Medicine, Faculty of
Population and Public Health (SPPH), School of
DSpace
UBCV
Gonzalez Arreola, Lourdes Atziri
Master of Science - MSc
University of British Columbia
Opioid use disorder (OUD) is a major Public Health concern in Canada. Injectable Opioid Agonist Treatments (iOAT) with diacetylmorphine (DAM) and hydromorphone (HDM) have proven to be safe and effective treatments for OUD. Currently, several sites in British Columbia and across Canada offer iOAT as part of their regular addiction care plan. While effectiveness and safety has been demonstrated, daily program features, such as regular doses, still need to be studied to improve efficiency. Importantly, typical doses of iOAT remain unknown. The aim of this thesis was to determine the most common dosage ranges of iOAT to support program planning. This thesis utilized data from a longitudinal cohort of participants receiving iOAT from August 2014 to April 2020 at the site with the most iOAT clients in Vancouver. Descriptive statistics including interquartile rage and histograms were obtained to illustrate typical doses of iOAT and define dosage groups. Using participants’ data from a double-blind clinical trial, paired t-tests and linear regression were performed to examine differences in double-blind versus open-label iOAT dose received. The open-label potency ratio between DAM and HDM was calculated and described with percentile ranks. A total of 595,305 injections were registered during the study period among 131 participants. Mean DAM doses ranged from 106 – 989 mg per day, with most clients using 150 – 300 mg per session (mean 225 mg) attending 2.7 sessions per day. Mean HDM doses ranged from 51.1 – 696.1 mg per day, the majority using 75 – 150 mg per session (mean 125 mg; 2.8 sessions). A moving average demonstrated that participants’ doses tend to remain stable over the study period. Paired t-test analyses demonstrated that participants received significantly less open-label DAM (-49 mg; p <0.01) but no significant difference in open-label HDM (5 mg; p >0.05). Further testing suggested this difference was attributed to drug preferences. Participants use the entire range of possible prescriptions, demonstrating the diversity and variability across people accessing iOAT, however stability in dosage can be expected. Providing these certainties will help providers to prepare for what they need to offer and facilitate the expansion of iOAT programs across Canada.
DETERMINING TYPICAL DOSES OF INJECTABLE DIACETYLMORPHINE AND HYDROMORPHONE FOR THE TREATMENT OF OPIOID USE DISORDER by Lourdes Atziri Gonzalez Arreola A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Population and Public Health) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) July 2022 © Lourdes Atziri Gonzalez Arreola, 2022 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Determining typical doses of injectable diacetylmorphine and hydromorphone for the treatment of opioid use disorder submitted by Lourdes Atziri Gonzalez Arreola in partial fulfillment of the requirements for the degree of Master of Science in Population and Public Health Examining Committee: Eugenia Oviedo-Joekes, Professor, School of Population and Public Health, UBC Supervisor Martin T. Schechter, Professor, School of Population and Public Health, UBC Supervisory Committee Member Scott MacDonald, Physician Lead, Providence Crosstown Clinic Supervisory Committee Member Michael Law, Professor, School of Population and Public Health, UBC Additional Examiner iii Abstract Opioid use disorder (OUD) is a major Public Health concern in Canada. Injectable Opioid Agonist Treatments (iOAT) with diacetylmorphine (DAM) and hydromorphone (HDM) have proven to be safe and effective treatments for OUD. Currently, several sites in British Columbia and across Canada offer iOAT as part of their regular addiction care plan. While effectiveness and safety has been demonstrated, daily program features, such as regular doses, still need to be studied to improve efficiency. Importantly, typical doses of iOAT remain unknown. The aim of this thesis was to determine the most common dosage ranges of iOAT to support program planning. This thesis utilized data from a longitudinal cohort of participants receiving iOAT from August 2014 to April 2020 at the site with the most iOAT clients in Vancouver. Descriptive statistics including interquartile rage and histograms were obtained to illustrate typical doses of iOAT and define dosage groups. Using participants’ data from a double-blind clinical trial, paired t-tests and linear regression were performed to examine differences in double-blind versus open-label iOAT dose received. The open-label potency ratio between DAM and HDM was calculated and described with percentile ranks. A total of 595,305 injections were registered during the study period among 131 participants. Mean DAM doses ranged from 106 – 989 mg per day, with most clients using 150 – 300 mg per session (mean 225 mg) attending 2.7 sessions per day. Mean HDM doses ranged from 51.1 – 696.1 mg per day, the majority using 75 – 150 mg per session (mean 125 mg; 2.8 sessions). A iv moving average demonstrated that participants’ doses tend to remain stable over the study period. Paired t-test analyses demonstrated that participants received significantly less open-label DAM (-49 mg; p <0.01) but no significant difference in open-label HDM (5 mg; p >0.05). Further testing suggested this difference was attributed to drug preferences. Participants use the entire range of possible prescriptions, demonstrating the diversity and variability across people accessing iOAT, however stability in dosage can be expected. Providing these certainties will help providers to prepare for what they need to offer and facilitate the expansion of iOAT programs across Canada. v Lay Summary Injectable Opioid Agonist Treatments (iOAT) have proven to be a safe and effective treatment for OUD, and thus are being offered at a few sites in Canada. Daily program features however, such as regular doses of iOAT, remain to be studied. Research on typical doses will improve efficiency and consequently support program expansion. This thesis determined the typical dosage ranges of iOAT in clients receiving these treatments in Vancouver. Clients` doses span the whole possible dosage range, indicating the diversity of people accessing iOAT. Doses, however, were stable over time, with most clients receiving doses in the middle range. These findings provide dosage certainty, which support program planning and therefore, the expansion of iOAT across Canada. vi Preface The work presented in this dissertation was analyzed and written by Lourdes Gonzalez Arreola, under the supervision of Dr. Eugenia Oviedo-Joekes and guidance from the committee members Dr. Martin Schechter and Dr. Scott MacDonald. The data analyzed in this dissertation was obtained from the dispensation records at the Providence Crosstown Clinic in Vancouver, British Columbia and from the data collected for the Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) and the Research on the Utilization of Therapeutic Hydromorphone Study (RUTH) projects conducted by Dr. Eugenia Oviedo-Joekes. The secondary analysis of this data for the present dissertation was approved by the University of British Columbia Providence Health Care Clinical Research Ethics Board (certificate number: H20-00794). Lourdes, with guidance from Dr. Eugenia Oviedo-Joekes developed the research questions. Data was extracted by Daphne Guh (statistician) and data cleaning, linkage and analysis was conducted by Lourdes supported by Daphne Guh. Interpretation of the results was supported by Drs. Eugenia Oviedo-Joekes and Scott MacDonald. Dr. Martin Schechter provided feedback on the results. Dr. Eugenia Oviedo-Joekes assisted with invaluable insights in the final manuscript which was further refined with input from Drs. Scott MacDonald and Martin Schechter. vii Table of Contents Abstract ......................................................................................................................................... iii Lay Summary ................................................................................................................................. v Preface ........................................................................................................................................... vi Table of Contents ......................................................................................................................... vii List of Tables ................................................................................................................................. xi List of Figures .............................................................................................................................. xii List of Abbreviations .................................................................................................................. xiii Acknowledgements ..................................................................................................................... xiv Dedication .................................................................................................................................... xvi Chapter 1: Introduction ................................................................................................................ 1 1.1 Positionality ..................................................................................................................... 1 1.2 Overview ......................................................................................................................... 2 1.3 Opioid use disorder .......................................................................................................... 3 1.4 Toxic opioid-drug supply and overdose crisis in Canada ............................................... 6 1.5 Pharmacokinetics, Pharmacodynamics and Pharmacogenetics of opioids ..................... 8 1.6 Pharmacological treatments for OUD ........................................................................... 13 1.6.1 Oral opioid agonist treatments (OAT) ................................................................... 14 1.6.1.1 Dosage in OAT .................................................................................................. 14 1.6.2 Injectable opioid agonist treatments (iOAT) ......................................................... 17 1.6.2.1 Dosage in iOAT ................................................................................................. 18 1.6.3 Access to treatment for opioid use disorder .......................................................... 20 viii 1.7 Study Objectives ............................................................................................................ 21 1.8 Thesis outline ................................................................................................................. 23 Chapter 2: Methodology Overview ............................................................................................ 25 2.1 Dissertation methodology .............................................................................................. 25 2.2 SALOME trial study methods ....................................................................................... 26 2.2.1 Design, Settings, and Participants ......................................................................... 26 2.2.2 SALOME Treatments ............................................................................................ 27 2.2.3 SALOME Assessments ......................................................................................... 29 2.2.4 SALOME Dispensation Records ........................................................................... 29 2.3 RUTH study methods .................................................................................................... 30 2.3.1 Design, Settings, and Participants ......................................................................... 30 2.3.2 Crosstown Clinic Treatments ................................................................................ 31 2.3.2.1 Additional considerations on availability of medications ................................. 32 2.3.3 RUTH assessments ................................................................................................ 33 2.3.4 Crosstown Dispensation Records .......................................................................... 33 2.3.5 Data period used in this dissertation ...................................................................... 