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Additional file 1: Table S1. Characteristics of anti-TNF users not satisfying selected criteria sets.

Additional file 2: Table S2. Total time on anti-TNF therapy among non-responders (from initiation until end of follow-up).

Additional file 3: Table S3. Comparative estimates of costs, QALYs, and ICERs in sensitivity analyses.

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Background: Substitution with opioid-agonists (e.g., methadone) has shown to be an effective treatment for chronic long-term opioid dependency. Survival sex work, very common among injection drug users, has been associated with poor Opioid Agonist Treatment (OAT) engagement, retention and response. Therefore, this study was undertaken to determine factors associated with engaging in sex work among long-term opioid dependent women receiving OAT. Methods: Data from a randomized controlled trial, the North American Opiate Medication Initiative (NAOMI), conducted in Vancouver and Montreal (Canada) between 2005-2008, was analyzed. The NAOMI study compared the effectiveness of oral methadone to injectable diacetylmorphine or injectable hydromorphone, the last two on a double blind basis, over 12 months. A research team, independent of the clinic services, obtained outcome evaluations at baseline and follow-up (3, 6, 9, 12, 18 and 24 months). Results: A total 53.6% of women reported engaging in sex work in at least one of the research visits. At treatment initiation, women who were younger and had fewer years of education were more likely to be engaged in sex work. The multivariate logistic generalized estimating equation regression analysis determined that psychological symptoms, and high illicit heroin and cocaine use correlated with women's involvement in sex work during the study period. Conclusions: After entering OAT, women using injection drugs and engaging in sex work represent a particularly vulnerable group showing poorer psychological health and a higher use of heroin and cocaine compared to women not engaging in sex work. These factors must be taken into consideration in the planning and provision of OAT in order to improve treatment outcomes. Trial Registration: NCT00175357.

Background: SALOME (Study to Assess Longer-term Opioid Medication Effectiveness) tested in a double-blind non-inferiority clinical trial if hydromorphone could be as effective as diacetylmorphine for severe opioid use disorder. Although participants did not guess treatment correctly beyond what is expected by chance, perceived treatment assignment could affect patients’ response to treatment. This study tested if treatment allocation guess is associated with treatment outcomes and identified predictors of guess. Methods: Data were obtained through questionnaires and clinical records. Participants were asked what medication they thought they were receiving (diacetylmorphine, hydromorphone or unsure) and their open-ended reasons. Multinomial logistic regression was used to assess the predictors of treatment guess. An inductive thematic analysis was used to code open-ended responses. This clinical trial was registered with U.S. National Institutes of Health (https://clinicaltrials.gov/ct2/show/NCT01447212). Findings: Participants referred to prior experiences with opioids and the presence or absence of specific drug effects as reasons for their guesses. There were no differences in illicit opioid use and retention by guess; however those who guessed diacetylmorphine had better physical and mental health scores. Participants with a treatment-related observed drowsiness event, and higher perceived drug-related high scores were more likely to guess diacetylmorphine compared to hydromorphone. Guessing hydromorphone was more likely among those who made negative comments as reasons for treatment guesses. Conclusions: Understanding the clues participants use for treatment allocation guesses and relating them to treatment expectations could be integrated with accurate information about the treatment, providing an opportunity for patient–physician shared decision-making in opioid maintenance treatment. Clinical trial registration: U.S. National Institutes of Health; ClinicalTrials.gov Identifier: NCT01447212; https://clinicaltrials.gov/ct2/show/NCT01447212

