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Centre for Health Evaluation & Outcome Sciences, Providence Health Care, St. Paul's Hospital, 575-1081 Burrard St., Vancouver, BC V6Z 1Y6, CanadaSchool of Population and Public Health, University of British Columbia, 2206 East Mall, Vancouver, BC V6T 1Z3, Canada
Centre for Health Evaluation & Outcome Sciences, Providence Health Care, St. Paul's Hospital, 575-1081 Burrard St., Vancouver, BC V6Z 1Y6, CanadaSchool of Population and Public Health, University of British Columbia, 2206 East Mall, Vancouver, BC V6T 1Z3, Canada
Centre for Health Evaluation & Outcome Sciences, Providence Health Care, St. Paul's Hospital, 575-1081 Burrard St., Vancouver, BC V6Z 1Y6, CanadaSchool of Population and Public Health, University of British Columbia, 2206 East Mall, Vancouver, BC V6T 1Z3, Canada
Northern Ontario School of Medicine, 935 Ramsey Lake Road, Sudbury, ON P3E 2C6, CanadaCanadian Addiction Treatment Centres, 175 Commerce Valley West, Suite 300, Markham, Ontario L3T 7P6, Canada
Centre for Health Evaluation & Outcome Sciences, Providence Health Care, St. Paul's Hospital, 575-1081 Burrard St., Vancouver, BC V6Z 1Y6, CanadaSchool of Population and Public Health, University of British Columbia, 2206 East Mall, Vancouver, BC V6T 1Z3, Canada
High retention rates observed in the clinical trial were maintained with open label.
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Daily hydromorphone doses did not differ in open label vs. double blind treatment.
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Hydromorphone offered open-label can retain patients into treatment.
Abstract
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.
The Global Burden of Disease projects: What have we learned about illicit drug use and dependence and their contribution to the global burden of disease?.
). In North America, this is compounded by the current opioid-overdose crisis that has further underscored the urgent need for improved access to effective care (
In Europe and Canada evidence from several randomized controlled trials (RCTs) has shown injectable opioid agonist treatment (iOAT), with diacetylmorphine (i.e., pharmaceutical-grade heroin), to be effective (
Supervised injectable heroin or injectable methadone versus optimised oral methadone as treatment for chronic heroin addicts in England after persistent failure in orthodox treatment (RIOTT): A randomised trial.
). For those settings a Canadian study (the Study to Assess Longer-term Opioid Medication Effectiveness; SALOME) demonstrated in a double-blind, non-inferiority RCT that injectable hydromorphone, a licensed short acting opioid analgesic, was as effective and cost-effective as diacetylmorphine for the treatment of severe opioid use disorder (
Oviedo-Joekes, E., Guh, D., Brissette, S., Marchand, K., MacDonald, S., Lock, K., … Schechter, M. T. (2016). Hydromorphone compared with diacetylmorphine for long-term opioid dependence: A randomized clinical trial. JAMA Psychiatry, 73(5), 1–9.
In SALOME participants had a clear preference for being randomized to diacetylmorphine (at baseline, 83% indicated they preferred injectable diacetylmorphine to injectable hydromorphone). However, during the study, they did not guess the medication they were receiving beyond what would be expected by chance, and thinking they were receiving hydromorphone did not lead to lower retention rates (
Predictors of treatment allocation guesses in a randomized controlled trial testing double-blind injectable hydromorphone and diacetylmorphine for severe opioid use disorder.
). As the expansion of treatment with injectable hydromorphone is considered across Canada, a natural subsequent question is whether hydromorphone can attract and retain patients on an open-label basis. The former SALOME study site (Crosstown Clinic in Vancouver) was the first to offer open-label hydromorphone. The present study aims to determine if treatment retention among participants receiving open-label injectable hydromorphone at Crosstown Clinic differed from the period when they received double-blinded iOAT treatment in SALOME. If patients are retained with open-label hydromorphone, policy makers and health care providers will have further evidence to support building capacity and offer iOAT with this current licensed medication.