34 2.4 Variables of interest ....................................................................................................... 34 2.5 Ethics and ethical considerations ................................................................................... 35 Chapter 3: Typical doses of injectable hydromorphone and diacetylmorphine ................... 37 3.1 Background .................................................................................................................... 37 3.2 Methods ......................................................................................................................... 39 3.2.1 Design, settings, and participants .......................................................................... 39 3.2.2 Crosstown Clinical Procedures .............................................................................. 40 ix 3.2.3 Data ........................................................................................................................ 40 3.2.4 Analysis ................................................................................................................. 42 3.3 Results ........................................................................................................................... 44 3.3.1 Participants ............................................................................................................ 44 3.3.2 Typical Dose Ranges in the study ......................................................................... 46 3.3.3 Dosage groups ....................................................................................................... 50 3.4 Discussion ...................................................................................................................... 54 3.5 Limitations ..................................................................................................................... 58 3.6 Conclusion ..................................................................................................................... 59 Chapter 4: Received doses of injectable hydromorphone and diacetylmorphine: Comparing open-label to double-blind ...................................................................................... 60 4.1 Background .................................................................................................................... 60 4.2 Objectives ...................................................................................................................... 62 4.3 Methods ......................................................................................................................... 63 4.3.1 Design, settings, and participants .......................................................................... 63 4.3.2 Crosstown Clinic Treatments ................................................................................ 63 4.3.3 Data ........................................................................................................................ 64 4.3.4 Analysis ................................................................................................................. 65 4.4 Results ........................................................................................................................... 67 4.4.1 Participants’ characteristics ................................................................................... 67 4.4.2 Dose: Double-blind vs Open-label ........................................................................ 70 4.4.3 DAM dose difference by blinding guess ............................................................... 72 4.4.4 DAM dose difference by client-characteristic ....................................................... 74 x 4.4.5 Potency Ratio ......................................................................................................... 77 4.4.5.1 Open-label potency ratio ................................................................................... 78 4.4.5.2 Switching opioids .............................................................................................. 79 4.5 Discussion ...................................................................................................................... 83 4.6 Limitations ..................................................................................................................... 87 4.7 Conclusion ..................................................................................................................... 88 Chapter 5: Conclusion ................................................................................................................ 89 5.1 Summary of findings ..................................................................................................... 89 5.1.1 Typical doses of injectable hydromorphone and diacetylmorphine ...................... 90 5.1.2 Received doses of injectable hydromorphone and diacetylmorphine: comparing open-label to double-blind ..................................................................................................... 91 5.2 Limitations ..................................................................................................................... 93 5.3 Significance and implications ........................................................................................ 95 5.4 Conclusion ..................................................................................................................... 96 Bibliography ................................................................................................................................. 97 xi List of Tables Table 1.1 Opioid use disorder criteria by DSM-5 (13) ................................................................... 4 Table 3.1 Characteristics of RUTH study participants ................................................................. 45 Table 3.2 Characteristics of study participants by dose group of hydromorphone ...................... 52 Table 3.3 Characteristics of study participants by dose group of diacetylmorphine .................... 53 Table 4.1 Socio-demographic characteristics of participants ....................................................... 69 Table 4.2 Double-blind and open-label doses in milligrams and dose difference in milligrams by drug ................................................................................................................................................ 71 Table 4.3 DAM dose and dose difference in milligrams for participants receiving DAM in SALOME and DAM in RUTH by blinding guess ........................................................................ 73 Table 4.4 DAM dose difference in milligrams for participants receiving DAM in SALOME and DAM in RUTH by client-characteristic ........................................................................................ 74 Table 4.5 Potency ratios between hydromorphone and diacetylmorphine ................................... 78 Table 4.6 Switching protocol for iOAT ........................................................................................ 81 Table 4.7 Example of cautious and aggressive approach ............................................................. 82 xii List of Figures Figure 3.1 Mean daily-total dose prescribed in milligrams of hydromorphone and diacetylmorphine during the study period from August 2014 to April 2020. ............................... 47 Figure 3.2 Mean daily-total dose received in milligrams of hydromorphone and diacetylmorphine during the study period from August 2014 to April 2020. ............................... 48 Figure 3.3 Mean daily-total dose prescribed and received of DAM equivalent by drug during the study period (August 2014 - April 2020). ..................................................................................... 50 xiii List of Abbreviations BC British Columbia DAM Diacetylmorphine DSM-5 Diagnostic and Statistical Manual for Mental Disorders, 5th edition HDM Hydromorphone iOAT injectable Opioid Agonist Treatments NAOMI North American Opiate Medication Initiative OAT Opioid Agonist Treatment OUD Opioid Use Disorder RUTH Research on the Utilization of Therapeutic Hydromorphone SALOME Study to Assess Longer-term Opioid Medication Effectiveness SROM Slow-release oral morphine xiv Acknowledgements I would like to thank my supervisor Dr. Eugenia Oviedo-Joekes for giving me the opportunity to come to Canada and do this relevant work, for your continuing support, guidance and words of encouragement that have allowed me to the face challenges that I have encountered while completing this work. I would also like to express my gratitude to Dr. Scott MacDonald and Dr. Martin Schechter for their countless hours of time, their valuable input and support throughout the development of this project as my committee members. I would also like to thank Daphne Guh for her insightful advice on data design and analysis. I would like to offer my gratitude to Drs. Shahin Jamal, Antonio Aviña-Zubieta, Neda Amiri, and Natasha Dehghan for supporting me in maintaining a work-study-life balance, for periodically monitoring my process, providing me with guidance throughout these years and creating opportunities for me to develop as a professional and an academic. To my dear parents, thank you for encouraging me to chase my dreams away from my home city and your unconditional support, both morally and financially while doing so, for always believing in me, and for celebrating my achievements from a distance. I am especially grateful to my partner, Sebastian, for your endless love, time and patience in our endless phone calls, your support particularly during trying times and for being the world’s best cheerleader. Thank you for constantly reminding me of the importance of taking the time to enjoy a social life and for the numerous laughs and adventures we have had throughout these years. xv Finally, I would also like to thank my Canadian family Paula and Sophie for making me part of your family since coming to Vancouver, for all your love, support, and delicious meals throughout these years, and for providing me with a place I can now truly call home. xvi Dedication To my sister, Rubria. No matter what is happening in your life, remember I am here for you, I will stand by you, and I will encourage you to remain hopeful no matter how hard life becomes, because I will always love you more than words can say. 1 Chapter 1: Introduction 1.1 Positionality Substance use disorders run in my family. My sister is a person with alcohol use disorder and one of my cousins has an opioid use disorder. However, given that I am not close to my family other than my parents and my sister, I had no knowledge surrounding opioid use disorder prior to coming to Canada. I was born in Mexico, in a small town called Morelia, but I moved to Guadalajara with my sister for university where I graduated from biotechnology engineering with a minor in molecular biology and a certification in pharmaceutical processes. While I was in university my sister’s alcohol use disorder first became noticeable to my family and, after several problematic episodes, my parents decided to send her to a treatment facility where she received abstinence-based treatment and was diagnosed with bipolar disorder. She started receiving pharmacological treatments for her mental health problems and eventually she recovered. Given my personal experience, my pharmaceutical background and coming from a family of physicians, my limited knowledge on substance use disorders was entirely medical. The topic was momentarily in the background until I came to UBC where I soon learned about the drug overdose crisis afflicting Vancouver and all the implications of substance use disorder. Just to mention a few, these go from prevention to pharmacological interventions, policy interventions, management of phycological and medical issues, employment, and housing, for example. Other 2 than the pharmacological interventions, these were new to me and completely outside of my area of expertise. I was able to see that treatments with injectable opioid agonists are just like any other treatment for substance use disorder. With my pharmaceutical background, that was very different from the background of my peers, I wanted my work to contribute in a meaningful way to help people directly affected or connected to iOAT. I saw value in contributing a different approach to the data (i.e., a pharmacological one). I realized that the clinical teams needed the simple work that I was interested in pursuing, and I was never overly concerned with non-significant results because I believe that all data is invariably important. My work informs the day-to-day work of clinical teams who are running the programs; hence my work contributes to the delivery of these treatments, which invariably was what I hoped my work and approach could achieve. 