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OBJECTIVE Patient ratings of physician communication in the setting of daily injectable opioid agonist treatment are reported. Associations between communication items and demographic, health, drug use, and treatment characteristics are explored. METHODS Participants (n = 121) were patients receiving treatment for opioid use disorder with hydromorphone (an opioid analgesic) or diacetylmorphine (medical grade heroin). Ratings of physician communication were collected using the 14-item Communication Assessment Tool. Items were dichotomized and associations were explored using univariate and multivariable logistic regression models for each of the 14 items. RESULTS Ratings of physician communication were lower than reported in other populations. In nearly all of the 14 multivariable models, participants with more physical health problems and with lower scores for treatment drug liking had lower odds of rating physician communication as excellent. CONCLUSIONS In physician interactions with patients with opioid use disorder, there is a critical need to address comorbid physical health problems and account for patient medication preferences. PRACTICE IMPLICATIONS Findings reinforce the role physicians can play in communicating with patients about their comorbid conditions and about medication preferences. In the patient-physician interaction efforts to meet patients' evolving treatment needs and preferences can be made by offering patients access to all available evidence-based treatments.

Aim: Ketamine is an anesthetic agent that at lower doses can be a potent analgesic. There has been an interest in the use of low dose ketamine in treatment of chronic pain syndromes. Patients & methods: We report the results of a retrospective observational study for patients diagnosed with a chronic noncancer pain syndrome receiving a 2-week continuous subanesthetic IV ketamine infusion. Results & conclusion: We conclude that a 10–14 days of subanesthetic ketamine infusion in chronic patients results in clinically significant lowering of patients' numerical pain score. Further studies looking at subanesthetic ketamine infusion in a prospective trial of multi-day IV ketamine infusion in chronic refractory chronic neuropathic pain are needed to further assess the efficacy of ketamine.

Supplemental Digital Content is available in the text, Objectives: The present study aims to describe a 3-day induction protocol for injectable hydromorphone (HDM) and diacetylmorphine (DAM) used in 3 Canadian studies and examine rates of opioid-related overdose and somnolence during this induction phase. Methods: The induction protocol and associated data on opioid-related overdose and somnolence are derived from 2 clinical trials and one cohort study conducted in Vancouver and Montreal (2005–2008; 2011–2014; 2014–2018). In this analysis, using the Medical Dictionary for Regulatory Activities coding system we report somnolence (ie, drowsiness, sleepiness, grogginess) and opioid overdose as adverse events. Overdoses requiring intervention with naloxone are coded as severe adverse events. Results: Data from the 3 studies provides a total of 1175 induction injections days, with 700 induction injection days for DAM, and 475 induction injection days for HDM. There were 34 related somnolence and adverse event (AE) overdoses (4.899 per 100 injection days) in DAM and 6 (1.467 per 100 days) in HDM. Four opioid overdoses requiring naloxone (0.571 per 100 injection days) were registered in DAM and 1 in HDM (0.211 per 100 injection days), all safely mitigated onsite. The first week maximum daily dose patients received were on average 433.62 mg [standard deviation (SD) = 137.92] and 223.26 mg (SD = 68.06) for DAM and HDM, respectively. Conclusions: A 3-day induction protocol allowed patients to safely reach high doses of injectable hydromorphone and diacetylmorphine in a timely manner. These findings suggest that safety is not an evidence-based barrier to the implementation of treatment with injectable hydromorphone and diacetylmorphine.

Background: Generic drug prices have been capped at specified percentages of the interchangeable branded drug’s price by the Canadian provincial public drug plans since 1993. The Pan-Canadian Pharmaceutical Alliance, formed as a coalition by the provinces/territories in Canada, implemented an alternative approach, a tiered-pricing framework (TPF) for new generic drugs on April 1, 2014, under which the percentage varies with the number of generic firms in each market. We evaluate the impact of the TPF on generic entry, ie, listing in public drug plans in Canada. Methods: Our study compared the pre-TPF period (01/01/2012-03/31/2014) with the TPF period (04/01/2014- 06/30/2016). Prescription drugs from nine provincial public drug plans were grouped into a "market" if they had the same active ingredient and strength, route of administration, and dosage form. Each "market" was contestable by generics and met the eligibility criteria for TPF. At the "market" level, Cox proportional-hazards models with time-varying covariates were used to measure the impact of the TPF on the first generic listing in any provincial public drug plan in Canada relative to the first launch date worldwide. Results: A total of 189 markets in Canada were selected for the analyses. Generic drugs in small markets were more likely to be listed in Canada during the TPF period compared to the pre-TPF period (hazard ratio [HR], 95% CI: 3.81, 1.51-9.62). There was no significant difference in generic drug listings in large markets between the two policy periods. Conclusion: TPF speeds up generic entry in small markets and generates the benefits of generic competition while avoiding the pitfalls of the previously employed price-cap regulations.

Background Patients' perceptions are vital to the delivery and evaluation of substance use treatment. They are most frequently collected at one time-point and measured using patient satisfaction questionnaires or qualitative methodologies. Interestingly, the findings of these studies often diverge, as satisfaction scores tend to be highly positive, while qualitative findings suggest dissatisfaction and areas for improvement. This divergence limits current understandings of patients' perceptions and their potential change over time in treatment. Objective This study explores the relationship between open-ended positive and negative perceptions of treatment and patient satisfaction scores over time. Methods The RUTH (Research on the Utilization of Therapeutic Hydromorphone) prospective cohort study included 131 participants receiving injectable diacetylmorphine or hydromorphone in Canada's first injectable opioid agonist treatment (iOAT) program. The study collected the Client Satisfaction Questionnaire (CSQ-8) at eight time-points over an 18-month period. Following a multi-methods approach, the study complemented the CSQ-8 with open-ended positive and negative comments of iOAT. The research team analyzed these comments thematically at each time-point to develop positive and negative perception themes. We then used growth curve modeling to explore the relationship between positive and negative perception themes and patient satisfaction over time. Findings Over the eight time-points, six positive and eight negative perception themes emerged, broadly reflecting structural (e.g., expansion of iOAT), process (e.g., schedules), relational (e.g., interactions with providers), and outcome-related (e.g., met/unmet needs) perceptions of iOAT. On average, participants reported high satisfaction (grand mean = 29.2 out of 32), and scores did not significantly change over time. However, we did find significant unexplained variation within participants in their satisfaction trajectories and between participants in their initial satisfaction scores. In conditional growth curve models, the theme “unfavorable interactions with providers” had the strongest independent effect on overall satisfaction trajectories. Conclusions This study provides an example of how open-ended comments can be integrated with patient satisfaction questionnaire data to gather a comprehensive and patient-centered evaluation of substance use treatment. Considering the iOAT context specifically, relational dynamics and daily treatment access were significant predictors of patient satisfaction over time and may be attributes of iOAT that require further investigation.