Background: To test whether there are gender differences in treatment outcomes among patients receiving injectable opioids for the treatment of long-term opioid-dependence. The study additionally explores whether men and women have different perceptions of treatment effectiveness. Methods: This study is a secondary analysis from SALOME, a double-blind, phase III, randomized controlled trial testing the non-inferiorirty of injectable hydromorphone to injectable diacetylmorphine among 202 long-term street opioid injectors in Vancouver (Canada). Given this was a secondary analysis, no a priori power calaculation was conducted. Differences in baseline characteristics and six-month treatment outcomes (illicit heroin use, opioid use, crack cocaine use, non-legal activities, physical and psychological health scores, urine positive for street heroin markers, and retention) were analysed by gender using fitted models. Responses to an open ended question on reasons for treatment effectiveness were explored with a thematic analysis. Results: Men and women differed significantly on a number of characteristics at baseline. For example, women were significantly younger, presented to treatment with significantly higher rates of prior month sex work (31.5% vs. 0%), and used significantly more crack cocaine (14.71 vs. 8.38 days). After six-months of treatment there were no significant differences in treatment outcomes by gender, after adjusting for baseline values. For both men and women, improved health and quality of life were the most common reasons provided for treatment effectiveness, however women were more specific in the types of health improvements. Conclusions: Despite presenting to treatment with vulnerabilities not faced to the same extent by men, at six-months women did not differ significantly from men in tested trial efficacy outcomes. While the primary outcome in the trial was the reduction of illicit opioid use, in the open-ended responses both men and women focused their comments on improvement in health and quality of life as reasons for treatment effectiveness. The supervised model of care with injectable medications provides a particularly suitable framework for providing care to opioid-dependent men and women not attracted or retained by other treatments. The absence of statistical differences reported in this secondary analysis may be due to lack of adequate statistical power to detect meaningful effects. Trial registration This trial is registered with ClinicalTrials.gov (NCT01447212) Registered: October 4, 2011 at the following link: https://clinicaltrials.gov/ct2/show/NCT01447212 .

Background: Substitution with opioid-agonists (e.g., methadone) has shown to be an effective treatment for chronic long-term opioid dependency. Patient satisfaction with treatment has been associated with improved addiction treatment outcomes. However, there is a paucity of studies evaluating patients' satisfaction with Opioid Substitution Treatment (OST). In the present study, participants' satisfaction with OST was evaluated at 3 and 12 months. We sought to test the relationship between satisfaction and patients' characteristics, the treatment modality received and treatment outcomes. Methods Data from a randomized controlled trial, the North American Opiate Medication Initiative (NAOMI), conducted in Vancouver and Montreal (Canada) between 2005-2008, was analyzed. The NAOMI study compared the effectiveness of oral methadone vs. injectable diacetylmorphine over 12 months. A small sub-group of patients received injectable hydromorphone on a double blind basis with diacetylmorphine. The Client Satisfaction Questionnaire (CSQ-8) was used to measure satisfaction with treatment. CSQ-8 scores, as well as retention and response to treatment, did not differ between those receiving hydromorphone and diacetylmorphine at 3 or 12 months assessments; therefore, these two groups were analyzed together as the 'injectable' treatment group. Results A total of 232 (92%) and 237 (94%) participants completed the CSQ-8 at 3 and 12 months, respectively. Participants in both groups were highly satisfied with treatment. Independent of treatment group, participants satisfied with treatment at 3 months were more likely to be retained at 12 months. Multivariate analysis indicated that satisfaction was greater among those randomized to the injection group after controlling for treatment effectiveness. Participants who were retained, responded to treatment, and had fewer psychological symptoms were more satisfied with treatment. Finally, open-ended comments were made by 149 (60.3%) participants; concerns about the randomization process and the study ending were most commonly reported by participants receiving the oral and injectable medications, respectively. Conclusions The higher satisfaction among those receiving medically prescribed injectable diacetylmorphine (or hydromorphone) supports current evidence regarding the attractiveness of this treatment for long-term, opioid-dependent individuals not benefiting sufficiently from other treatments. In addition, the measurement of treatment satisfaction provides valuable information about participants at risk of relapse and in need of additional services. Trial Registration ClinicalTrials.gov Identifier: NCT00175357