1.2 Overview Individuals with substance use disorders have had experiences that have molded their life’s journey. With their unique perspectives, new approaches and responses to the opioid crisis have arisen, unfortunately, the system has been slow to scale-up evidence-based interventions and policies, particularly injectable opioid agonist treatments (iOAT). The history of iOAT in Canada can be dated to 1998 when North America’s first heroin trial (NAOMI) began the regulatory and funding approval processes which were lengthy and grinding, resulting in its delayed launching in 2005 (1). Roughly and slowly iOAT expanded and these treatments are now being offered or planned to be offered at several sites across Canada (2). 3 Since the efficacy of iOAT has been extensively demonstrated in Europe and Canada (3–9) the focus of service users and providers has shifted to the everyday routine aspect of the program to better support the diverse client’s needs, and promote treatment uptake. With this focus, information regarding typical doses of iOAT (i.e., hydromorphone and diacetylmorphine) is a day-to-day topic amongst clinical teams and service providers given that dose has never been studied as a main outcome, thus there is a paucity of guidance to determine typical doses of these medications. Providing this information would improve the shared decision making between clients and prescribers when determining individual safe and effective doses of iOAT. To contextualize the work on typical doses, the present chapter aims to briefly describe opioid use disorder and iOAT in terms of 1) pharmacokinetics, pharmacodynamics, and pharmacogenetics of opioids to understand how opioids work on the body, produce the effects and the similarities and differences between these drugs; and 2) as pharmacological treatments and its dosage to contextualize iOAT dosage, and iOAT’s history and availability in Canada. 1.3 Opioid use disorder Opioid use disorder (OUD) is a chronic relapsing disease characterized by the compulsion to take an opioid which results in a loss of control in limiting the amount of drug taken and consequently developing a negative emotional state when the opioid is unavailable (10–12). The excessive intake of opioids directly activates the brain reward neurocircuits, producing a feeling of pleasure, often referred as a “high”. This excessive intake consequently produces the opposite effect generating withdrawal which drives negative emotional states and relapse (i.e., recurrence of drug seeking and drug use) (13–15). 4 According to the American Psychiatric Association’s Diagnostic and Statistical Manual for Mental Disorder’s (DSM-5), OUD is classified as a mental health disorder and its severity its determined based on the number of symptom criteria (Table 1.1), where mild is the presence of two to three symptoms, moderate by four to five symptoms and severe by six or more (13). Table 1.1 Opioid use disorder criteria by DSM-5 (13) Diagnostic criteria for OUD manifested by at least 2 of the following, occurring within a 12-month period 1. Opioids are often taken in larger amounts or over a longer period than was intended. 2. There is a persistent desire or unsuccessful effort to cut down or control opioid use. 3. A great deal of the time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects. 4. Craving, or a strong desire or urge to use opioids. 5. Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home. 6. Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids. 7. Important social, occupational, or recreational activities are given up or reduced because of opioid use. 8. Recurrent opioid use in situations in which it is physically hazardous. 9. Continued opioid use despite knowledge of having a persistent or recurrent physical or physiological problem that is likely to have been caused or exacerbated by the substance. OUD is a multifaceted disorder in which societal norms, mental disorders, drug exposure, market availability and genetic factors can impact the initial drug use and the progression and development of OUD (10, 16–19). This disorder can involve the use of natural compounds such 5 as morphine and codeine, synthetic opioids such as hydrocodone and oxymorphone, semi-synthetic opioids such as heroin and illicitly manufactured opioids such as fentanyl (10, 17, 20). OUD carries a significant health burden to communities, accounting for 70% of the total 18 million years of healthy life lost globally in 2019 due to drug use disorders (including OUD, amphetamine use disorder, cocaine use disorder, cannabis use disorder, and other drug use disorders, excluding tobacco dependence and alcohol use disorder) (21,22). OUD is associated with high rates of morbidity including infections as HIV and HCV (23,24) that cause the greatest harm in terms of premature deaths and number of healthy life years lost even while receiving opioid agonist treatments (25). OUD is also associated with hepatitis, bacterial endocarditis and neonatal abstinence syndrome (10, 21, 25, 26), with societal cost such as violence, crime and social disintegration and with mortality caused by unintentional fatal overdoses (10, 17, 21) which, according to a recent systematic review and metanalysis by Santo et al. (25) people who are not receiving oral opioid agonist treatments are at higher risk of unintentional drug-related deaths. Globally, the burden of disease caused by OUD is aggravated by the poorly available evidence-based treatments such as opioid agonist treatments (OAT) and naloxone to manage overdose cases (17, 26), the low prevention and treatment of HCV that causes liver cancer, cirrhosis, and others (27). In North America, it is exacerbated by the toxic opioid-drug supply by fentanyl and its analogues, the inequities in access to OAT and the lack of treatment expansion, beyond OAT (21,24). In Canada specifically, treatment with injectable diacetylmorphine and hydromorphone remains limited to individual providers (i.e., only a few clinicians provide access) due to 6 financial, structural and practice barriers from the government which in turn limits the number of people who can access these treatments, leaving many people outside of treatment. For example, the government of Alberta terminated the funding of the iOAT program, resulting in the termination of the program in 2021 (28). Another example, is the “carries” program at the Crosstown Clinic that enabled clients to take home syringes of diacetylmorphine, which initiated in July 2021 and was cancelled by the Ministry of Health just two months after (29). Finally, delivery of these treatments was restricted to physicians for many years, which fortunately, it is not the case anymore, however these treatments still need to be delivered at specialized and supervised settings (30). Thus, the harms related to OUD in Canada continue to increase by not scaling up these already proven effective treatments (31). 1.4 Toxic opioid-drug supply and overdose crisis in Canada An estimated 62 million people use opioids (pharmaceutical and illegally manufactured opioids) for non-medical purposes globally (including occasional use) which corresponds to a prevalence of 1.2% with North America having the highest prevalence (3.6%) (32). OUD continues to defy the health care system in North America by the triple overdose crisis of pharmaceutical opioids, heroin and fentanyl and its analogues where Western Canada and the Eastern United States are the most affected areas, and with the onset of the COVID-19 pandemic, a spike in opioid overdose deaths has been seen in these areas (21,33). The opioid overdose crisis is evolving in North America, where the number of deaths related to prescription opioids and heroin have been declining over the past five years, while most deaths are related to illicit fentanyl and its analogues (20,21,24). Fentanyl is up to 100 times more 7 potent than morphine, which makes small doses of fentanyl lethal (21,34). In addition, fentanyl has been detected in more than half of the deaths attributed to heroin (21,35). From January 2016 to September 2021 across Canada there were more than 26,690 apparent opioid toxicity deaths (36). In 2021 alone, between January to September, there were 5,368 apparent opioid toxicity deaths, representing a 67% increase compared to the deaths that occurred on the same period in 2018 (36). Ninety-eight percent of the deaths between January to September 2021 were deemed unintentional (36) and the majority (86%) involved fentanyl and its analogues (20,36). In British Columbia (BC), between May and July 2020, the highest ever overdose death monthly numbers were recorded with approximately 170 persons dying per month and a total of 1,724 people died from overdose in 2020 (37). Between January 2021 and October 2021 there were 1,782 suspected illicit drug overdose deaths which was the highest ever recorded in a calendar year, and in October 2021 alone there were 201 suspected overdose deaths, the largest monthly number ever recorded, exceeding those from May to July 2020 (38). In total, in 2021 there were 2,232 illicit drug overdose deaths in BC and fentanyl (alone or in combination with other drugs) was detected in 84% of them (39). Overall in BC, fentanyl-related overdose deaths have increased from 5% in 2012 to 84% in 2021 whereas for other opioid-related deaths, the numbers have steadily declined since 2012 (38). Hydromorphone was detected in less than 2% of overdose deaths from March 2020 to May 2021 (37). 8 1.5 Pharmacokinetics, Pharmacodynamics and Pharmacogenetics of opioids While opioids can be very similar, there are important inter-individual variabilities, that make people choose, respond, or accept one medication over the other (i.e., preference). This preference posits an impact in treatment adherence (40). Understanding some of the pharmacological features of opioids, including oral, inhaled, and injectable, can support the discussions around the diverse choices in dose and medication by clients during treatment with iOAT. Pharmacokinetics refers to the movement of the drug through the body, encompassing the absorption of the drug, the distribution in the organism, metabolism and excretion; in other words is “what the body does to the drug” (41,42). Pharmacodynamics on the other hand, describe the drug effects relating to its concentrations at the site of action; to rephrase it is “what the drug does to the body” (41). Pharmacogenomics encompasses the study of the interindividual differences in drug response and efficacy in terms of genetic variability (43). The pharmacodynamic properties of opioids (i.e., mechanism of action) are derived from those metabolites that are agonists. An agonist is a substance that when it binds to the receptor, produces a biological effect (42). Examples of opioid agonists are diacetylmorphine, hydromorphone, morphine and methadone, but there are also partial agonists such as buprenorphine (42). Opioids provide analgesia by binding to one or more and strongly or weakly to the different opioid receptors: µ, δ and κ (44). There is a high density of opioid receptors in the reward system as well as in the pain pathway of the brain, hence their main functions are in these systems. µ receptors produce euphoria, physical dependence, and analgesia primarily, and 9 they also produce respiratory depression, sedation, miosis (i.e., excessive constriction of the pupil) and reduce gastrointestinal motility (42). δ receptors produce euphoria and analgesia while κ produce dysphoria, analgesia and sedation (42). The preferred opioids by people with opioid use disorder, which also have a greater analgesic effect, are the ones that bind preferentially to the µ receptor (42,45) and, concerning the amount of µ-receptors, some studies have shown sex differences with the use of positron emission tomography (PET), demonstrating that females have more µ receptors in several brain regions compared to men (46). Agonists bind to the opioid receptor resulting in a modification of the calcium and potassium influx, a complex multistep process where the cations (i.e., calcium or potassium) move through and into the cell (47), which essentially blocks the release of pain-related neurotransmitters (44). In principle, agonists produce the