Background To monitor the magnitude of the drug shortage problem in Canada, since 2017, Health Canada has required manufacturers to report drug shortages. This study aimed to identify the factors associated with drug shortages in Canada. Methods We conducted a retrospective cohort study of all prescription drugs available on the market between Mar. 14, 2017, and Sept. 12, 2018, in Canada. All drugs of the same active ingredient, dosage form, route of administration and strength were grouped into a "market." Our main outcome was shortages at the market level, determined using the Drug Shortages Canada database. We used logistic regression to identify associated factors such as market structure, route or dosage form, and Anatomic Therapeutic Chemical (ATC) classification. Results Among the 3470 markets included in our analysis, 13.3% were reported to be in shortage. Markets with a single generic manufacturer were more likely to be in shortage than other markets. Markets with oral nonsolid route or dosage form were more likely to be in shortage than those that were oral solid with regular release (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.11 to 2.49). Markets for sensory organs were more likely to be in shortage than most other ATC classes. Markets with a higher proportion of drugs covered by public insurance programs were more likely to be in shortage (OR 1.03, 95% CI 1.00 to 1.05 per 10% increase). Interpretation Markets with a single generic manufacturer were most likely to be in shortage. To ensure the security of drug supply, governments should be vigilant in monitoring markets with a single generic manufacturer, with complex manufacturing processes, with higher demand from public programs or those that are in certain ATC classes.

Cocaine use is prevalent among people receiving injectable opioid agonist treatment. Investigations of cocaine use in this population have been descriptive and the potential heterogeneity existing in patterns of use have not been characterized. As such, among patients receiving injectable opioid agonist treatment, this study aimed to: 1) quantify intra- and inter-individual variation in cocaine use over 24-months and; 2) determine how predictors of interest explained this variation.Participants were patients receiving injectable opioid agonist treatment for opioid use disorder. Study visits were completed at baseline prior to receiving treatment, and 3,6,9,12,18, and 24 months after baseline. A multi-level regression approach to growth curve modeling was employed to estimate and explain intra- (within-person) and inter-individual (between-person) variation in cocaine use.Significant intra and inter-individual variation in cocaine use was identified over 24-months. Treatment engagement was on average associated with reductions in the prior month number of days of cocaine use (range: 0-30)(Estimate (standard error): -0.05(0.02), p = 0.003). On average, men reported less cocaine use compared to women (Estimate (standard error): -5.91(1.57), p=0.001), and participants reporting ever regularly using cocaine at baseline reported more cocaine use over 24-months compared to participants reporting never regularly using cocaine (Estimate (standard error): 4.72 (1.91), p = 0.013).Significant reductions in cocaine use were observed and significant heterogeneity in patterns of cocaine use was identified. These heterogeneous cocaine use profiles suggest that an individualized approach to care will be critical in responding to patients' cocaine use in injectable opioid agonist treatment.

Objective.To evaluate a classification system to define adherence to axial spondyloarthritis (axSpA) anti-tumor necrosis factor (anti-TNF) use recommendations and examine the effect of adherence on outcomes in the DESIR cohort (Devenir des Spondylarthropathies Indifférenciées Récentes).Methods.Using alternate definitions of adherence, patients were classified as adherent “timely” anti-TNF users, nonadherent “late” anti-TNF users, adherent nonusers (“no anti-TNF need”), non-adherent nonusers (“unmet anti-TNF need”). Multivariate models were fitted to examine the effect of adherence on quality-adjusted life-years (QALY), total costs, and nonbiologic costs 1 year following an index date. Generalized linear regression models assuming a γ-distribution with log link were used for costs outcomes and linear regression models for QALY outcomes.Results.Using the main definition of adherence, there were no significant differences between late anti-TNF users and timely anti-TNF users in total costs (RR 0.86, 95% CI 0.54–1.36, p = 0.516) or nonbiologic costs (RR 0.72, 95% CI 0.44–1.18, p = 0.187). However, in the sensitivity analysis, late anti-TNF users had significantly increased nonbiologic costs compared with timely users (RR 1.58, 95% CI 1.06–2.36, p = 0.026). In the main analysis, there were no significant differences in QALY between timely anti-TNF users and late anti-TNF users, or between timely users and patients with unmet anti-TNF need. In the sensitivity analysis, patients with unmet anti-TNF need had significantly lower QALY than timely anti-TNF users (−0.04, 95% CI −0.07 to −0.01, p = 0.016).Conclusion.The effect of adherence to anti-TNF recommendations on outcomes was sensitive to the definition of adherence used, highlighting the need to validate methods to measure adherence.

Introduction and Aims. To determine the effectiveness of injectable hydromorphone and dicaetylmorphine for Indigenous participants in the Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) clinical trial. The study additionally aims to explore the prevalence and frequency of crack cocaine use among subgroups of participants (by gender and ethnicity). This secondary analysis is particularly relevant given the current need for expanded medication assisted treatments for opioid dependence across North America. Design and Methods. Participants self-identifying as First Nations, Metis or Inuit were included in the analysis of Indigenous participants. Six-month treatment outcomes are reported as the difference between diacetylmorphine and hydromorphone treatment arms among Indigenous participants and change from baseline to 6 months in each treatment arm. Differences in outcomes are tested between Indigenous and non-Indigenous participants. Crack cocaine use was explored to determine differences between and within subgroups. Results. Approximately one-third of SALOME participants self-identified as Indigenous. Indigenous participants presented to treatment with more structural vulnerabilities (e.g. lower education, higher rates of foster care and separation from biological parents) compared to non-Indigenous participants. After 6 months, Indigenous participants in both treatment arms had a significant reduction in days of street heroin use, opioid use, crack cocaine use and illegal activity. Treatment retention did not differ by treatment arm. Discussion and Conclusions. Indigenous people that are not engaged by first-line treatments for opioid dependence are in need of effective alternative treatments. Given the political and logistical barriers facing diacetylmorphine, hydromorphone could serve as a more accessible medication to reach and treat this population. [Oviedo-Joekes E, Palis H, Guh D, Marchand K, Brissette S, Lock K, MacDonald S, Harrison S, Anis AH, Krausz M, March DC, Schechter MT. Characteristics and response to treatment among Indigenous people receiving injectable diacetylmorphine or hydromorphone in a randomised controlled trial for the treatment of long-termopioid dependence. Drug Alcohol Rev 2017;00:000-000]

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. 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. 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. 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. This trial is registered with ClinicalTrials.gov (NCT01447212) Registered: October 4, 2011 at the following link: https://clinicaltrials.gov/ct2/show/NCT01447212 .

In 1998, the province of Ontario, Canada implemented price-cap '70/90' regulations: the first generic must be priced at ≤70% of the associated brand-name price and subsequent generics must be priced at ≤90% of the first generics' price. The price-cap was further lowered to 50% in 2006 and 25% in 2010 for all generic drugs regardless of the first or subsequent generic entrants. This study assessed the impact of such price-cap regulations on market entry by generic firms using the formulary database from 9 provinces (January 2004-March 2013).A logistic regression was estimated to compare the probability of entry during the three policy periods in Ontario ('70/90', '25', versus '50'). Since different price-caps were subsequently introduced in other provinces, Alberta, British Columbia, New Brunswick and Saskatchewan, difference-in-differences was used to compare market entry.In Ontario, compared with the period '50', generic firms were 76% and 63% less likely to enter markets in the periods '25' and '70/90', respectively. The difference-in-differences showed that the entry probability decreased the most in Ontario during the '25' period from the '50' period.Lowering the price-cap level to 25% leads to a significantly lower probability of market entry by generic firms.

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/NCT0144...

