), with lost to follow-up considered as a therapeutic failure (opioid users). Additional analyses will be performed without ITT, focusing on the most recent available information about opioid use during treatment. Mixed generalized linear models analyses will be used to identify predictors of the different outcomes. Non-inclusion or non-termination biases will be controlled for using selection models - including Heckman type models
Flowchart for patient inclusion and study design
Flowchart for patient inclusion and study design.
Discussion
To date, the ANRS-Methaville study is the first in France to be requested by a governmental agency with the objective of potentially changing the existing legal framework of an opioid maintenance treatment (OMT). We hope that methadone will be initiated by trained primary care physicians and in turn, that it will contribute to providing improved access to methadone in France.
However, the risk of overdose occurring during the induction phase of treatment
This is why the present trial is based not only on guidelines for methadone prescription and provision in primary care but also on a shared-care model.
Primary care physicians should work within a drug dependence care network and/or specialized centre, such as a CSAPA, and have documented experience of care for drug users. In addition, pharmacists must have direct contact with the methadone prescribing physician and must be involved from the beginning of the trial in order to guarantee effective supervision and follow-up of patients. This important responsibility may integrate pharmacists more into the health care system for drug users. Some previous studies have already shown that pharmacists appear to be in favour of providing OMT, supervising intake
This study may inform the development of any improved structuring of the existing framework for OMT induction in primary care through training and networking between physicians and pharmacists. The improved treatment efficacy of involving pharmacists as a key component of prevention for drug users has already been shown through the widespread provision of sterile injecting equipment
In this trial, because the recruitment of primary care physicians had to be carried out in close collaboration with a drug and alcohol centre, it was impossible to include primary care physicians in sites without any CSAPA (especially in rural settings where primary care physicians are mostly general practitioners). The representativeness of the study sample would certainly have been better if we had been able to include such rural-based physicians. However, we can hypothesize that whatever results we find will also be applicable to these latter as our intervention included pre-training for all the physicians who initiated methadone treatment.
This trial is a unique opportunity to encourage increased access to OMT, especially for opioid dependent individuals who do not have access to methadone for geographical reasons or for reasons of preference. In addition, it is an innovative experiment in France using preventive intervention research in opioid dependent individuals.
Abbreviations
AFSSAPS: French Agency of Pharmaceutical Products; ANRS: Aids Agency; CEIP: Centre of evaluation and information on drug dependence; CMM: Centre of methodology and management; CPP: Committee and the Ethical Committee; CSAPA: Medical centre for drug and alcohol dependence; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; IDU: Injecting drug user; INSERM: National Institute of Health and Medical Research; ITT: Intention to treat; MINI: Mini-International Neuropsychiatric Interview; OMT: Opioid Maintenance Treatment; OTI: Opiate Treatment Index.
Competing interests
All authors have no financial interests that may be relevant to the submitted work.
Authors’ contributions
MPC, LM, PR, BS, JFA, AM and JCD designed the study and wrote the protocol. PR and MPC managed the literature searches, formulated the research questions and PR wrote the first draft of the manuscript. JC and MM participated in the data collection and JC will undertake the statistical analyses. All authors contributed to and have approved the final manuscript.