same effect, however the subjective differences are explained by the pharmacokinetic properties of each substance (42). Understanding these properties is necessary for making shared decisions around the drug, its dose and encouraging autonomy. A pharmacokinetic curve represents the temporal course of the concentration in the plasma as a function of time. The time required to reach the maximum concentration in the plasma is called CMAX, whereas TMAX represents the maximum time required to observe a drug effect. These two properties are a function of the absorption and distribution which in turn are a function of the solubility of the molecule and route of administration (42,44). Hydrophilic drugs such as morphine have a CMAX of approximately 60 minutes if administered orally, whereas the CMAX if administered intravenously ranges from 6 to 15 minutes (44). On the other hand, lipid-soluble drugs such as methadone, diacetylmorphine, hydromorphone and fentanyl have shorter CMAX as 10 they are absorbed easier and faster through the membranes (42,44). As for TMAX, substances that are ingested orally, such as methadone remain in the stomach for over half an hour and they can last up to 3 hours to reach a TMAX, while substances administered intravenously have a TMAX of only a few seconds and only 5 – 10 minutes when inhaled (42,48). This is why drugs such as diacetylmorphine, when administered intravenously or inhaled, provide a rapid delivery of the highly active metabolite 6-monoacetylmorphine into the systemic circulation, resulting in a rapid occupation of the µ receptors and hence a “high” effect (49,50), which does not occur when drugs are taken orally due to the first pass effect (i.e., the metabolism of drugs in the intestine or liver prior to reaching the systemic circulation) (51). Diacetylmorphine is quickly absorbed by the tissues and is metabolized through a process of deacetylation (removal of an acetyl group) to obtain 6-monoacetylmorphine (6-MAM) which is later transformed almost entirely into morphine by removing the second acetyl group (42). Morphine is broken down into morphine-3-glucuronide, which is inactive, and into morphine-6-glucoronide, which is the active metabolite, by glucuronidation in the liver and then excreted through the kidneys (42,44,52). Similarly, by glucuronidation, hydromorphone is metabolized into hydromorphone-3-glucoronide and excreted by the kidneys (44,52). On the other hand, methadone and buprenorphine go through first pass effect, thus are initially metabolized in the liver by cytochrome P450 CYP2D6, CYP1A2 and CYP3A4. These enzymes are subject to genetic mutations, hence there is much inter-individual variability in the metabolism of opioids caused by these genetic mutations (42,53). 11 Genetic polymorphisms (i.e., variations in a gene) have been observed in pharmacogenomic studies of opioids to which differences in opioid metabolism are attributed (44,53). Variations on the enzyme CYP2D6, involved in the metabolism of methadone, have been identified by ethnicity, which can lead to slow or rapid metabolizers (53) where slow metabolizers have been observed at higher rates in Caucasians, and rapid metabolizers are more prevalent amongst the Middle Eastern population (54). Similarly, the enzyme responsible of glucuronidation, UDP-glucuronosyltransferase (UGT) is encoded by polymorphic genes (52,55). Variations in UGT2B, involved in the metabolism of opioids such as diacetylmorphine and hydromorphone, have been found at different frequencies among Caucasians and Asians, as well as between women and men (56,57). Some variations in UGT2B could reduce the metabolism and elimination of opioids by prolonging the half-life as seen for other drugs metabolized by that enzyme (56). Additional polymorphisms have been observed in OPRM1 which encodes for the µ receptor influencing the expression of these receptors in the brain and the sensitivity to opioids, hence the susceptibility to opioid addiction in persons with this polymorphism (10). Excretion of substances follows an exponential function: as time increases the concentration of drug decreases and therefore less of the substance is eliminated since there is less to eliminate (42). In this case, the term half-life is used to better describe this pharmacokinetic property (i.e., elimination). Elimination half-life is the time needed to reduce by half the amount of a drug after its metabolism and/or excretion; in other words, it is the time at which the administered dose of a drug exerts only half of its effect (42). In the context of OAT, the half-life of the opioid will determine the frequency of administration of these treatments. 12 Opioids such as methadone and buprenorphine have prolonged half-lives of around 22 – 36 hours, and 31 – 42 hours respectively (42,53,58,59) whereas injectable morphine, diacetylmorphine and hydromorphone have shorter half-lives. Morphine half-life is 3 – 4 hours (42), diacetylmorphine has a similar profile (42,60) and hydromorphone half-life is about 2.4 hours (61,62). When consumed repeatedly, these opioids with shorter half-lives tend to accumulate less compared to those with prolonged half-lives, and thus fluctuate more in terms of concentration (42). The steady state is described by a level of concentration that is flat and constant, with minimum fluctuations (42). OAT and iOAT pursue to reach this steady with the intent of producing the desired effects and thus, reaching and maintaining clients in these treatments. Methadone reaches a steady state after approximately 4.5 half-lives when consumed daily, whereas opioids with shorter half-lives such as diacetylmorphine and hydromorphone, require 3 doses a day to reach a steady state comparable to that of methadone (42). Over time, the same dose might no longer produce the same effect, and this decline is in the effect caused by repeated administration of the drug called tolerance (10,42). Tolerance to opioids is manifested in the effects of analgesia, euphoria, and sedation. Due to this tolerance, people with opioid use disorder can consume opioid doses that would be lethal for opioid-naïve individuals (42). Years of prescribing opioids in Europe and Canada show, however, that it can be managed, although more research is needed to support transitions and rotations between opioids given that conversion tables oftentimes do not accurately display potency ratios (63). 13 Opioid rotation should be an individualized shared-decision process, implementing dose titrations that maintain efficacy and avoid adverse events or abstinence (64). 1.6 Pharmacological treatments for OUD Agencies such as the World Health Organization (WHO) and the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), in addition to clinical guidelines and systematic reviews have concluded that effective long-term treatment for opioid use disorder often requires a combination of treatments and responses and generally as repeated occasions. Such treatment typically entails pharmacological interventions, behavioral and psychosocial interventions, residential rehabilitation, self-help and mutual aid groups and recovery/reintegration support services. The second and third are often used in conjunction with pharmacological interventions (65–68). Pharmacological interventions, such as opioids to assist treatment with opioid agonists keep clients in treatment, reduce illicit opioid use, decrease morbidity and mortality, and improve mental health (4,5,65,66,69–71). For example, a recent study in the US demonstrated that pharmacological interventions were significantly associated with reduced overdoses, recurrence of illicit opioid use and opioid-related morbidity compared with non-pharmacological treatments (69). These opioid assisted treatments, known in Canada as opioid agonist treatments (OAT), usually include oral agonist treatments such as methadone and buprenorphine but they also include injectable opioid agonist treatments (iOAT) (68,72,73). 14 1.6.1 Oral opioid agonist treatments (OAT) Methadone is a long-acting oral medication that binds to the µ-receptor, and it is the most common pharmacological therapy to treat OUD used in western countries (10,73,74). In Canada, the oral OAT includes buprenorphine/naloxone (Suboxone®), methadone and increasingly slow-release oral morphine (24-hour formulation; e.g.,Kadian®) as treatments (72,73). Buprenorphine is a long acting (24 – 36 hours) partial µ-receptor agonist and κ-receptor antagonist, and therefore produces weaker effects and lowers the risk of respiratory depression (10,59,66,75). Buprenorphine as OAT is combined with naloxone to prevent potential parenteral misuse (10,75). Naloxone is a µ-receptor antagonist, and it is poorly absorbed when administered sublingually, but when administered intravenously, it precipitates opioid withdrawal and produces and unpleasant and dysphoric effects (59,75). Slow-release oral morphine (SROM) is a µ-receptor agonist. The 24-hour slow release formulation has been studied as OAT for OUD, suggesting that SROM is effective for withdrawal suppression and it can be helpful alternative for clients with intolerance to other OAT such as methadone and buprenorphine/naloxone (76–80) 1.6.1.1 Dosage in OAT Considering that methadone is the most commonly prescribed therapy, several studies over time have been conducted to determine effective doses (81–85). Some studies claim that >100 mg/day methadone doses are more desirable regarding heroin use reduction (82,83); whereas others have found that doses >100 mg/day of methadone offer no greater benefit than 100 mg/day (81,84). 15 Nevertheless, as research on methadone dosing is plenty and robust, a general conclusion for optimal methadone dosing has been reached. Optimal methadone doses will vary across individuals due to differences in metabolism, genetic mutations, comorbidities (e.g. prolonged QT interval and liver disease, for example) or drug interactions, and dosing should be based on clinical judgment (82,86). However, most studies have suggested that methadone in higher doses (between 60 mg – 120 mg/day) are more effective for treatment retention and reduction of illicit drug use and that doses above 120 mg/day may provide better outcomes in some clients who would not respond to moderate doses due to insufficient opioid blockade (85,87). Similarly, for buprenorphine/naloxone, studies have been conducted to determine optimal doses to achieve illicit opioid use suppression (determined by negative urinalysis). A Cochrane review found that buprenorphine/naloxone at doses ³16 mg/day are effective at suppressing illicit opioid use and that these high doses are comparable to high methadone doses (³85 mg/day) in terms of effectiveness (i.e., treatment retention and suppression of illicit opioid use) (66). As well, prescription guidelines for buprenorphine/naloxone state that the maximum dosage is 24 mg/ 6 mg a day (88). Regarding slow-release oral morphine (SROM), studies have been conducted to determine the efficacy of SROM in terms of illicit opioid use (determined by urinalysis), opiate withdrawal symptoms, retention (proportion of participants at the end of the study period) and number of adverse events (76–80,89). All of these have reported effective mean doses ranging from 347 – 791 mg/day. A prospective study in Slovenia showed that clients who have inadequate withdrawal suppression have higher mean daily doses of 1100 mg/day (80). Similarly, clinical 16 trials have reported effective SROM mean daily doses of up to 1200 mg/day (78,79). Canadian clinical guidelines report mean prescribed dose ranges of 235 – 791 mg/day, where the full range of doses for SROM is be 60 – 1200 mg/day (90). In the last years, studies have shown that in addition to determining an effective dose (i.e., reducing withdrawal, appropriate blockage), the concept of dose adequacy (i.e., clients’ perceptions) matter as these client’s perceptions on the drug can affect both the dose they receive and outcomes such as retention in treatment, mental health problems, legal problems, among others (91,92). For example, studies investigating dose adequacy of methadone have found that clients on higher doses of methadone reported to be more inadequately dosed in terms of heroin consumption, narcotic blockade, physical and mental opiate withdrawal, craving for heroin and methadone overdose than those with lower doses (84,93). In addition, methadone clients define their perceptions on dose adequacy mainly in terms of “function” and “comfort” (40). Discomfort can lead to either stopping methadone treatment or having an increased need to get “high” with the use of street opioids (40). Adding to that, some clients may simply wish to cease methadone treatment as they perceive that methadone is not appropriate for them and/or to avoid the side effects related to methadone. In British Columbia for example, a study by Nosyk et al. (94) found that during 2012 – 2018, on average there was a monthly methadone treatment discontinuation of 10% and 21.2% for buprenorphine/naloxone. 