Aim The COVID-19 pandemic may influence the willingness of bystanders to engage in resuscitation for out-of-hospital cardiac arrest. We sought to determine if and how the pandemic has changed willingness to intervene, and the impact of personal protective equipment (PPE). Methods We distributed a 12-item survey to the general public through social media channels from June 4 to 23, 2020. We used 100-point scales to inquire about participants’ willingness to perform interventions on “strangers or unfamiliar persons” and “family members or familiar persons”, and compared mean willingness during time periods prior to and during the COVID-19 pandemic using paired t-tests. Results Survey participants (n = 1360) were from 26 countries; the median age was 38 years (IQR 24–50) and 45% were female. Compared to prior to the pandemic, there were significant decreases in willingness to check for breathing or a pulse (mean difference −10.7% [95%CI −11.8, −9.6] for stranger/unfamiliar persons, −1.2% [95%CI −1.6, −0.8] for family/familiar persons), perform chest compressions (−14.3% [95%CI −15.6, −13.0], −1.6% [95%CI −2.1, −1.1]), provide rescue breaths (−19.5% [95%CI −20.9, −18.1], −5.5% [95%CI −6.4, −4.6]), and apply an automated external defibrillator (−4.8% [95%CI −5.7, −4.0], −0.9% [95%CI −1.3, −0.5]) during the COVID-19 pandemic. Willingness to intervene increased significantly if PPE was available (+8.3% [95%CI 7.2, 9.5] for stranger/unfamiliar, and +1.4% [95%CI 0.8, 1.9] for family/familiar persons). Conclusion Willingness to perform bystander resuscitation during the pandemic decreased, however this was ameliorated if simple PPE were available.

Background In a double-blind, non-inferiority randomized controlled trial injectable hydromorphone, a licensed short acting opioid analgesic, was shown to be as effective as diacetylmorphine for the treatment of severe opioid use disorder. An appropriate question is whether hydromorphone offered open-label can attract and retain patients. Methods This is a retrospective study, using daily prescription data from the Crosstown Clinic in Vancouver, Canada. Treatment retention among participants who had the opportunity to receive open-label injectable hydromorphone for at least 90 consecutive days (n = 108) before having the choice of receiving open-label diacetylmorphine, was compared to their retention outcomes with double-blind injectable opioid agonist treatment (iOAT). McNemar tests analyzed differences in proportions; a conditional logistic model estimated exact odds ratios; Pairwise t-tests analyzed differences in total number of treatment days; and Kaplan-Meier curves and clustered log-rank tests compared time to first 30 continuous days without injectable treatment. Results A total of 74 participants (68.5%) were retained in both open-label hydromorphone and double-blind iOAT. Open-label hydromorphone was not significantly associated with lower retention (OR = 0.5; 95% CI: 0.2, 1.1; p = .10). Participants attended a mean of 84.4 (SD = 15.8) days of iOAT in the trial and 80.5 (SD = 22.0) days in open-label hydromorphone (mean difference of −3.9; 95% CI = −8.9, 1.1). Kaplan-Meier curves and log-rank tests were not statistically significant. Conclusion As treatment with injectable hydromorphone expands across Canada, our study contributes in a unique manner by providing evidence that the high retention rates observed during the clinical trial were maintained when participants started open-label hydromorphone.

AimsTo investigate baseline and concurrent predictors of non-use of illicit heroin among participants randomized to injectable opioids in the North American Opiate Medication Initiative (NAOMI) clinical trial.MethodsNAOMI was an open-label randomized controlled trial comparing the effectiveness of injectable diacetylmorphine and hydromorphone for long-term opioid-dependency. Outcomes were assessed at baseline and during treatment (3, 6, 9, 12months). Days of non-use of illicit heroin in the prior month at each follow-up visit were divided into three categories: Non-use; Low use (1 to 7days) and High use (8days or more). Tested covariates were: Sociodemographics, Health, Treatment, Drug use and illegal activities. Mixed-effect proportional odds models with random intercept for longitudinal ordinal outcomes were used to assess the predictors of the non-use of illicit heroin.Results139 participants were included in the present analysis. At each follow-up visit, those with non-use of illicit heroin represented 47.5% to 54.0% of the sample. Fewer days of cocaine use (p=0.074), fewer days engaged in illegal activities at baseline (p

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. Electronic supplementary material The online version of this article (doi:10.1186/s12962-017-0081-8) contains supplementary material, which is available to authorized users.

One justification for using expensive biologic therapy in rheumatoid arthritis (RA) has been that it can reduce future healthcare utilization such as joint surgeries and physician visits. However, the evidence to support this assertion is unclear. We conducted a review of the literature for studies which have analyzed the trends in resource use of RA patients, and then undertook a retrospective observational analysis of a Canadian administrative database using instrumental variable methods. Our review found a trend in reduced resource utilization prior to the introduction of biologics and no evidence that biologic therapies have specifically contributed to this reduction. Our observational analysis, which overcame some of the epidemiological challenges with determining the influence of biologics on resource utilization, found a possible reduction in other medications but possible increases rather than decreases in physician visits and hospitalizations. However, our sample was not sufficiently large to make definitive conclusions. Over 15 years since the introduction of biologics for RA, no evidence exists supporting the assumption that biologic therapies reduce future healthcare utilization. While such a question is challenging to generate evidence for, and so an absence of evidence does not suggest that the hypothesis is incorrect, an instrumental variable analysis using sufficient data could provide definitive evidence.

Previous research has found diacetylmorphine, delivered under supervision, to be cost-effective in the treatment of severe opioid use disorder, but diacetylmorphine is not available in many settings. The Study to Assess Long-term Opioid Maintenance Effectiveness (SALOME) randomized controlled trial provided evidence that injectable hydromorphone is non-inferior to diacetylmorphine. The current study aimed to compare the cost-effectiveness of hydromorphone directly with diacetylmorphine and indirectly with methadone maintenance treatment.A within-trial analysis was conducted using the patient level data from the 6-month, double-blind, non-inferiority SALOME trial. A life-time analysis extrapolated costs and outcomes using a decision analytical cohort model. The model incorporated data from a previous trial to include an indirect comparison to methadone maintenance.A supervised clinic in Vancouver, British Columbia, Canada.A total of 202 long-term street opioid injectors who had at least two attempts at treatment, including one with methadone (or other substitution), were randomized to hydromorphone (n = 100) or diacetylmorphine (n = 102).We measured the utilization of drugs, visits to health professionals, hospitalizations, criminal activity, mortality and quality of life. This enabled us to estimate incremental costs, quality-adjusted life years (QALYs) and cost-effectiveness ratios from a societal perspective. Sensitivity analyses considered different sources of evidence, assumptions and perspectives.The within-trial analysis found hydromorphone provided similar QALYs to diacetylmorphine [0.377, 95% confidence interval (CI) = 0.361-0.393 versus 0.375, 95% CI = 0.357-0.391], but accumulated marginally greater costs [$49 830 ($28 401-73 637) versus $34 320 ($21 780-55 998)]. The life-time analysis suggested that both diacetylmorphine and hydromorphone provide more benefits than methadone [8.4 (7.4-9.5) and 8.3 (7.2-9.5) versus 7.4 (6.5-8.3) QALYs] at lower cost [$1.01 million ($0.6-1.59 million) and $1.02 million ($0.72-1.51 million) versus $1.15 million ($0.71-1.84 million)].In patients with severe opioid use disorder enrolled into the SALOME trial, injectable hydromorphone provided similar outcomes to injectable diacetylmorphine. Modelling outcomes during a patient's life-time suggested that injectable hydromorphone might provide greater benefit than methadone alone and may be cost-saving, with drug costs being offset by costs saved from reduced involvement in criminal activity.