2. Methods
2.1 Design, setting, and participants
This is a retrospective study involving long-term opioid-dependent people that were participants in the SALOME clinical trial and subsequently were offered and received open-label injectable hydromorphone at the Crosstown Clinic (for detailed trial patients' profile see: (
Oviedo-Joekes, E., Marchand, K., Guh, D., MacDonald, S., Lock, K., Brissette, S., … Schechter, M. T. (2015a). History of treatment access and drug use among participants in a trial testing injectable opioids under supervision for long-term heroin injectors. Journal of Addiction Medicine, 3(1), 1015.
). The SALOME trial randomized 202 participants; however the study site only had capacity to treat approximately 90 patients on injectable medications at a time (e.g., due to trial-related pre-post safety assessments and protocols) (
). Thus, as SALOME participants completed their injectable treatment periods, those who were willing were transferred to oral agonist treatment. When the trial was reaching completion, in the summer of 2014, all former trial participants still receiving treatment at the study site were offered open-label injectable hydromorphone (i.e., as off-label, but licensed in Canada for pain). With the trial period over (i.e., now the site running as a program), greater flexibility in the treatment protocols allowed Crosstown Clinic to expand to 140 spaces for injectable treatment. At the same time, requests to the federal government under Health Canada's Special Access Programme (SAP) were being made for individual patients to be dispensed diacetylmorphine (not manufactured or licensed in Canada) on the basis of compassionate access. Physicians submitted SAP requests for individual patients to Health Canada including letters detailing patient history and current health and drug use. Patients' SAPs were approved on a case-by-case basis. Patients with approved SAPs were started on injectable diacetylmorphine (first individual doses arrived on November 2014) as diacetylmorphine supplies were available from abroad. This process took between 3 and 6 months. To date, Crosstown Clinic is the only site in North America that delivers iOAT with diacetylmorphine.
Treatment protocols have been described elsewhere (
Oviedo-Joekes, E., Guh, D., Brissette, S., Marchand, K., MacDonald, S., Lock, K., … Schechter, M. T. (2016). Hydromorphone compared with diacetylmorphine for long-term opioid dependence: A randomized clinical trial. JAMA Psychiatry, 73(5), 1–9.
). Briefly, injectable medications were self-administered under the observation of Registered Nurses (RN) and could not be taken outside of the clinic. RNs monitored patients to ensure their safety both before (e.g., no signs of intoxication) and after (e.g., no signs of over-sedation, respiratory depression, etc.) taking the medications. Participants could receive up to three doses per day: up to 200 mg per dose and up to 500 mg per daily-total of hydromorphone, and up to 400 mg per dose and 1000 mg per daily-total of diacetylmorphine. During the trial, doses were presented in diacetylmorphine equivalents to preserve the double-blind. In addition to RNs and Physicians, participants had access to Social Workers, Nutritionists and Allied Health Professionals on site during both double-blind and open-label periods. The interdisciplinary care team focuses on building a care environment that is safe and inclusive for all patients. Care is provided with a patient centered approach, where patients are active partners in decisions about their care (e.g. dose.) (
Nursing therapeutic relationship and its role on patients' daily attendance and street opioid use among patients receiving injectable opioid agonist treatment at Crosstown Clinic.
Paper presented at the Canadian Society of Addiction Medicine Annual Conference in Vancouver, BC, Canada on October 26th 2018. 2018
A total of 150 of the SALOME participants receiving treatment at the study site at the end of the trial were eligible for this study. Of these, 129 participants were transitioned to open-label hydromorphone while 21 were transitioned directly to open-label diacetylmorphine because their SAPs started before they received open-label hydromorphone. Of the 129 participants transitioned to open-label hydromorphone, 21 had their SAPs approved and began receiving diacetylmorphine <90 days after they were offered open-label hydromorphone. The analysis of this study involves the remaining 108 participants who had the possibility to receive open-label injectable hydromorphone for at least 90 consecutive days before a diacetylmorphine SAP started (if requested and approved by Health Canada). This allowed for a comparison period for open-label hydromorphone when diacetylmorphine was still not certainly available to the patient, since our prior studies have shown a clear patient preference for diacetylmorphine over hydromorphone if both were available to be offered (
Predictors of treatment allocation guesses in a randomized controlled trial testing double-blind injectable hydromorphone and diacetylmorphine for severe opioid use disorder.