17 1.6.2 Injectable opioid agonist treatments (iOAT) Injectable opioid agonist treatments (iOAT), as diacetylmorphine (DAM) and hydromorphone (HDM), arise as treatment options for those clients not benefiting from oral opioid agonist treatments (i.e., methadone or buprenorphine/naloxone). But the history of iOAT is controversial and lengthy (95,96). iOAT in Europe has been around since the 1920s (95), but the first clinic to provide pharmaceutical-grade heroin under supervised on-site clinic settings for clients who were not benefiting from conventional treatments opened in Switzerland in 1992, demonstrating improvements in illicit heroin and cocaine use, physical and mental health status, and social functioning in clients receiving injectable heroin (97). Following the Swiss model, other European countries such as the Netherlands (4,96), Spain (71), Germany (5), and the United Kingdom (UK) (98) implemented supervised injectable heroin as treatment for OUD. In Canada, after years of political, funding, regulatory and operational barriers, in 2005 the first North American RCT evaluating injectable heroin vs. oral methadone began (NAOMI) (1,74). This trial also included a pilot double-blind study on injectable hydromorphone, given to a few participants randomized to the injectable heroin arm. Results from this pilot study led to subsequent clinical trial SALOME and the observational cohort study RUTH. Studies performed on iOAT in Europe and in Canada have focused on the efficacy of iOAT compared to methadone and have demonstrated that iOAT, under supervised on-site clinic settings (to ensure safety since these medications can cause serious adverse reactions such as respiratory depression (99)), are effective at reducing illicit drug use, retention in treatment and improvements in health status and social functioning (4,5,74,97,98,100,101). iOAT in the 18 Canadian setting showed to be more effective at retaining people in treatment than methadone, which lead to improvements on health outcomes for people with many individual and structural vulnerabilities (74,100,101). 1.6.2.1 Dosage in iOAT In contrast to methadone, at present it appears that there has been no study involving dosing of iOAT medications as a main outcome. Moreover, there is little flexibility for prescribers as current prescription recommendations are adapted from the protocol of the European clinical trials (102) (see section 2.2.2 of this dissertation for more details) and in some cases, there are regulatory barriers around iOAT prescription (e.g., restricted availability of diacetylmorphine). Despite these constrains, doses are prescribed in an individualized basis. However, as mentioned, there are no data on typical dose ranges of iOAT. Effective doses of iOAT are determined individually for each patient by physician/nurse recommendation (to ensure safety) with input from the patient, until reaching an effective dose with which the patient feels comfortable (i.e., one feels a “high” if it is tolerated). Therefore, unlike oral therapies (i.e., methadone or buprenorphine/naloxone) for iOAT there are currently no general fixed rules that state optimal dosages in milligrams (i.e., typical doses) (73,102). Briefly, for establishing individual doses, clients on iOAT undergo a 3-day induction protocol adapted from the protocol by Seidenberg and Honegger (42,101) (more details are described in Chapter 2). Based on that protocol, doses of either medication (DAM or HDM) are individually titrated upwards to match the client’s needs, always starting with a safe dose (10 mg for HDM 19 and 20 mg for DAM) and increased until reaching a maximum dose of 500 mg/day of HDM or 1000 mg/day for DAM. Current guidelines state that stable doses must be individually determined but mean daily doses from the European and Canadian RCTs may be instructive where the mean daily dose for DAM is 443 mg and 244 mg for HDM (30). However, as previously mentioned, specified doses are illustrative only and can vary widely (Table 1.2) depending on individual sensibility and the tolerance of each client. In SALOME for example, daily doses received by clients of iOAT medications varied from a range of 50 mg/day to 500 mg/day for HDM and from 100 mg/day to 1000 mg/day for DAM, with mean doses of 506 mg/day and 261 mg/day for DAM and HDM respectively (100). In the European RCTs, the range of mean daily dose of DAM go from 274 mg/day reported in Spain (71) to 573 mg/day reported in Belgium (103) (Table 1.2). Table 1.2 Mean daily doses of diacetylmorphine and hydromorphone from RCTs RCT Participants DAM dose in mg Mean (SD) HDM dose in mg Mean (SD) Switzerland, 1998a 51 509 (NA) Netherlands, 2003b 174 548 (NA) Spain, 2006c 62 274 (146) Germany, 2007d 1032 442 (NA) NAOMI, 2009e 226 392 (NA) 212 (NA) UK, 2010f 127 399 (164) Belgium, 2015g 74 573 (230) SALOME, 2016h 202 506 (206) 261(104) DAM: diacetylmorphine; HDM: hydromorphone NAOMI DAM to HDM ratio 3:1; SALOME ratio was 2:1 a. Perneger et al. (3). b. van den Brink et al. (4). c. March et al. (71). d. Haasen et al. (5). e. Oviedo-Joekes et al. (74). f. Strang et. al. (98). g. Dermaret et al. (103). h. Oviedo-Joekes et al. (100) 20 1.6.3 Access to treatment for opioid use disorder Many countries recognize that pharmacological interventions with psychosocial interventions are beneficial for the treatment of opioid use disorder. Nonetheless, access to treatment is not equitable as treatments are usually poorly funded and supported (10). Availability of pharmaceutical interventions in low- and middle-income countries in Africa, South Asia, Central and South America is less that 1% of the availability in North America (33,104). There are also pronounced inequities within North America, especially in Canada, where minorities (e.g., race) and people with structural disadvantages (e.g., income, disabilities, psychiatric disorders) receive inferior care (105). Evidence is robust in favor of pharmacological interventions for the treatment of OUD, nonetheless a persistent bias in clinicians and the public in general against these interventions remains (10). In addition, there are political barriers interfering with the use of pharmacological interventions and the duration of treatment (when available) (10,21). Despite the barriers that hinder the access to treatments for OUD, there has been a global increased trend in availability of the oral opioid agonist treatments methadone and buprenorphine that provides an opportunity to accelerate access to evidence-based opioid agonist treatments (21). Similarly, evidence has been favorable and robust for iOAT, and these treatments are starting to expand across Canada (2). Nonetheless, access to iOAT in Canada is limited to a few locations in 21 BC (n=6), Ontario (n=3), and Alberta (n=2) with a combined capacity of approximately 420 clients which is significantly small compared to the roughly 351,000 Canadians with OUD (2,106). In May 2019, the Minister of Health Ginette Petitpas Taylor, announced that Health Canada approved hydromorphone for the treatment of severe opioid use disorder in adults, and added diacetylmorphine to the List of Drugs for an Urgent Public Health Need which was approved in February 2022 by Health Canada as a new treatment option for severe opioid use disorder in adults, (107,108). This allows every province and territory to provide these drugs, meaning that people seeking treatment will have now access to iOAT. In addition, during the COVID-19 pandemic new approaches had to be adopted which demonstrated that access to treatment can be maintained during difficult situations by providing scalable take-home therapy (109,110). In Canada, some positive adaptations were noted such as tele-medicine prescription renewals, weekly dispensing (instead of daily), and the main one being access to “carries” (extended take-home doses of OAT that were restricted to a clinic) which was an adaptation that had been long asked before the COVID-19 pandemic (111). 1.7 Study Objectives In the continuum of care for OUD where opioid agonist treatments, including iOAT, expand across Canada, program providers would need to account for typical doses to forecast resources such as syringes, vials, pharmacy services, nursing staff and physicians. Now that policy is 22 moving in favor of iOAT, it is worth focusing on typical doses and predictors of dose, if any, to account for at the system level. To date, studies have mainly focused on demonstrating the effectiveness of iOAT compared to oral OAT (i.e., methadone) and safety of these injectable medications (74,100,101). Dose, as it has been provided in an individualized manner, has not shown to affect outcomes in the RCTs (112). Nevertheless, understanding dose trajectories both daily and over time, can support program managers and service providers in order that they can plan and support individualized care. Thus, the overarching research questions of this thesis are as follows: under the wide range of dosages, are there typical doses for iOAT? Are there any factors, beyond the already known inter-individual differences (i.e., metabolism, genetic mutations, comorbidities) that influence iOAT dose changes? Are there systematic differences between clients within the different dosage cohorts (e.g., for HDM, do clients within the dose rage of 100 mg – 200 mg differ in a determined factor (e.g., age) compared to clients in the dose range of 300 mg – 400 mg)? All these unsolved questions are current barriers that prevent these treatments from being fully expanded and being optimally delivered across North America (e.g., vial size for optimal delivery). As well, findings from this research will contribute to the Federal Actions on Opioids for Increased Access to Treatment on their initiative to support the development of a national treatment guideline for injectable opioid agonist treatment and funding pilot projects on opioid agonist treatment (113). 23 Treatment with injectable diacetylmorphine has been prescribed for several decades and more recently with hydromorphone. While some clinical teams hold a breadth of experience and know what to expect regarding typical doses or range of doses to be prescribed, to date, no study has investigated that question. Thus, the objectives of this dissertation are aimed at supporting clinical teams on making shared decisions with their clients when choosing the medication dose. The main objective of this thesis is to determine the typical doses of iOAT with diacetylmorphine and hydromorphone. The specific objectives and research questions are as follows: Objective 1: Describe prescribed and received doses of injectable diacetylmorphine and hydromorphone and identify potential dosage cohorts. Objective 2: Determine if there were differences in dose received of injectable diacetylmorphine and hydromorphone between open-label compared to double-blind. Objective 3: Identify the potency ratio between injectable diacetylmorphine and hydromorphone in an open-label basis. 1.8 Thesis outline This thesis is comprised of 5 chapters. Chapter 1 offers a brief overview of opioid use disorder epidemiology in a Canadian context, pharmacological oral treatments, its dosage, pharmacodynamics and pharmacokinetics of opioids, dose adequacy and expectations, and the current situation of iOAT in a Canada. Chapter 2 describes the methodology used to approach the research questions of this dissertation. Chapter 3 presents the findings from objective 1 and Chapter 4 the findings from objectives 2 and 3. These chapters have the format of introduction, 24 methodology, findings, and discussion. Finally, Chapter 5 summarizes the overall findings from this study, contributions, and directions on clinical practice and further research. 