Long-term (1- to 10-year) outcomes after severe sepsis in previously healthy persons are unknown. We aimed to determine the 1- to 10-year mortality rates of previously healthy patients with severe sepsis and compare these to mortality rates of patients with nonseptic critical illness and the general population.A prospective cohort study of 2,289 patients from one mixed medical-surgical ICU and one cardiovascular surgery ICU. Age- and gender-comparable general British Columbia population was used as comparison. Patients were followed from the date of admission to the ICU to January 31, 2013. Provincial vital statistics were used to determine the patients' date of death. For the general population comparison, expected survival was obtained from life tables of the population of British Columbia, Canada.A quaternary-level provincial referral hospital in Vancouver, British Columbia, Canada.Two thousand two hundred eighty-nine patients from one mixed medical-surgical ICU and one cardiovascular surgery ICU. Age- and gender-comparable general British Columbia population was used for comparison.None.Patients with severe sepsis without comorbidities had higher mortality from 1 to 10 years than general British Columbia population (p0.01). Younger patients with severe sepsis (60 yr) had the worst 1- to 5-year and 5- to 10-year mortality (hazard ratio [95% CI], 17.8 [13.4-24.8] and 6.0 [4-9]) compared with the general population. Patients with severe sepsis had significantly poorer 1- to 10-year mortality rates (30.5%) compared with patients with nonseptic critical illness (22.1%) and patients who have undergone cardiovascular surgery (15.9%). Patients with sepsis had higher mortality rates from 1-5 years and 5-10 years than the general British Columbia population (hazard ratio [95% CI], 4.5 [2.2-9.1] and 2.2 [0.9-14.7]).Previously healthy patients suffering an episode of severe sepsis have increased long-term mortality compared with patients with nonseptic critical illness and a general population.

To determine the effectiveness of injectable hydromorphone and dicaetylmorphine for Indigenous participants in the Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) clinical trial. The study additionally aims to explore the prevalence and frequency of crack cocaine use among subgroups of participants (by gender and ethnicity). This secondary analysis is particularly relevant given the current need for expanded medication assisted treatments for opioid dependence across North America.Participants self-identifying as First Nations, Métis or Inuit were included in the analysis of Indigenous participants. Six-month treatment outcomes are reported as the difference between diacetylmorphine and hydromorphone treatment arms among Indigenous participants and change from baseline to 6 months in each treatment arm. Differences in outcomes are tested between Indigenous and non-Indigenous participants. Crack cocaine use was explored to determine differences between and within subgroups.Approximately one-third of SALOME participants self-identified as Indigenous. Indigenous participants presented to treatment with more structural vulnerabilities (e.g. lower education, higher rates of foster care and separation from biological parents) compared to non-Indigenous participants. After 6 months, Indigenous participants in both treatment arms had a significant reduction in days of street heroin use, opioid use, crack cocaine use and illegal activity. Treatment retention did not differ by treatment arm.Indigenous people that are not engaged by first-line treatments for opioid dependence are in need of effective alternative treatments. Given the political and logistical barriers facing diacetylmorphine, hydromorphone could serve as a more accessible medication to reach and treat this population. [Oviedo-Joekes E, Palis H, Guh D, Marchand K, Brissette S, Lock K, MacDonald S, Harrison S, Anis AH, Krausz M, March DC, Schechter MT. Characteristics and response to treatment among Indigenous people receiving injectable diacetylmorphine or hydromorphone in a randomised controlled trial for the treatment of long-termopioid dependence. Drug Alcohol Rev 2018;37:137-146].

Aims To review the safety profile of injectable hydromorphone and diacetylmorphine and explore if adverse events (AEs) or serious adverse events (SAEs) were associated with dose and patterns of attendance. Methods This was a non-inferiority randomized double-blind controlled trial (Vancouver, Canada) testing hydromorphone (n = 100) and diacetylmorphine (n = 102) for the treatment of severe opioid use disorder. Medications were delivered under the supervision of trained Registered Nurses up to three times daily. AEs were described using MedDRA codes. Results Most common related AEs included immediate post-injection reaction or injection site pruritus reactions, somnolence and opioid overdoses. Adjusted analysis indicated that participants in the hydromorphone group were less likely to have any related AE or SAE compared to the diacetylmorphine group. Related somnolence and opioid overdose events were distributed throughout the six months treatment period. In the diacetylmorphine group, five of the eleven related SAE opioid overdoses (requiring naloxone) occurred in the first 30 days since most recent treatment initiation. Analysis of somnolence and opioid overdose (AEs and SAEs) event rates by received dose suggested a non-linear relationship. However, in the diacetylmorphine group higher event rates per person days were recorded at lower doses. Conclusions When injectable hydromorphone and diacetylmorphine are individually dosed and monitored, their opioid-related side effects, including potential fatal overdoses, are safely mitigated and treated by health care providers. In the midst of an opioid overdose epidemic, injectable options are timely to reach a very important minority of people who inject street opioids and are not attracted to other treatments.

Background: In 1998, the Province of Ontario in Canada adopted price-cap “70/90” regulations whereby the first generic entrant was required to be priced at ≤70% of the associated brand-name product and subsequent generics were priced at ≤90% of the first generic price. The price-caps were further lowered to 50% in 2006 and 25% in 2010. This study assessed the impact of such price-cap regulations on exit by generic drug firms. Methods: Formulary (2003–2012) listings of prescription drugs covered under the Ontario Drug Benefit program were used. The formulary tracks the “status” (on formulary, discontinued by manufacturer, and delisted for other reasons) for each drug. Markets were defined based on unique active ingredient and form within Ontario. Firm exit occurred when a manufacturer discontinued all its generic drugs within a market. The exit rate was defined as the number of generic firm-market exits divided by total generic firm-market follow-up years. Poisson regression was used to compare the exit rates during the 3 policy periods (“25,” “50,” and “70/90”). Results: A total of 1126 generic manufacturers paired with 290 markets were identified. The exit rate ratio during the 25% price-cap period compared with the 70%/90% period was 2.42 (95% confidence interval, 1.56–3.77). A small manufacturer or a manufacturer in a market with ≥3 competitors or in an older market was more likely to exit. Conclusions: Lowering the price-cap level is associated with a higher incidence of generic firm exit from markets. Continuously reducing price-caps may have the unintended consequence of forcing generic firms to exit.

Importance Diacetylmorphine hydrochloride (the active ingredient in heroin), delivered under supervision, is effective for the treatment of severe opioid use disorder. However, owing to political and regulatory barriers, it is not available in many settings around the world, which limits the options for many long-term street opioid injectors not attracted into or retained in available treatments. Objective To test if injectable hydromorphone hydrochloride is noninferior to injectable diacetylmorphine in reducing illicit heroin use for chronic injection opioid users after 6 months of intervention. Design, Setting, and Participants The Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) was a phase 3, double-blind, noninferiority trial. The study randomized 202 long-term street opioid injectors in Vancouver, British Columbia, Canada. Eligible participants were recruited between December 19, 2011, and December 18, 2013. Both intent-to-treat (ITT) and per-protocol (PP) analyses were conducted. Interventions Participants were randomly assigned to receive injectable diacetylmorphine or hydromorphone (up to 3 times daily) for 6 months under supervision. Main Outcomes and Measures Primary and coprimary efficacy outcomes were self-reported days of street heroin use (primary), days of any street-acquired opioids in the prior 30 days (noninferiority margin, 4 days), and the proportion of urinalyses positive for street heroin markers (margin, 10% of the observed rate in the diacetylmorphine group). The mean differences between diacetylmorphine and hydromorphone for the ITT and PP analyses were reported. Results The study included 202 participants; 100 randomized to receive hydromorphone and 102 to diacetylmorphine. Their mean (SD) age was 44.33 (9.63) years, and 30.7% (62 of 202) were women. Noninferiority of hydromorphone was confirmed in the PP analysis (−1.44; 90% CI, −3.22 to 0.27) for street heroin use, although the margin of 4 days was not excluded in the ITT analysis (−2.34; 90% CI, −4.14 to −0.52). Noninferiority was confirmed for any street opioids in the ITT analysis (−0.85; 90% CI, −2.97 to 1.25) and the PP analysis (−0.15; 90% CI, −2.09 to 1.76), as well as for the urinalyses (0.09; 90% CI, −0.02 to 0.19 for the ITT analysis and 0.13; 90% CI, 0.02-0.24 for the PP analysis). There were 29 SAEs considered to have some relationship with the injection medication, 5 in the hydromorphone group and 24 in the diacetylmorphine group (rate ratio, 0.21; 95% CI, 0.06-0.69). Seizures and overdoses accounted for 25 of the 29 related SAEs. Conclusions and Relevance This study provides evidence to suggest noninferiority of injectable hydromorphone relative to diacetylmorphine for long-term opioid dependence. In jurisdictions where diacetylmorphine is currently not available or for patients in whom it is contraindicated or unsuccessful, hydromorphone could be offered as an alternative. Trial Registration clinicaltrials.gov Identifier:NCT01447212