Using daily prescription data from our clinical database, we defined retention as having come to the clinic to receive medication at least 28 out of the prior 30 days at the three-month mark (i.e. from day 60 to day 90 of treatment). We also measured retention by calculating the total number of days receiving treatment (out of a total of 90) and time to first 30 days without injectable treatment. We also present average number of daily visits and daily dose prescribed and received. While transitioning and being retained on other treatments (e.g. oral methadone, buprenorphine, etc.) is a positive outcome, in this analysis, retention outcomes include only open-label injectable hydromorphone, as the variable of interest. These outcomes were compared to those from the same participant during their double-blind treatment in SALOME. Given that diacetylmorphine and hydromorphone could not be distinguished by participants better than would be expected by chance in SALOME and showed no differences in retention rates (E.
Oviedo-Joekes, E., Guh, D., Brissette, S., Marchand, K., MacDonald, S., Lock, K., … Schechter, M. T. (2016). Hydromorphone compared with diacetylmorphine for long-term opioid dependence: A randomized clinical trial. JAMA Psychiatry, 73(5), 1–9.
Predictors of treatment allocation guesses in a randomized controlled trial testing double-blind injectable hydromorphone and diacetylmorphine for severe opioid use disorder.
), they were analyzed together as a “double-blind” group.
Pairwise t-tests were used to analyze the difference in number of days receiving iOAT. McNemar tests were used for the difference in the proportions retained and exact odds ratios from conditional logistic model were estimated. Kaplan Meier curves and clustered log-rank tests were used to compare time to first 30 days without injectable treatment.
3. Results
Table 1 shows the proportion of participants who received injectable medication at least 28 out of 30 days in the third month of their treatment. With double-blind treatment, 87.0% were retained according to this definition and with open-label hydromorphone 77.8% were retained. A total of 74 participants (68.5%) were retained in both open-label and double-blind. Open-label hydromorphone was not significantly associated with lower retention (OR = 0.5; 95% CI: 0.2, 1.1; p = .10).
Table 1Comparison of proportion of patients that received at least 28 out of 30 days of open-label hydromorphone and injectable opioid agonist treatment double-blind at three months.
Double-blinda iOAT
Open-labelb HDM
Total
<28 days
≥28 days
<28 days
4 (3.7%)
10 (9.3%)
14 (13%)
≥ 28 days
20 (18.5%)
74 (68.5%)
94 (87%)
Totals
24 (22.2%)
84 (77.8%)
108 (100%)
HDM: hydromorphone; iOAT: injectable opioid agonist treatment with either hydromorphone or diacetylmorphine.
Time point: a) Data are for the prior 30 days at three months into double blind treatment, and thus includes treatment days 60–90. b) The present analysis is for the prior 30 days at three months into open label treatment, and thus includes treatment days 60–90.
Analysis: McNemar tests were used for the difference in the proportions and exact odds ratios from conditional logistic model were estimated. Open-label HDM was not significantly associated with lower retention.
Excludes days where patients received oral opioid agonist treatment only (counted as no treatment for this analysis).
Table 2 shows the comparison of number of days receiving injectable opioid agonist treatment out of 90 days. Participants received 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 with a mean difference of −3.9 (95% CI = −8.9, 1.1) days. Fig. 1 shows a Kaplan Meier curve with time to the first 30 continuous days without iOAT in both open-label hydromorphone and double-blind. Differences between open-label and double-blind were not statistically significant in number of days and time to discontinuation. Only 7 (6.5%) of the 108 patients who were offered open-label hydromorphone had a 30-day discontinuation beginning in the first week of the offer.
Table 2Comparison of number of days receiving open-label hydromorphone and injectable opioid agonist treatment during a 90 day period.
Total number of days in treatment (out of 90)
Double-blinda iOAT
Open-labelb HDM
Difference (open-label − double-blind)
Mean
SD
Mean
SD
Mean
SD
Mean (95%CI)
84.4
15.8
80.5
22.0
−3.9
26.2
−3.9 (−8.9, 1.1)
HDM: hydromorphone; iOAT: injectable opioid agonist treatment with either hydromorphone or diacetylmorphine.