25 Chapter 2: Methodology Overview 2.1 Dissertation methodology This dissertation uses data from the dispensation records of the Providence Health Care’s Crosstown Clinic and the prospective cohort study Research on the Utilization of Therapeutic Hydromorphone (RUTH). RUTH was the first iOAT program in North America (i.e., injectable medications were provided beyond the scope of a clinical trial). This dissertation also makes use of The Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) data, the clinical trial from where participants transitioned to the RUTH program. Quantitative methods were implemented throughout this dissertation to address the objectives. Chapter 3 and Chapter 4 used descriptive statistics to present the daily dose prescribed and received of iOAT during RUTH. Chapter 4 also uses inferential statistics to address the second objective using longitudinal and fixed data from RUTH and SALOME. These specific quantitative methods are described in detail in their respective sections. The following is a description of the SALOME and RUTH studies, the dispensation records of the Providence Health Care’s Crosstown Clinic, the delivery of treatments, variables of interest and ethical considerations. The delivery of treatments and clinical procedures surrounding dose selection and use are described to provide a better framework to the upcoming analyses. The methods to respond to the objectives of the present thesis are described in their respective chapters. 26 2.2 SALOME trial study methods 2.2.1 Design, Settings, and Participants This study was a two-phase single-site (Vancouver, Canada) phase III, randomized, double-blind, non-inferiority clinical trial that tested if hydromorphone, a licensed opioid analgesic medication, was as good as diacetylmorphine, the active ingredient in heroin, for the treatment of people with severe opioid use disorder who were not benefitting from available therapies (Phase I). Secondly, this trial was aimed at testing if people who were effectively treated with the injectable medications (HDM and DAM) could be switched and retained to the oral formulations of these (Phase II). The SALOME trial was funded by the Canadian Institutes of Health Research (Grant: MCT-103817) in March 2009 and received ethics approval from the University of British Columbia and Providence Health Care Research Ethics Board (H09-01455) in November 2009. Section 56 of the Canadian Federal Controlled Drugs and Substances Act Exception needed to operate was obtained in June 2011. Recruitment began in December 2011 and ended in December 2013, where a total of 202 participants were recruited. Phase I of SALOME started in January 2012 and involved 6 months of treatment. Phase II started after participants terminated Phase I and involved 6 months of treatment as well. A total of 144 participants transitioned from Phase I to Phase II and 97 completed the 6 months of treatment for this phase. Phase II was ceased for lack of effectiveness in June 2014, with a small number of participants completing this phase. 27 The treatments for SALOME were delivered at the Providence Health Care’s Crosstown Clinic in Vancouver’s Downtown Eastside neighborhood. Beyond medications, clients had access on-site to doctors, nurses, social workers, addictions counsellors, life-skills counsellors housing referrals and legal assistance. Once the SALOME trial was terminated, the Providence Health Care’s Crosstown Clinic continued to provide these treatments to former SALOME participants through Health Canada’s Special Access Programme (for diacetylmorphine) and by compassionate access (for hydromorphone) in compliance with article 34 of the Declaration of Helsinki (100,114,115). 2.2.2 SALOME Treatments Treatments were self-administered (i.e., clients injected the medications themselves). Injectable hydromorphone and diacetylmorphine could be administered a maximum of three times a day, with a mandatory period of minimum of three hours between doses due to their pharmacokinetic properties (i.e., half-life) outlined in section 1.1.3 of this dissertation. Participants received individualized and adjustable doses of injectable diacetylmorphine or hydromorphone prescribed as diacetylmorphine equivalents to maintain double-blind (using a ratio of 2:1 DAM:HDM as seen in NAOMI (116)). Participants underwent an induction phase of 3 days; this procedure was conducted by the physician and nurse with active input from the client. By protocol, participants arrived at the clinic, and they were observed for 5 to 10 minutes before their dose dispensation to ensure their safety (i.e., no signs of intoxication from opioids, alcohol, or benzodiazepines). Participants then moved into the injection room where they were given pre-filled syringes of their medication and they had up to 7 minutes to self-administer the 28 medication either intravenously or intramuscularly (new patients had up to 15 minutes to allow for adjustments to the setting and equipment). Participants were assessed during this time and after self-injection for 15 to 30 minutes to ensure safety (i.e., no signs of drowsiness or respiratory depression) prior to leaving the clinic. These wait periods were flexible during the study period to adapt to the circumstances and participants needs (101,117,118). For this induction phase, if a client missed a dose or a full day, the process was restarted from the last tolerated dose at the clinic. However, if more than one day was missed, the induction procedure had to be started from the beginning. In addition, to prevent withdrawal symptoms and use of street drugs during this period, methadone could be co-prescribed at an initial dose of 30 mg and increased by 10 mg steps as needed. Details on the titration protocol have been provided in previous studies (118). The protocol used in SALOME was adapted from the diacetylmorphine programs pioneered in Switzerland in early 1990s (42). The protocol allows to safely increase doses while avoiding over and under dosing. Generally, initial induction individual doses of hydromorphone start at 10 mg and reach to 90 mg on the third day. Individual doses for diacetylmorphine start at 15 mg and reach to 180 mg on the third day. From day 4 and on after induction (stabilization phase) doses can be adjusted once a week up to a maximum of 400 mg/dose or 1000 mg/day for diacetylmorphine and 200 mg/dose or 500 mg/day of HDM (42,118). 29 2.2.3 SALOME Assessments SALOME participants underwent face-to-face fully confidential interviews by a team that worked in collaboration but independently from the clinical team. There was not transferring of information between research and clinical data, unless consent was given (i.e., access to test, signing of release of information forms). During these interviews, standardized questionnaires were used to collected self-reported information. The questionnaires included: Baseline and follow-up European version of the Addiction Severity Index (EuropASI), EQ-5D (EuroQoL), Opioid Treatment Index (OTI), SCL-90‐R, Maudsley Addiction Profile (MAP), and Health Utilities Index (HUI). These collect information on socio-demographic characteristics, health, substance use, and treatment history domains, and record clients’ behaviors from the previous 30 days to the day the questionnaire is done. All questionnaires were administered at baseline 3, 6, 9, 12, 18 and 24 months from randomization. 2.2.4 SALOME Dispensation Records The present dissertation uses data of the first 6-month randomized study period, recorded in the SALOME Crosstown dispensation records (i.e., SALOME clinical database). The SALOME clinical database includes daily prescribed and received injections, daily number of prescribed and attended sessions, dose prescribed and received of HDM and DAM in DAM-equivalents per session as well as daily total co-prescribed oral medications, treatment arm and type of injection (i.e., titration or regular). The database consists of 81,770 injections, 42,318 injections of diacetylmorphine and 39,452 of hydromorphone. 30 This database was maintained by the clinical team, mostly the pharmacy, in collaboration with the statisticians and investigators since it was the main source of control of the substances by Health Canada. 2.3 RUTH study methods 2.3.1 Design, Settings, and Participants RUTH was a longitudinal prospective cohort study of people receiving open label injectable hydromorphone or diacetylmorphine (iOAT) and oral hydromorphone at Providence Health Care Crosstown Clinic as they transitioned from the randomized control trial SALOME. The purpose of this study was to determine the effectiveness of open-label iOAT and the role of program-related factors on treatment outcomes. RUTH was funded by the Canadian Institutes of Health Research (Grant: MOP-142443) in 2015 and received ethics approval from the University of British Columbia and Providence Health Care Research Ethics Board (H15-02064) in 2016. Recruitment began in March 2016 and ended in June 2016. A total of 137 former SALOME participants that were receiving iOAT at the Crosstown Clinic at the time of enrollment were contacted by the research team to be invited to participate in the RUTH study. A total of 131 participants were enrolled in the study. 31 2.3.2 Crosstown Clinic Treatments Randomization in the SALOME study was staggered due to lack of sufficient space at the Crosstown Clinic to fit the total necessary sample size to test the non-inferiority hypothesis. At the end of the trial, SALOME participants were offered to transition to open-label injectable hydromorphone and later to open-label injectable diacetylmorphine, until reaching clinic capacity. The clinic capacity was expanded from approximately 80 to 125 once running as a program. Spots were first offered to those receiving injectable medications, then to those in oral medications and finally to those who were not receiving medications at the clinic at the time (earlier randomized SALOME participants). The Crosstown clinical procedures, when running as a program, were overall akin to those of the SALOME clinical trial outlined previously (2.2.2. Salome Treatments). Overall, clients received individualized and adjustable doses of open-label injectable diacetylmorphine or hydromorphone through a 3-day induction phase, nurse driven, followed by a stabilization phase, allowing for shared-decision making. During SALOME the ceiling doses specified on protocols for hydromorphone (42,118) were 200 mg per injection and 500 mg a day. Nonetheless, after SALOME ended, prescribers at the Crosstown Clinic provided higher doses of hydromorphone to participants who needed it to be adequately dosed and retained in treatment, given that hydromorphone in Canada is a licensed opioid analgesic for the management of severe pain, and most recently for supervised injectable opioid agonist therapy (62). That was not the case for diacetylmorphine (until February 2022), 32 for which ceiling doses specified on protocols (400 mg per injection and 1000 mg a day) had to be maintained. Finally, during the study period an accelerated protocol for hydromorphone was adopted in response to the client’s higher opioid tolerance given their exposure to more potent opioids such as fentanyl. This 3-day hydromorphone induction protocol increased the starting dose to 20 mg so maximum individual dose on the third day, if they attended all sessions, was 130 mg (101). 2.3.2.1 Additional considerations on availability of medications During SALOME, as a double-blind clinical trial, participants did not have the option to choose the medications they received (i.e., either hydromorphone or diacetylmorphine), and after the trial ended, clients started receiving open-label hydromorphone. However, advocacy efforts made possible the expansion (one client at a time), over time, of open-label injectable diacetylmorphine at the Crosstown Clinic. Once access (i.e., funding, and regulatory barriers) to diacetylmorphine was secured, clients could at any time switch between injectable medications (i.e., switch from injectable hydromorphone to injectable diacetylmorphine and vice versa). Although some clients may wish to switch medications, this is often not the case (i.e., some preferred to remain on hydromorphone). Nonetheless, there was an unanticipated national shortage of diacetylmorphine during the study period when all clients that were on diacetylmorphine had to be switched to injectable hydromorphone. In situations such as this, when a participant wishes or needs to switch medications, they follow a similar procedure to the 3-day induction phase as outlined 33 previously (section 2.2.2.) with the difference that a conversion is made (following a 2:1 potency ratio hydromorphone to diacetylmorphine) based on known tolerance of the current medication, and a modest reduction of the corresponding dose following a 2:1 potency ratio is administered given intolerances across medications (detailed explanation is further provided in section 4.4.5.2). 