International audience; Objectives: To value health resource utilisation and productivity losses in DESIR, a longitudinal French cohort of 708 patients with early spondyloarthritis (SpA) enrolled between 2007 and 2010, and identify factors associated with costs in the first 3 years of follow-up. Methods: Self-reported clinical data from DESIR and French public data were used to value health resource utilisation and productivity losses in 2013 Euros. Factors associated with costs, including and excluding biological drugs, were identified in generalised linear models using the generalised estimating equations algorithm to account for repeated observations over participants. Results: The mean (±SD) annual cost per patient was €5004±6870 in year 1, decreasing to €4961±7457 in year 3. Patients who never received a biologic had mean 3-year total costs of €4789±6022 compared to €38 206±19 829 among those who received a biologic. Factors associated with increased total costs were peripheral arthritis (rate ratio (RR) 1.19; 95% CI 1.04 to 1.37; p

Objectives. To understand the impact of the early years of RA on all aspects of work productivity, and determine how this is related to clinical markers. Previous research on work productivity has examined predominantly early retirement and absenteeism. The impact of reduced work performance (presenteeism) and activity impairment is less well understood in early RA populations. Methods. Working patients enrolled in an RA inception cohort were recruited into a nested study. A questionnaire incorporating the Work Productivity and Activity Impairment (WPAI) instrument was administered with a number of clinical outcomes, including the Multidimensional Health Assessment Questionnaire (MD-HAQ) and scales for pain, fatigue and patient assessment of disease patient global assessment (PtGA). Results. Analysis included 150 RA patients, with the mean age at onset being 48 years (S.D. 10 years) and disease duration from symptom onset being 49 months. Patients had relatively mild disease: MD-HAQ (0.6), pain (3.6), PtGA (3.6) and fatigue (4.6). Of the 92% patients working for pay, 19% reported missing work (absenteeism) in the past week due to their health, accounting for 46% of their working time. Even while at work, 25% of actual hours was lost due to poor health, while outside work 33% of patients’ regular daily activities were prevented. In multivariate analyses, disease severity was associated with the presence of absenteeism, presenteeism and activity impairment. Patients able to self-schedule their work had lower presenteeism and activity impairment. Conclusions. Productivity loss is common in patients in the first years of RA who are in paid work and was associated with work characteristics and adverse clinical outcomes.

Objective To provide a comparative analysis of the psychometric properties of eight measures of health status among chronic opioid-dependent patients. Study Design and Setting Longitudinal data were analyzed for 251 patients enrolled in the North American Opiate Medication Initiative randomized controlled trial, conducted in Vancouver, British Columbia and Montreal, Quebec, Canada. Content validity, evidence of floor and ceiling effects, internal consistency, construct validity, and responsiveness were assessed for the Addiction Severity Index (ASI) medical and psychiatric (ASImed and ASIpsych) composite scores, the Maudesley Addiction Profile (MAP) physical and mental health scores (MAP-physical health score [MAP-PHS], MAP-mental health score [MAP-MHS]), the World Health Organization Disability Assessment Schedule-II, the EuroQol Group's EQ-5D index score and visual analog scale, EuroQol visual analog scale (EQ-VAS), and the Short Form SF-6D index score. Results ASImed was best able to discriminate among patients with and without chronic conditions. The MAP-PHS and MAP-MHS were not unidimensional. ASImed and ASIpsych had prominent ceiling effects. ASImed, MAP-MHS, MAP–PHS, EQ-VAS, and EQ-5D were all responsive to decreases in illicit drug use. Conclusion None of the instruments performed uniformly as “best” or “worst.” The EQ-5D appeared to be the preferable generic, indirect utility measure. Our results provide an evidence base to inform selection and further development of health status measures in opioid-dependent populations.

Background: There is consistent evidence showing women access treatment with more severe substancerelated profiles relative to men; however, treatment outcome evaluation shows inconclusive results regarding gender differences. Furthermore, few studies evaluate response by gender. Methods: The present analyses were performed using data from the NAOMI study, an open-label, phase III randomized controlled trial, carried out between 2005 and 2008 in Vancouver and Montreal, Canada. A total of 226 long-term treatment-refractory opioid dependent individuals were randomized to receive injectable diacetylmorphine or oral methadone for 12 months. Patients in both treatment groups were offered psychosocial and primary care services. Main outcomes were retention in addiction treatment at 12 months. Drug use, health, psychosocial adjustment and health-related quality of life were examined at baseline and during treatment, using the European Addiction Severity Index, Maudsley Addiction Profile, SF-6D and EuroQol EQ-5D. Results: A total of 88 (38.9%) females and 138 (61.1%) males were included in the present analysis. Retention rates among female participants in the diacetylmorphine group were significantly higher than oral methadone (83.3% vs. 47.8%). Males receiving diacetylmorphine improved significantly more than females in physical health, health-related quality of life, and family relations but female participants in the diacetylmorphine group had significantly greater improvements in illicit drug use scores and psychological health compared to females allocated to oral methadone. Conclusions: Among long-term opioid dependent women who have not benefited sufficiently from available treatments, medically prescribed diacetylmorphine is more effective than oral methadone. Men receiving diacetylmorphine showed more improvements than women.

Using data from the North American Opioid Maintenance Initiative study, a Phase III randomized and parallel arm trial, this pilot study is aimed at testing if treatment response with injectable hydromorphone differs compared to diacetylmorphine in the treatment of long-term opioid addiction. A total of 140 long-term, treatment-refractory opioid-dependent individuals received either injectable diacetylmorphine (n = 115) or hydromorphone (n = 25), in a double-blind fashion, over 12 months. At the end of the study, none of the participants in the hydromorphone group thought they were definitely receiving this drug. Retention rates at 12 months with diacetylmorphine (87.8%; 95% confidence interval [CI] = 80.5%-92.7%) and hydromorphone (88.0%; 95% CI = 68.7%-96.1%) were virtually identical. The use of illicit heroin in the prior month declined from a mean of 26.6 and 26.3 days at baseline to 5.3 and 5.2 days at 12 month in the diacetylmorphine and hydromorphone groups, respectively. There were no differences between diacetylmorphine and hydromorphone in the adjusted mean scores of the European Addiction Severity Index. There were no differences in the safety profile of the medications. Hydromorphone may be similarly safe and effective as diacetylmorphine as opioid-agonist substitution treatment; future studies are required to confirm it. Further study will also be required to show that open-label hydromorphone can also successfully attract patients into care and retain them.