Time point: a) For double-blind (clinical trial) includes from treatment initiation to day 90; b) Open-Label HDM includes from first dose of open label injectable HDM to day 90.
Pairwise t-tests were used to analyze the difference in number of days; differences were not significant.
Excludes days where patients received oral opioid agonist treatment only (counted as no treatment for this analysis).
Fig. 1Kaplan Meier Curve comparing differences in time to first 30 continuous days without injectable opioid agonist treatment during a 90 day period, in both open-label hydromorphone and double-blind injectable treatment.
HDM: hydromorphone; iOAT: injectable opioid agonist treatment with either hydromorphone or diacetylmorphine.
Time point: a) For double-blind (clinical trial) includes from treatment initation to day 90; b) Open-label HDM includes from first dose of open-label injectable HDM to day 90. Excludes days where patients received oral opioid agonist treatment only (counted as no treatment for this analysis).
Analysis: Kaplan Meier curves and clustered log-rank tests were used to compare time to first 30 continuous days without injectable treatment.
As seen in Table 3, there were no significant differences between the double-blind period and the open-label period with respect to the average daily doses of hydromorphone prescribed and the average doses received.
Table 3Comparison of daily visits and hydromorphone daily dose during a 90-day period, open-label and double-blind.
HDM: hydromorphone; iOAT: injectable opioid agonist treatment with either hydromorphone or diacetylmorphine. SD: Standard deviation.
Time point: a) For double-blind (clinical trial) includes from treatment initiation to day 90; b) Open-Label HDM includes from first dose of open label injectable HDM to day 90.
All doses are in milligrams. Only patients receiving HDM entered the analysis of dose comparison. For dose prescribed n = 51; for dose received n = 52. Maximum daily dose allowed was 400 mg. Doses prescribed refer to the prescription, used are what the patient actually took at the clinic.
As the expansion of treatment with injectable hydromorphone is considered in settings in Canada and elsewhere where diacetylmorphine still remains inaccessible, a valid question is whether open-label injectable hydromorphone can achieve the same effectiveness as it demonstrated within the double-blind SALOME trial. To address this question the present study utilized the unique opportunity of the only addiction treatment program in the world at the time using open-label injectable hydromorphone. Our analyses indicated that there were no statistically significant differences in treatment retention between the double-blind and open-label treatment periods, suggesting that patients can be successfully attracted and retained in treatment with open-label hydromorphone.
iOAT is provided under direct observation by RNs usually in dedicated settings, with the aim of reaching and treating individuals in need of structured care. The direct observation ensures patient safety (e.g. onsite treatment of respiratory depression), and the daily contact with RNs and other health care providers offers opportunities to build relationships with patients and to offer them comprehensive care (
). Through this contact, the staff develops an awareness of each patient's health and social circumstances and a strong therapeutic relationship. With 77.8% of the study participants coming to treatment at least 28 out of 30 days in the prior month (at 90 days) this study suggests that open-label hydromorphone programs using similar approaches to care as the Crosstown Clinic will be able to reach and treat patients with severe opioid use disorder. This brings a tremendous opportunity to offer a patient centered approach to care for individuals who have been struggling with long-term opioid use disorder.
Our analysis of open-label hydromorphone should be interpreted in light of the fact that patients have a preference for diacetylmorphine. We observed this in the SALOME trial and there is no reason to expect that this will not be the case in other settings. For example, participants were more likely to think they were receiving hydromorphone when they did not like the effect of the drug regardless of which drug they were actually receiving (
Predictors of treatment allocation guesses in a randomized controlled trial testing double-blind injectable hydromorphone and diacetylmorphine for severe opioid use disorder.
). The key question facing future iOAT program planners is whether patients will be attracted to open-label hydromorphone programs given their preference for diacetylmorphine. However, if this bias were strong enough to deter many people from accepting open-label hydromorphone, we would have expected to observe a large number of patients discontinuing treatment at the time open-label hydromorphone was offered to them (particularly when the possibility of receiving diacetylmorphine with an SAP was not certain or even on the horizon yet for many). It is therefore reassuring to observe such high retention rates in this study, and to observe that open-label hydromorphone was discontinued (for 30 days or more) for very few patients (6.5%) in the first week it was offered. Thus, as evidenced by the consistent results obtained in this study, patients' preference for diacetylmorphine, if not accessible, does not seem to affect the retention outcomes in open-label hydromorphone, assuming similar conditions and care provided.