2.3.3 RUTH assessments Participants were given RUTH study questionnaires that collected self-reported information on socio-demographic characteristics, health, substance use, and treatment history (the same questionnaires as in SALOME). These questionnaires record clients’ behaviors from the previous 30 days to the day the questionnaire is performed. All domains were measured at baseline and every two months for a total of 12 months and then 6 months after (at 18 months). 2.3.4 Crosstown Dispensation Records Crosstown prescription and dispensation records (i.e., clinical database) is a continuation of the SALOME clinical database but adapted to the necessities of a program and not of a clinical trial. For this dissertation, it is worth reiterating that it includes daily prescribed and received injections, daily number of prescribed and attended sessions, dose prescribed and received of HDM and DAM in DAM-equivalents per session as well as daily total (i.e., the sum of the dose per session per day), co-prescribed oral medications, drug prescribed (i.e., HDM or DAM) and type of injection (i.e., titration, regular or accelerated). 34 Enrolled participants were granted access for linkage of the RUTH study questionnaires and clinical data with their SALOME questionnaires and clinical data. To avoid duplication of data and reduce the burden on participants, the baseline characteristics that were collected in the SALOME clinical trial were used for RUTH. Hence this dissertation makes use of the SALOME baseline socio-demographic characteristics (e.g., gender) and lifetime events (e.g., chronic medical problems). The recording of injection dispensation by Crosstown Clinic would appear to be unique in Canada and allows for meaningful analysis of patters of drug dispensation and use. This database consists of prescribed and received injection for the study period (595,305 prescribed injections, where 457,292 of those were received injections). 2.3.5 Data period used in this dissertation This dissertation uses data from the dispensation records from August 2014 to April 2020. When pertinent, data from the RUTH questionnaires are incorporated at the adequate timelines, or as fixed characteristics (i.e., gender and baseline conditions, for example.) 2.4 Variables of interest Prescribed doses refer to the dose prescribed by the physician (i.e., quantity of drug in milligrams (mg) prescribed in DAM-equivalents) for each session, that is determined after the titration period outlined above (i.e., the dose reached at the stabilization phase). This is the quantity that the pharmacy dispenses to the client. 35 Received doses concern to the quantity in mg that the client self-administers at each session, which can be smaller than the prescribed doses due to remnants left on syringes and dose adjustments, for example. As in the case of prescribed doses, received doses are recorded in DAM-equivalents. Daily total doses of prescribed medication refer to the sum of the quantity prescribed in each of the possible three sessions in a day. Similarly, daily total received doses refer to the sum of the quantity received in each of the three possible sessions in a day. Prescribed sessions are the number of sessions prescribed by the physician for the client to attend and receive their medication in a day. The possible number of sessions that a client can be prescribed to attend in a day range from a minimum of one to a maximum of three. Attended sessions indicate the number of sessions out of the possible three that the clients showed up to. This number can be lower than prescribed sessions, as it reflects missed sessions in a day. A client could have missed one or two sessions in a day; if the number of missed sessions is equal to the prescribed session in a day it is treated a missed day (instead of missed sessions). 2.5 Ethics and ethical considerations Ethics approval to conduct the research for this dissertation was obtained from the UBC Providence Health Care Clinical Research Ethics Board; certificate number H20-00794, last approved in September 2021. Given that this dissertation is a retrospective analysis of data from 36 participants in the RUTH and SALOME studies, this study was considered minimal risk as per Tri-Council Policy Statement (TCPS2). There were no further ethical considerations in this dissertation. 37 Chapter 3: Typical doses of injectable hydromorphone and diacetylmorphine 3.1 Background Injectable Opioid Agonist Treatments (iOAT) have been demonstrated to be safe and effective for the treatment of Opioid Use Disorder (OUD) (69, 93, 94). Efficacy of iOAT has been measured in relation to methadone in terms of reduction of illicit drug use, health outcomes, and social functioning (69, 92, 93, 111–116). As most research on iOAT has focused on demonstrating the effectiveness of iOAT (i.e., retention, health, drug use), apparently there have been no studies on iOAT dosage as the outcome of interest, only as a co-variate. The study of iOAT dosage continues to be highly relevant for clinical practice, even within individualized dose prescribing. Determining and understanding the typical safe and effective range of dosages of iOAT that clients utilize has the potential to guide service providers in terms of program planning and prescribing practices. In addition, the identification of factors, if any, associated with dose ranges (e.g., lower, or higher), could support the prediction of adequate doses for clients. In contrast, for the most commonly prescribed and highly researched medication in opioid agonist treatment (OAT), oral methadone, several studies over time have been conducted to determine effective doses (81–85). Mixed results have been found regarding the effective mg per day. Some studies claim that methadone doses greater than 100 mg per day are better in terms of heroin use reduction (82,125); whereas others have found than methadone doses greater than 100 mg per day are no better than 100 mg per day (81,84). Nonetheless, these studies suggest that 38 there is a proportion of individuals who require higher doses. Must studies have suggested that methadone in higher doses (between 60 mg – 120 mg per day) are more effective in terms of treatment retention and reduction of illicit drug use (80, 82). While the studies in early years focused on ensuring clients received a minimum effective dose, over the years the research evolved to identify not just ranges but also adequacy of the dose (93). Unlike in the case of methadone, for iOAT there are currently no general guidelines that state how to anticipate effective doses. Doses in iOAT are determined individually by physician/nurse recommendation with active input from the client, during the induction phase, until a dose that meet the client’s needs is reached (94, 95). Current Canadian guidelines state that mean daily doses obtained from RCTs could be instructive, where the mean daily dose for diacetylmorphine (DAM) was 443 mg and 244 mg for hydromorphone (HDM) (30,73). In addition to determining effective doses, exploring factors that may influence these doses is relevant. For methadone, basic science studies have shown that methadone doses vary across individuals due to differences in metabolism, genetic mutations (e.g., CYP3A4 and CYP2B6), comorbidities (prolonged QT interval and liver disease, for example) or drug interactions (77, 81, 118–120). Those same factors that influence methadone doses are true for most opioids, hence it is known that iOAT dosages will vary due to the previously listed inter-individual differences. Differences in quantity of µ-opioid receptors have been observed in females and males, where females have a higher amount than males (46), which could increase the dose of iOAT received in males compared to females to produce a similar effect. Age also influences µ-opioid receptor 39 biding; older people have an increased µ-opioid receptor binding compared to younger people (46) which can decrease the dose of iOAT an older person needs to produce a similar effect in a younger individual. In addition, age can alter the muscle to fat ratio where older people tend to have increased fat mass compared to younger individuals (44) that facilitates the absorption of lipid-soluble drugs, such as hydromorphone and diacetylmorphine, and therefore, a decrease in dose compared to younger individuals. Finally, differences in opioid metabolism have been observed by ethnicity with Caucasians being slow metabolizers (54); this can decrease the dose a Caucasian person requires to experience a similar effect to that of a non-Caucasian. Thus, this study aims to determine typical doses of iOAT by analyzing daily dosage data on clients attending the Crosstown Providence Healthcare Clinic from August 2014 to April 2020. Second, this study explores factors that could influence iOAT dose, beyond the already known inter-individual differences, and compare these factors across different dosage ranges to determine if there are any differences between the dosage groups. 3.2 Methods 3.2.1 Design, settings, and participants This is a retrospective longitudinal descriptive study. The study population for this chapter included all 131 participants from The Research on the Utilization of Therapeutic Hydromorphone (RUTH) who received injectable medications at the Crosstown Clinic during August 2014 to April 2020. Briefly, RUTH was a longitudinal cohort study of people receiving injectable diacetylmorphine or injectable hydromorphone as they transitioned from the randomized control trial SALOME. 40 3.2.2 Crosstown Clinical Procedures When SALOME ended, participants continued to receive iOAT or oral hydromorphone at Crosstown through supervised care. This model was described in detail in Chapter 2 of this dissertation. As per protocol (42), clients attend the clinic a maximum of three times a day to receive their medication, where the maximum daily-total dose of injectable hydromorphone is 500 milligrams (mg) and 1000 mg for diacetylmorphine, and the maximum dose of hydromorphone is 200 mg and 400 mg of diacetylmorphine. Nonetheless, as hydromorphone is licensed as treatment for opioid use disorder (107), prescribers at Crosstown Clinic allowed single-doses greater than 200 mg and daily-total doses greater that 500 mg. 3.2.3 Data The Crosstown clinical data consists of daily injections during the study period from August 2014 to April 2020. Data of days with co-prescription of oral medications (i.e., hydromorphone, methadone, morphine) and titration days (first 30 days of treatment as per SALOME (118)) were removed from the analysis. To determine typical prescribed doses a total of 587,361 injections were used: 416,160 of diacetylmorphine and 171,201 of hydromorphone. Regarding typical received doses, 450,915 injections were analyzed: 317,537 and 133,363 for diacetylmorphine and hydromorphone respectively. The clients’ characteristics presented in this analysis were chosen since they can have a relationship (e.g., clinical, social, or psychological) with the dose of injectable medications. Given that RUTH participants come from the SALOME clinical trial, baseline socio-41 demographic characteristics such as age, gender, and ethnicity for these participants were obtained from the baseline SALOME questionnaires. Other socio-demographic characteristics such as housing, chronic medical problems, and comorbidities (i.e., physical, and psychological health scores) as well as other drug use (i.e., illicit opioids, stimulants, and alcohol) were obtained from the RUTH study questionnaires. Drug use variables were measured every 2 months for a year, and then once at 18 months. These variables are continuous and indicate the number of days using the drug in the prior month that the questionnaire was administered. For this analysis, these variables were not treated as longitudinal given that the time points at which they were measured do not match the clinical data (i.e., daily dosage), therefore the total number of days of drug use were averaged, and this average was used in the analysis. Dose-related variables such as dose satisfaction and the Visual Analog Scale (VAS) were obtained from the RUTH questionnaires. Dose satisfaction for this study was categorized as a) yes (i.e., at every time point), b) no (i.e., at least in one time point) and c) unknown (for participants who never provided an answer). The VAS measures 6 perceived drug effects on a scale from 0 to 100, where higher scores indicate a larger magnitude of the perceived effect. For this analysis only the drug liking effect was reported since it is the effect that has demonstrated previously to have a strong association with dosage (129,130). Dose satisfaction and VAS were measured every 2 months for a year, and then once at 18 months. However, the collection of these variables does not match the clinical records i.e., daily collections that started since 2014, whereas the first-time collection point (T0) in RUTH was in 2016 and since 2015 diacetylmorphine was available open-label for clients at the Crosstown 42 clinic. Thus, by T0 in RUTH most of the clients were already on diacetylmorphine plus they had the option to switch between medications during the 18-month collection period in RUTH. Hence, the dose satisfaction variable was analyzed altogether for the 18-month period (as per the previously described categories) and only the 12-month RUTH VAS scores were used. In addition, the SALOME VAS scores that were only measured once at the end of the 6-month blinding period were analyzed. 