This study is to update the estimates of the economic burden of illness because of overweight and obesity in Canada by incorporating the increase in prevalence of overweight and obesity, findings of new related comorbidities and rise in the national healthcare expenditure. The burden was estimated from a societal perspective using the prevalence-based cost-of-illness methodology. Results from a literature review of the risks of 18 related comorbidities were combined with prevalence of overweight and obesity in Canada to estimate the extent to which each comorbidity is attributable to overweight and obesity. The direct costs were extracted from the National Health Expenditure Database and allocated to each comorbidity using weights principally from the Economic Burden of Illness in Canada. The study showed that the total direct costs attributable to overweight and obesity in Canada were $6.0 billion in 2006, with 66% attributable to obesity. This corresponds to 4.1% of the total health expenditures in Canada in 2006. The inclusion of newly identified comorbidities increased the direct cost estimates of obesity by 25%, while the rise in national healthcare expenditure accounted for a 19% increase. Policies to reduce being overweight and obese could potentially save the Canadian healthcare system millions of dollars.

Studies in Europe have suggested that injectable diacetylmorphine, the active ingredient in heroin, can be an effective adjunctive treatment for chronic, relapsing opioid dependence.In an open-label, phase 3, randomized, controlled trial in Canada, we compared injectable diacetylmorphine with oral methadone maintenance therapy in patients with opioid dependence that was refractory to treatment. Long-term users of injectable heroin who had not benefited from at least two previous attempts at treatment for addiction (including at least one methadone treatment) were randomly assigned to receive methadone (111 patients) or diacetylmorphine (115 patients). The primary outcomes, assessed at 12 months, were retention in addiction treatment or drug-free status and a reduction in illicit-drug use or other illegal activity according to the European Addiction Severity Index.The primary outcomes were determined in 95.2% of the participants. On the basis of an intention-to-treat analysis, the rate of retention in addiction treatment in the diacetylmorphine group was 87.8%, as compared with 54.1% in the methadone group (rate ratio for retention, 1.62; 95% confidence interval [CI], 1.35 to 1.95; P0.001). The reduction in rates of illicit-drug use or other illegal activity was 67.0% in the diacetylmorphine group and 47.7% in the methadone group (rate ratio, 1.40; 95% CI, 1.11 to 1.77; P=0.004). The most common serious adverse events associated with diacetylmorphine injections were overdoses (in 10 patients) and seizures (in 6 patients).Injectable diacetylmorphine was more effective than oral methadone. Because of a risk of overdoses and seizures, diacetylmorphine maintenance therapy should be delivered in settings where prompt medical intervention is available. (ClinicalTrials.gov number, NCT00175357.)

To assess the concurrent validity and responsiveness of the Health Utility Index 3 (HUI3) in patients with advanced HIV/AIDS, and to determine the responsiveness of this measure, the MOS-HIV and EQ-5D to HIV-related clinical events.Data from the OPTIMA (OPTions In Management with Antiretrovirals) trial was analyzed. Two aspects of the validity of the HUI3 were considered: concurrent validity was evaluated using Spearman correlations with MOS-HIV component and summary scores. Responsiveness to AIDS-defining events (ADE) and all adverse events (our external change criterion) was assessed using area under the receiver operating characteristic (AUROC) curves.The study enrolled 368 patients (mean follow-up: 3.66 years); 82% had at least one severe adverse event and 27% had at least one ADE. The HUI3 scale and items showed good concurrent validity, with 85% of the expected relationships with the MOS-HIV subscales verified. The HUI3 was responsive to both adverse events (AUROC [95%CI]: 0.68 [0.57, 0.80]) and ADEs (0.62 [0.51, 0.74]). The EQ-5D was responsive to ADEs (0.66 [0.56, 0.76]), but not responsive to adverse events (0.56 [0.46, 0.68]).The HUI3 is a valid and responsive measure of the change in HRQoL associated with clinical events in an advanced HIV/AIDS population.

Background There is evidence that utility elicitation methods used in the calculation of quality-adjusted life years (QALYs) yield different results. It is not clear how these differences impact economic evaluations. Methods Using a mathematical model incorporating data on efficacy, costs, and utility values, we simulated the experiences of 100,000 hypothetical rheumatoid arthritis patients over 10 years (50,000 exposed to infliximab plus methotrexate [MTX] and 50,000 exposed to MTX alone). QALYs, were derived from the Health Utilities Index 2 and 3 (HUI2 and HUI3), the Short Form 6-D (SF-6D), and the Euroqol 5-D (EQ-5D). Incremental cost-utility ratios were determined using each instrument to calculate QALYs and the results were compared using cost-effectiveness acceptability curves. Results Using the different utility measurement methods, the mean difference in QALYs between the infliximab plus MTX and MTX groups ranged from a high of 1.95 QALYs (95% CI = 1.93–1.97) using the HUI3 to 0.89 QALYs (95% CI = 0.88–0.91) using the SF-6D. Adopting the commonly cited value of society's willingness to pay for a QALY of $50,000, 91% of the simulations favored the cost utility of infliximab plus MTX when using the HUI3 to calculate QALYs. However, when using the EQ-5D, HUI2, or the SF-6D utility values to calculate QALYS, the proportion of simulations that favored the cost utility of infliximab were 63%, 45%, and 12%, respectively. Conclusion Depending on the method for determining utility values used in the calculation of QALYs, very different incremental cost-utility ratios are generated.

Purpose: A recent randomized clinical trial has demonstrated that direct decompressive surgery plus radiotherapy was superior to radiotherapy alone for the treatment of metastatic epidural spinal cord compression. The current study compared the cost-effectiveness of the two approaches. Methods and Materials: In the original clinical trial, clinical effectiveness was measured by ambulation and survival time until death. In this study, an incremental cost-effectiveness analysis was performed from a societal perspective. Costs related to treatment and posttreatment care were estimated and extended to the lifetime of the cohort. Weibull regression was applied to extrapolate outcomes in the presence of censored clinical effectiveness data. Results: From a societal perspective, the baseline incremental cost-effectiveness ratio (ICER) was found to be $60 per additional day of ambulation (all costs in 2003 Canadian dollars). Using probabilistic sensitivity analysis, 50% of all generated ICERs were lower than $57, and 95% were lower than $242 per additional day of ambulation. This analysis had a 95% CI of $72.74 to 309.44, meaning that this intervention ranged from a financial savings of $72.74 to a cost of $309.44 per additional day of ambulation. Using survival as the measure of effectiveness resulted in an ICER of $30,940 per life-year gained. Conclusions: We found strong evidence that treatment of metastatic epidural spinal cord compression with surgery in addition to radiotherapy is cost-effective both in terms of cost per additional day of ambulation, and cost per life-year gained. © 2006 Elsevier Inc. Metastatic spinal cord compression, Cost-effectiveness, Clinical trials, Radiotherapy, Surgery, Secondary neoplasm.