Background: SALOME (Study to Assess Longer-term Opioid Medication Effectiveness) tested in a double-blind non-inferiority clinical trial if hydromorphone could be as effective as diacetylmorphine for severe opioid use disorder. Although participants did not guess treatment correctly beyond what is expected by chance, perceived treatment assignment could affect patients’ response to treatment. This study tested if treatment allocation guess is associated with treatment outcomes and identified predictors of guess. Methods: Data were obtained through questionnaires and clinical records. Participants were asked what medication they thought they were receiving (diacetylmorphine, hydromorphone or unsure) and their open-ended reasons. Multinomial logistic regression was used to assess the predictors of treatment guess. An inductive thematic analysis was used to code open-ended responses. This clinical trial was registered with U.S. National Institutes of Health (https://clinicaltrials.gov/ct2/show/NCT01447212). Findings: Participants referred to prior experiences with opioids and the presence or absence of specific drug effects as reasons for their guesses. There were no differences in illicit opioid use and retention by guess; however those who guessed diacetylmorphine had better physical and mental health scores. Participants with a treatment-related observed drowsiness event, and higher perceived drug-related high scores were more likely to guess diacetylmorphine compared to hydromorphone. Guessing hydromorphone was more likely among those who made negative comments as reasons for treatment guesses. Conclusions: Understanding the clues participants use for treatment allocation guesses and relating them to treatment expectations could be integrated with accurate information about the treatment, providing an opportunity for patient–physician shared decision-making in opioid maintenance treatment. Clinical trial registration: U.S. National Institutes of Health; ClinicalTrials.gov Identifier: NCT01447212; https://clinicaltrials.gov/ct2/show/NCT01447212

Background: The Study to Assess Long-term Opioid Medication Effectiveness (SALOME) is a two-stage phase III, single site (Vancouver, Canada), randomized, double blind controlled trial designed to test if hydromorphone is as effective as diacetylmorphine for the treatment of long-term illicit opioid injection. Recruiting participants for clinical trials continues to be a challenge in medical and addiction research, with many studies not being able to reach the planned sample size in a timely manner. The aim of this study is to describe the recruitment strategies in SALOME, which offered appealing treatments but had limited clinic capacity and no guaranteed post-trial continuation of the treatments. Methods SALOME included chronic opioid-dependent, current illicit injection opioid users who had at least one previous episode of opioid maintenance treatment. Regulatory approvals were received in June 2011 and recruitment strategies were implemented over the next 5 months. Recruitment strategies included ongoing open communication with the community, a consistent and accessible team and participant-centered screening. All applicants completed a pre-screening checklist to assess prerequisites. Applicants meeting these prerequisites were later contacted to commence the screening process. Results A total of 598 applications were received over the two-year recruitment period; 130 were received on the first day of recruitment. Of these applicants, 485 met prerequisites; however, many could not be found or were not reached before recruitment ended. For the 253 candidates who initiated the screening process, the average time lapse between application and screening date was 8.3 months (standard deviation [SD] = 4.44) and for the 202 randomized to the study, the average processing time from initial screen to randomization was 25.9 days (SD = 37.48; Median = 15.0). Conclusions As in prior trials offering injectable diacetylmorphine within a supervised model, recruiting participants for this study took longer than planned. The recruitment challenges overcome in SALOME were due to the high number of applicants compared with the limited number that could be randomized and treated. Our study emphasizes the value of integrating these strategies into clinical addiction research to overcome study-specific barriers. Trial registration ClinicalTrials.gov: NCT01447212 .