The study presents important limitations due to the available data. First, clinical records are the only data source available from the moment participants were offered open-label treatment and thus our analysis does not include any other self-reported outcomes such as street opioid use and health status. Nevertheless, retention is the most important indirect measure of positive outcomes during and post-treatment (
Sordo, L., Barrio, G., Bravo, M. J., Indave, B. I., Degenhardt, L., Wiessing, L., … Pastor-Barriuso, R. (2017). Mortality risk during and after opioid substitution treatment: Systematic review and meta-analysis of cohort studies. BMJ, 357, j1550. doi:https://doi.org/10.1136/bmj.j1550.
). Second, only participants of the SALOME trial have received iOAT both double blind and open-label, making our sample quite homogeneous. As such, caution is required when generalizing the results. At the same time, there is no RCT testing differences in retention in hydromorphone open-label vs. double-blind, and as such the present analysis is only possible with SALOME participants. Third, the present analysis of retention on open-label hydromorphone is limited to 90 days (and not six months as in the SALOME trial), given most of the patients at the clinic were offered (and accepted) injectable diacetylmorphine by six months of open-label treatment. Nevertheless, our study time frame follows closely with other studies in addiction treatment that use an end-point of 12–13 weeks (i.e. <91 days) to measure treatment retention (
). Finally, our small sample size precludes a definitive answer, and therefore results should be discussed with caution and in the appropriate context.
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 compared with their outcomes with double-blind treatment.
Funding statement
The RUTH Study was funded by a Canadian Institutes of Health Research Project Grant. Further financial support was provided by the Michael Smith Foundation for Health Research Career Award and the Canada Institutes of Health Research New Investigator Award (EOJ) and the Canada Research Chairs Program (MTS). The funding sources had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript.
Declaration of authors
The authors have no competing interests to declare.
References
Bansback N.
Guh D.
Oviedo-Joekes E.
Brissette S.
Harrison S.
Janmohamed A.
Anis A.H.
Cost-effectiveness of hydromorphone for severe opioid use disorder: Findings from the SALOME randomized clinical trial.
The Global Burden of Disease projects: What have we learned about illicit drug use and dependence and their contribution to the global burden of disease?.
Nursing therapeutic relationship and its role on patients' daily attendance and street opioid use among patients receiving injectable opioid agonist treatment at Crosstown Clinic.
Paper presented at the Canadian Society of Addiction Medicine Annual Conference in Vancouver, BC, Canada on October 26th 2018. 2018
Oviedo-Joekes, E., Guh, D., Brissette, S., Marchand, K., MacDonald, S., Lock, K., … Schechter, M. T. (2016). Hydromorphone compared with diacetylmorphine for long-term opioid dependence: A randomized clinical trial. JAMA Psychiatry, 73(5), 1–9.
Oviedo-Joekes, E., Marchand, K., Guh, D., MacDonald, S., Lock, K., Brissette, S., … Schechter, M. T. (2015a). History of treatment access and drug use among participants in a trial testing injectable opioids under supervision for long-term heroin injectors. Journal of Addiction Medicine, 3(1), 1015.
Predictors of treatment allocation guesses in a randomized controlled trial testing double-blind injectable hydromorphone and diacetylmorphine for severe opioid use disorder.
Sordo, L., Barrio, G., Bravo, M. J., Indave, B. I., Degenhardt, L., Wiessing, L., … Pastor-Barriuso, R. (2017). Mortality risk during and after opioid substitution treatment: Systematic review and meta-analysis of cohort studies. BMJ, 357, j1550. doi:https://doi.org/10.1136/bmj.j1550.
Supervised injectable heroin or injectable methadone versus optimised oral methadone as treatment for chronic heroin addicts in England after persistent failure in orthodox treatment (RIOTT): A randomised trial.
Daily visits p value = .036.
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