Background: Previous research has shown that patient cost-sharing leads to a reduction in overall health resource utilization. However, in Canada, where health care is provided free of charge except for prescription drugs, the converse may be true. We investigated the effect of prescription drug cost-sharing on overall health care utilization among elderly patients with rheumatoid arthritis. Methods: Elderly patients (≥ 65 years) were selected from a population-based cohort with rheumatoid arthritis. Those who had paid the maximum amount of dispensing fees ($200) for the calendar year (from 1997 to 2000) were included in the analysis for that year. We defined the period during which the annual maximum co-payment had not been reached as the “cost-sharing period” and the one beyond which the annual maximum co-papyment had been reached as the “free period.” We compared health services utilization patterns between these periods during the 4 study years, including the number of hospital admissions, the number of physician visits, the number of prescriptions filled and the number of prescriptions per physician visit. Results: Overall, 2968 elderly patients reached the annual maximum cost-sharing amount at least once during the study periods. Across the 4 years, there were 0.38 more physician visits per month ( p p = 0.001) and 0.52 fewer prescriptions filled per physician visit ( p p = 0.03). Interpretation: In a predominantly publicly funded health care system, the implementation of cost-containment policies such as prescription drug cost-sharing may have the unintended effect of increasing overall health utilization among elderly patients with rheumatoid arthritis.

Objective Treatment guidelines for rheumatoid arthritis (RA) now recommend early, aggressive, and persistent use of disease-modifying antirheumatic drugs (DMARDs) to prevent joint damage in all people with active inflammation, and evaluation by a rheumatologist, when possible. This research assesses whether care for RA, at a population level, is consistent with current treatment guidelines. Methods Using administrative billing data from the Ministry of Health in 1996–2000, all prevalent RA cases in British Columbia, Canada were identified. Data were obtained on all medications and all provincially-funded health care services. Results We identified 27,710 RA cases, yielding a prevalence rate of 0.76%, consistent with epidemiologic studies. DMARD use was inappropriately low. Only 43% of the entire RA cohort received a DMARD at least once over 5 years, and 35% over 2 years. When used, DMARDs were started in a timely fashion, but were not used consistently. Care by a rheumatologist increased DMARD use 31-fold. Yet, only 48% and 34% saw a rheumatologist over 5 and 2 years, respectively. DMARD use was significantly more frequent, persistent, and more often used as combination therapy with continuous rheumatologist care. DMARDs were used by 84% and 73%, 40%, and 10% of people followed by rheumatologists continuously and intermittently, internists, and family physicians, respectively (P < 0.001). NSAID use, physiotherapy, and orthopedic surgeries were similar across these 4 care groups. Conclusion RA care in the British Columbia population was not consistent with current treatment guidelines. Efforts to educate family physicians and consumers about the shift in RA treatment paradigms and to improve access to rheumatologists are needed.

Background Leaving the hospital against medical advice has been associated with increased morbidity and readmission. Factors associated with the risk of leaving against medical advice among HIV/AIDS patients or injection drug users have not been examined in detail. Objectives To examine the clinical and social factors associated with leaving against medical advice (AMA) from a specialized HIV/AIDS ward among patients who reported a history of injection drug use. Methods All patients with a history of injection drug use admitted to the HIV/AIDS ward at St. Paul's Hospital, Vancouver, British Columbia (the largest specialized HIV/AIDS hospital ward in Canada) between April 1997 and October 2000 were reviewed retrospectively. A multivariate logistic regression model utilizing a generalized estimating equation algorithm identified factors associated with leaving the hospital AMA. Results Of the 1056 hospital admissions to the HIV/AIDS ward by patients with a history of injection drug use, 263 (24.9%) resulted in leaving the hospital AMA. Independent positive predictors of leaving AMA included recent injection drug use (adjusted odds ratio [AOR] = 2.08, 95% confidence interval [CI]: 1.41-3.07) and aboriginal ethnicity (AOR = 1.55, 95% CI: 1.05-2.28). Discharge AMA was also more likely to occur on weekends (AOR = 2.27, 95% CI: 1.49-3.48) and on days when social assistance payments were issued (AOR = 2.95, 95% CI: 1.70-5.10). Factors that independently reduced the odds of hospital discharge AMA included in-hospital methadone use (AOR = 0.49, 95% CI: 0.32-0.76), social support (AOR = 0.33, 95% CI: 0.21-0.51), and older age (per 10-year increment, AOR = 0.56, 95% CI: 0.43-0.73). Conclusions Among HIV-positive patients with a history of injection drug use, the odds of leaving the hospital AMA were reduced for subjects who received inpatient methadone treatment, were of older age, or had social supports. Addiction treatment and interventions that enhance social supports in marginalized populations at risk for hospital discharge AMA should be further explored.

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. Each province in Canada independently assesses drugs for their reimbursement eligibility. Publicly funded access to specific drugs is therefore dependent on province of residence. Objective. Evaluate the variability of access and its determinants for publicly available prescription drugs across Canada, and discuss the feasibility of implementing a national plan. Methods. For a sample of 58 drugs receiving Health Protection Branch approval in Canada between 01/01/1996 and 12/31/1997, all provinces were surveyed about their formulary inclusion/exclusion decision. Kappa values were estimated to measure concordance between provincial coverage decisions. Logistic analysis using Generalized Estimating Equations was used to assess the impact of key features of provincial plans on the decision. Results. Among the 58 drugs, 5 (9%) were included in all 10 and 14 (24%) by at least 8 provincial formularies. None were e-cluded by all the provinces. Concordance rates among provinces were low (overall κ-like statistic = 0.20 and range of pairwise κ = -0.11 to 0.64). Logistic regression showed that therapeutic category, price ratio to comparator, the integration of public with private coverage, and the e-istence of ability-to-pay criteria were significant determinants of the inclusion decision. Conclusions. Findings show that public access to the same prescription medications differs widely across provinces. If Canada were to adopt a “National” plan without disrupting current individual prescriptions, all currently funded drugs in each province would have to be “grandfathered” and included in the new National formulary. Such an all-inclusive list would also make such a plan unaffordable.

Objective. To determine factors associated with response or toxicity to cyclosporin A (CSA) in a population-based inception cohort with rheumatoid arthritis (RA). Methods. Prospectively collected longitudinal measures including tender joint count (JC), duration of morning stiffness (MS), systolic and diastolic blood pressure (SBP, DBP), and serum creatinine (SCr) were modeled using generalized estimating equations. Survival methods were used to estimate CSA continuation time and its determinants. Results. Of 133 patients (75% female, median RA duration 13 years), 37 discontinued CSA because of ineffectiveness (19) or because of toxicity (18) including increased SCr in 10, hypertension in 4, infections in 3, and gingival hyperplasia in 1. Patients remained on CSA a median of 75 months (95% confidence interval [CI] 38 ‐112). Those receiving concomitant methotrexate (MTX) were more than 4 times as likely to continue on CSA therapy (hazard ratio 0.22, 95% CI 0.10 ‐ 0.94). A lower final JC was predicted by a longer CSA treatment duration (relative risk [RR] 0.99 per month, 95% CI 0.98 ‐ 0.99) and concomitant MTX therapy (RR 0.79, 95% CI 0.63‐ 0.99); decreased MS was predicted only by longer CSA treatment duration (reduction of 2.0 minutes per month, 95% CI 1.1‐3.0). Each previous disease-modifying antirheumatic drug (DMARD) exposure predicted a rise in SCr (35 mmole/liter, 95% CI 22‐ 48), SBP (7.2 mm Hg, 95% CI 2.7‐11.7), and DBP (3.8 mm Hg, 95% CI 3.0 ‐ 6.4). Conclusions. Combination CSA/MTX prolongs therapy and reduces JC. Long-term CSA treatment was fairly well tolerated. Previous DMARD use appears to be a determinant for the development of toxicity.