Background: 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. Results: 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). 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 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

Background: Anti-tumor necrosis factor (anti-TNF) agents are an effective, but costly, treatment for spondyloarthritis (SpA). Worldwide, multiple sets of access criteria aim to restrict anti-TNF therapy to patients with specific clinical characteristics, yet the influence of access criteria on anti-TNF cost-effectiveness is unknown. Our objective was to use data from the DESIR cohort, a prospective study of early SpA patients in France, to determine whether the French anti-TNF access criteria are the most cost-effective in that setting relative to other potential restrictions. Methods: We used data from the DESIR cohort to create five study populations of patients meeting anti-TNF access criteria from Canada, France, Germany, United Kingdom, and Hong Kong, respectively. For each study population, we calculated the costs and quality-adjusted life years (QALYs) over 1 year of patients treated and not treated with anti-TNF therapy. To control for differences between anti-TNF users and non-users, we used linear regression models to derive adjusted mean costs and QALYs. We calculated incremental cost-effectiveness ratios (ICERs) representing the incremental cost per additional QALY gained by treating with an anti-TNF within each of the five study populations, using bootstrapping to explore the range of uncertainty in costs and QALYs. A series of sensitivity analyses was conducted, including one to simulate the effect of a 24-week stopping rule for anti-TNF non-responders. Results: Anti-TNF access criteria from France were satisfied by the largest proportion of DESIR patients (27.8%), followed by Germany (25.1%), Canada (23.8%), the UK (12.1%) and Hong Kong (8.6%). Confidence intervals around incremental costs and QALYs in the basecase analysis were overlapping, indicating that anti-TNF cost-effectiveness estimates derived from each subset were similar. In the sensitivity analysis that examined the effect of excluding costs accumulated past 24 weeks by anti-TNF non-responders, the incremental cost per QALY was reduced by approximately 25% relative to the basecase analysis (France: €857,992 vs. €1,105,859; Canada: € 626,459 vs. €818,186; Germany: € 422,568 vs. €545,808); UK €578,899 vs. €766,217; Hong Kong €335,418 vs. €456,850). Conclusions: Anti-TNF cost-effectiveness is strongly affected by treatment continuation among non-responders. Access criteria could improve anti-TNF cost-effectiveness by defining patients likely to respond.

Background: Substitution with opioid-agonists (e.g., methadone) has shown to be an effective treatment for chronic long-term opioid dependency. Patient satisfaction with treatment has been associated with improved addiction treatment outcomes. However, there is a paucity of studies evaluating patients' satisfaction with Opioid Substitution Treatment (OST). In the present study, participants' satisfaction with OST was evaluated at 3 and 12 months. We sought to test the relationship between satisfaction and patients' characteristics, the treatment modality received and treatment outcomes. Methods Data from a randomized controlled trial, the North American Opiate Medication Initiative (NAOMI), conducted in Vancouver and Montreal (Canada) between 2005-2008, was analyzed. The NAOMI study compared the effectiveness of oral methadone vs. injectable diacetylmorphine over 12 months. A small sub-group of patients received injectable hydromorphone on a double blind basis with diacetylmorphine. The Client Satisfaction Questionnaire (CSQ-8) was used to measure satisfaction with treatment. CSQ-8 scores, as well as retention and response to treatment, did not differ between those receiving hydromorphone and diacetylmorphine at 3 or 12 months assessments; therefore, these two groups were analyzed together as the 'injectable' treatment group. Results A total of 232 (92%) and 237 (94%) participants completed the CSQ-8 at 3 and 12 months, respectively. Participants in both groups were highly satisfied with treatment. Independent of treatment group, participants satisfied with treatment at 3 months were more likely to be retained at 12 months. Multivariate analysis indicated that satisfaction was greater among those randomized to the injection group after controlling for treatment effectiveness. Participants who were retained, responded to treatment, and had fewer psychological symptoms were more satisfied with treatment. Finally, open-ended comments were made by 149 (60.3%) participants; concerns about the randomization process and the study ending were most commonly reported by participants receiving the oral and injectable medications, respectively. Conclusions The higher satisfaction among those receiving medically prescribed injectable diacetylmorphine (or hydromorphone) supports current evidence regarding the attractiveness of this treatment for long-term, opioid-dependent individuals not benefiting sufficiently from other treatments. In addition, the measurement of treatment satisfaction provides valuable information about participants at risk of relapse and in need of additional services. Trial Registration ClinicalTrials.gov Identifier: NCT00175357