Background: Medically prescribed diacetylmorphine, the active ingredient of heroin, has been shown to be effective for the treatment of severe opioid addiction. However, there are no data regarding its effectiveness among Aboriginal heroin injectors. Methods: The present analyses were performed using data from the NAOMI study (North American Opiate Maintenance Initiative), an open-label randomized controlled trial that compared the effectiveness of injectable diacetylmorphine (45.8%) and hydromorphone (10%) vs. oral methadone (44.2%) among long-term treatment-refractory opioid-dependent individuals. Rates of retention and response to treatment were analyzed among participants from the Vancouver site (n=192). Results: Baseline profiles were similar among Aboriginal (n=60) and non-Aboriginal (n=132) participants except for higher HIV positive rates among Aboriginal people (23.3% vs. 8.3%). Among Aboriginal participants in the injection and methadone groups, retention rates at 12 months were 84.4% vs. 57.1% and response rates were 68.8% vs. 53.4%, respectively. Aboriginal and non-Aboriginal rates were not significantly different. Discussion: Offering treatment assisted with medically prescribed diacetylmorphine or hydromorphone to long-term treatment-refractory opioid-dependent Aboriginal people could be an effective way to attract them into and retain them in treatment as well as dramatically reduce the risk of HIV infection. Key words: Aboriginal, Canada; opioid-dependence; substitution treatment; diacetylmorphine, injectable; hydromorphone, injectable; methadone, oral

To estimate survival, the number of life-years gained and cost effectiveness of antiretroviral therapy (ART) regimens, denoted as ERA-I [zidovudine + (didanosine or zalcitabine)]; ERA-II [stavudine + (didanosine or zalcitabine) or lamivudine + (zidovudine or didanosine or zalcitabine or stavudine)]; and ERA-III [2 nucleoside reverse transcriptase inhibitors + (1 protease inhibitor or 1 non-nucleoside reverse transcriptase inhibitor)].Modelling of drug cost, cost of opportunistic diseases and survival of HIV positive men and women in the province of British Columbia who were first prescribed any ART between October 1992 and June 1996. A 'reference cohort' was modelled upon individuals in a longitudinal cohort of homosexual men followed since 1982. PERSPECTIVE AND SETTING: Third-party payer perspective in British Columbia, Canada.All HIV-positive men and women agedor =18 years with CD4+ countsor =350 cells/microL who were enrolled in the province-wide drug treatment programme.Annual costs, survival and cost-effectiveness ratios of successive ART regimens.Total costs [1997 Canadian dollars ($Can)] at 12 months under ERA-I, -II and -III were $Can4897, $Can6620 and $Can 11 914, respectively. Survival at 12 months under ERA-I, -II and -III was 89.6%, 91.0% and 97.6%, respectively. The annual incremental cost (estimated by the total incremental cost at 12 months) between ERA-II and ERA-I was $Can1723. The incremental cost-effectiveness ratios between ERA-III and ERA-I, and between ERA-III and ERA-II were $Can58 806 and $Can46 971 per life-year gained, respectively.We found the cost effectiveness of ERA-III ART regimens well within the range of currently funded therapies for the treatment of other chronic diseases.

Numerous websites offer direct-to-consumer (DTC) genetic testing, yet it is unknown how individuals will react to genetic risk profiles online. The objective of this study was to determine the feasibility of using a web-based survey and conjoint methods to elicit individuals' interpretations of genetic risk profiles by their anticipated worry/anxiousness and health-seeking behaviors.A web-based survey was developed using conjoint methods. Each survey presented 12 hypothetical genetic risk profiles describing genetic test results for four diseases. Test results were characterized by the type of disease (eight diseases), individual risk (five levels), and research confidence (three levels). After each profile, four questions were asked regarding anticipated worry and health-seeking behaviors. Probabilities of response outcomes based on attribute levels were estimated from logistic regression models, adjusting for covariates.Overall, 319 participants (69%) completed 3828 unique genetic risk profiles. Across all profiles, most participants anticipated making doctor's appointments (63%), lifestyle changes (57%), and accessing screening (57%); 40% anticipated feeling more worried and anxious. Higher levels of disease risk were significantly associated with affirmative responses.Conjoint methods may be used to elicit reactions to genetic information online. Preliminary results suggest that genetic information may increase worry/anxiousness and health-seeking behaviors among consumers of DTC tests. Further research is planned to determine the appropriateness of these affects and behaviors.

Background: Although diacetylmorphine has been proven to be more effective than methadone maintenance treatment for opioid dependence, its direct costs are higher. We compared the cost-effectiveness of diacetylmorphine and methadone maintenance treatment for chronic opioid dependence refractory to treatment. Methods: We constructed a semi-Markov cohort model using data from the North American Opiate Medication Initiative trial, supplemented with administrative data for the province of British Columbia and other published data, to capture the chronic, recurrent nature of opioid dependence. We calculated incremental cost-effectiveness ratios to compare diacetylmorphine and methadone over 1-, 5-, 10-year and lifetime horizons. Results: Diacetylmorphine was found to be a dominant strategy over methadone maintenance treatment in each of the time horizons. Over a lifetime horizon, our model showed that people receiving methadone gained 7.46 discounted quality-adjusted life-years (QALYs) on average (95% credibility interval [CI] 6.91–8.01) and generated a societal cost of $1.14 million (95% CI $736 800–$1.78 million). Those who received diacetylmorphine gained 7.92 discounted QALYs on average (95% CI 7.32–8.53) and generated a societal cost of $1.10 million (95% CI $724 100–$1.71 million). Cost savings in the diacetylmorphine cohort were realized primarily because of reductions in the costs related to criminal activity. Probabilistic sensitivity analysis showed that the probability of diacetylmorphine being cost-effective at a willingness-to-pay threshold of $0 per QALY gained was 76%; the probability was 95% at a threshold of $100 000 per QALY gained. Results were confirmed over a range of sensitivity analyses. Interpretation: Using mathematical modelling to extrapolate results from the North American Opiate Medication Initiative, we found that diacetylmorphine may be more effective and less costly than methadone among people with chronic opioid dependence refractory to treatment.

Objective. To explore rates of and reasons for work disability in an early RA cohort with median 10 years follow-up. Methods. One thousand four hundred and sixty patients with early RA (

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 While opioid substitution treatment (OST) provides the opportunity for substantial improvements in health related quality of life (HRQoL), this relationship is seldom documented and poorly understood. Our objectives were to identify differences in trajectories of HRQoL among chronic opioid-dependent patients and factors associated with improvement and deterioration in HRQoL following enrolment in opioid substitution treatment. Methods In the North American Opiate Medication Initiative (NAOMI) randomized controlled trial, the Euroqol (EQ-5D) and other measures of demographic, health and drug use characteristics were collected at baseline and quarterly follow-up. Latent class growth analysis was applied to identify classes of HRQoL trajectories during treatment, while baseline correlates of class membership and factors associated with changes in HRQoL were identified in multivariate analyses. Results Three classes of individual HRQoL growth trajectories were identified: class 1: low and constant (19.5%), class 2: moderate and improved (61.2%), and class 3: high and constant (19.3%). Class 1 members were younger and more likely to be female, while class 3 members were less likely to have chronic conditions and had lower illicit drug use severity at baseline. Changes in HRQoL were associated with improvements in housing status (positive), medical events (negative) and decreases in illicit drug use (positive). Conclusions Insight into the extent of HRQoL response and characteristics of patients responding to treatment can be used to design interventions that maximize HRQoL improvement. Given its role in economic evaluation and subsequent resource allocation decisions, HRQoL should be considered an endpoint in treatment evaluations for opioid dependence.