3.2.4 Analysis Descriptive statistics (i.e., mean, standard deviation, interquartile range, histograms, scatterplots) were used to present daily-total prescribed and received doses of iOAT as well as demographic and the previously mentioned characteristics of the study population. Summary statistics and visual summaries were obtained with the statistical software R (Version 1.4.1106). Daily-total doses were calculated in an individual basis, taking the total quantity of medication prescribed or received in a day as outlined in Chapter 2. To further investigate the dose of iOAT, dosage groups were created by medication (i.e., dosage groups). Histograms of mean dose prescribed per session were generated and based on how participants were distributed amongst all range of doses (23 mg – 240 mg for hydromorphone; 39 mg – 384 mg for diacetylmorphine) and in discussion with the clinical team at the Crosstown clinic three dosage brackets were set per drug. As a reminder, there are rules for how much a person can be prescribed per session, and in some cases there is a cap for DAM and not for HDM. For example, if the daily dose allowed is 1,000 mg for DAM and no more than 400 mg per dose, clients will not be able to have 3 sessions of 400 mg. They sessions will be set up in a 43 way that fits their needs and those combinations, nuances, might be difficult to catch with the dataset. The following brackets were made following carefully iterative process between the data itself, consultation with clinical leads and epidemiologist (i.e., the thesis committee) and varication with knowledge users (people who use the treatment). These conversations are ongoing, and continue to shed light to our work. Dosage groups, prescribed dose per session, for hydromorphone: 1. The first group (n=8) included those participants who received prescriptions of: o less than 75 mg per session (any out of the 3 possible) 2. The second group (n=90) compromised the largest number of participants, who received prescriptions of: o 75 to 190 mg per session (any out of the 3 possible) 3. The third group (n=31) included a small number of participants who received prescriptions of: o 190 or more mg per session (any out of the 3 possible) Dosage groups, prescribed dose per session, for diacetylmorphine: 1. The first group (n=23) comprised those participants who received prescriptions of o less than 150 mg per session (any out of the 3 possible) 2. The second group (n=82) included the largest number of participants, who received prescriptions of: o 150 to 300 mg per session (any out of the 3 possible) 3. The third group (n=21) included participants who received prescriptions of: 44 o 400 mg per session (any out of the 3 possible) OR o 300 mg or more in the 3 sessions 3.3 Results 3.3.1 Participants The majority of the 131 participants that were enrolled in RUTH received both drugs (i.e., switched medications) at some point during the study period (August 2014 – April 2020). A total of 126 participants received open-label diacetylmorphine and 129 participants received open-label hydromorphone. RUTH participants were on average 45 (SD = 9.3) years of age, 28.2% were woman (n = 37), 29.8% self-identified as indigenous (n = 39), 92% had stable housing at baseline (n = 70.2), 92.4% had chronic medical problems that interfere with life at baseline (n = 121). The average physical health score was 24.9 (SD = 9.8) (total health scores range from 0 to 51, higher scores suggest more physical conditions) and the average psychological health score was 8.8 (SD = 6.4) (psychological health scores range from 0 to 40, higher scores indicate poorer psychological health). The average number of days using any illicit opioids, stimulants and alcohol during the previous month were 5.9 (SD = 7.7), 10.3 (SD = 10.5) and 2.8 (SD = 6.1) correspondingly. More than half of participants were not satisfied with their dose (62.2%) at least once. Drug liking at 12 months in RUTH was higher for both hydromorphone (mean = 69.1; SD = 24.1) and diacetylmorphine (mean = 72.7; SD = 24.6) than the drug liking in SALOME (mean = 61.0; SD = 33.3) (Table 3.1). 45 Table 3.1 Characteristics of RUTH study participants Characteristics Participants n=131 Mean ± SD; n (%) Age 45 ± 9.3 Gender: Woman 37 (28.2) Man 94 (71.8) Ethnicity: Indigenous 39 (29.8) Non-indigenous 92 (70.2) Stable housing a: Yes 92 (70.2) No 39 (29.8) Had chronic medical problems in RUTH b: Yes 121 (92.4) No 10 (7.6) Physical health score in RUTH c: 24.9 ± 9.8 Psychological health score in RUTH d: 8.8 ± 6.4 Days in the prior month using alcohol e: 2.8 ± 6.1 Days in the prior month using any opioid e: 5.9 ± 7.7 Days in the prior month using any stimulant e: 10.3 ± 10.5 Dose satisfaction Yes 46 (35.1) No 82 (62.6) Unknown 3 (2.3) VAS in SALOME (blinded) f: Drug Liking 61.0 ± 33.3 VAS in RUTH (T12 – HDM) f, g: n=24 Drug Liking 69.1 ± 24.1 VAS in RUTH (T12 – DAM) f, g: n=90 Drug Liking 72.7 ± 24.6 a. At first visit in RUTH (T0). Unstable housing is single resident occupancy hotel rooms with restrictions or couch surfing, and street housing defined as outdoor, vehicles or in public places. b. At first visit in RUTH (T0). c. OTI (Opioid Treatment Index) total health scores range from 0 to 51, higher scores suggest more physical conditions. 46 d. MAP (Maudsley Addiction Profile) psychological health scores range from 0 to 40, higher scores indicate poorer psychological health. e. Days are in the prior 30 days of the interview. f. Visual Analog Scale (VAS) scores range from “not at all” [0] to “extremely” [100] and measures the experienced opioid drug effects. SALOME was double-blind; therefore, VAS scores are not associated with the drug, but rather their treatment allocation guess. g. RUTH VAS scores at 12 months (T12) correspond to the year 2017. 3.3.2 Typical Dose Ranges in the study Since doses in RUTH were titrated by physician and nurse recommendation to ensure safety with active input from the client, it is assumed that prescribed doses were safe (i.e., well tolerated) and effective (i.e., produced the desired effects). Excluding days with missed sessions and co-prescriptions of oral medications, during the study period a total of 595,305 injections were prescribed for participants, 417,603 injections of diacetylmorphine and 177,702 injections of hydromorphone. As seen in Figure 3.1, excluding the first 30 days of treatment to allow for titration and dose adjustments, the mean daily-total prescribed dose of hydromorphone was 348.03 mg (SD=136.75). The mean daily-total prescribed dose of diacetylmorphine was 524.1 mg (SD=212.89). Contrastingly, over the study period participants received a total of 457,292 injections (318,813 injections of diacetylmorphine and 138,464 injections of hydromorphone). The mean daily-total dose received of hydromorphone was 294.84 mg (SD = 131.80) and for diacetylmorphine was 455.6 milligrams (SD = 202.11), excluding days with missed sessions and co-prescriptions of oral medications (Figure 3.2). 47 Figure 3.1 Mean daily-total dose prescribed in milligrams of hydromorphone and diacetylmorphine during the study period from August 2014 to April 2020. Doses of hydromorphone varied from a range of 65 mg/day to 700 mg/day while doses for diacetylmorphine ranged from 110 mg/day to 1000 mg/day. 48 Figure 3.2 Mean daily-total dose received in milligrams of hydromorphone and diacetylmorphine during the study period from August 2014 to April 2020. Received doses of hydromorphone varied from 50 mg/day to 700 mg/day and from 105 mg/day to 990 mg/day for diacetylmorphine. 49 Prescribed doses are higher than received doses (Figure 3.3). These observed differences reflect missed sessions, and adjustments in dose received per session performed by the clients themselves or instructed by the nurses due to safety concerns (e.g., potential combination of substances or exacerbation of comorbidities). Average-daily prescribed and received doses of hydromorphone were higher than those for diacetylmorphine. Doses of diacetylmorphine were more stable over time compared to doses of hydromorphone that exhibited a lot of variability, without considering the substantial incline and decline in hydromorphone and diacetylmorphine, respectively from May to November 2016, which reflect the shortage of diacetylmorphine at the Crosstown clinic when all the clients had to be switched to hydromorphone. 50 Figure 3.3 Mean daily-total dose prescribed and received of DAM equivalent by drug during the study period (August 2014 - April 2020). A simple 30-day moving average was used. 3.3.3 Dosage groups Prescriptions for most clients were on the middle dosage group for both medications (75 – 150 mg for hydromorphone, 150 – 400 mg for diacetylmorphine). Clients had prescriptions of approximately 115 mg per session of hydromorphone, and an average of 2.8 sessions prescribed per day (out of the 3 possible), while they had average prescriptions of 205 mg per session of diacetylmorphine with an average of 2.7 sessions per day. There were no differences in mean attended sessions per day between hydromorphone and diacetylmorphine (mean = 2.4; SD = 0.4). The remainder of the clients had stable doses over time on the other two dosage range groups (<75 mg / ≥190 for hydromorphone, and <150 mg / ≥ 400 mg (or ≥ 300 mg) for 51 diacetylmorphine, as specified in section 3.2.4). However, there is an important group of clients who were stable over time on prescriptions of £ 150 mg per session for diacetylmorphine (lowest dosage group), that is considerably larger compared to the group of only 8 participants who were stable over time on doses £ 75 mg per session of hydromorphone, which is the equivalent dosage group. While there were no noteworthy observed differences across the dosage groups neither for hydromorphone nor diacetylmorphine terms of the clients’ characteristics (Tables 3.2 and 3.3). The observed tendencies were that clients on the dosage group of ≥ 190 mg per session (highest dosage group) were on average a couple of years older, used on average less illicit opioids and alcohol, and more stimulants than clients in the other two groups. Also, the proportion of indigenous clients tend to decrease as the dosage increases, whereas the proportion of females increases as dosage increases. Similar patterns for diacetylmorphine were observed for ethnicity, and use of illicit opioids, alcohol, and stimulants. Nonetheless, there were no age tendencies across groups for diacetylmorphine. There is not sufficient power in some groups for hydromorphone and diacetylmorphine to conduct statistical analyses to determine if these observed differences between groups are significant due to the small sample sizes. However, beyond discerning if the proportions (or means) significantly differ across groups, is relevant to determine whether the observed trends (upward or downward) are significant. Therefore, tests for linear trends in proportions and linear regressions by drug were performed for each variable. The majority yielded not significant 52 results, but there was a significant downward trend in stable housing (p<0.01) for diacetylmorphine. Table 3.2 Characteristics of study participants by dose group of hydromorphone Characteristics Doses ≤ 75 mg n=8 Mean ± SD; n (%) Doses >75 <190 mg n=90 Mean ± SD; n (%) Doses ≥ 190 mg n=31 Mean ± SD; n (%) Age 45.5 ± 9.8 44.0 ± 9.7 47.3 ± 6.8 Gender: Female 1 (12.5) 25 (27.8) 10 (32.3) Male 7 (87.5) 65 (72.2) 21 (67.7) Ethnicity: Indigenous 4 (50) 27 (30) 7 (22.6) Non-indigenous 4 (50) 63 (70) 24 (77.4) Stable housing a: Yes 6 (75) 66 (73.3) 22 (71) No 2 (25) 24 (26.6) 9 (29) Had chronic medical problems in SALOME b: Yes 2 (25) 50 (55.6) 17 (54.8) No 6 (75) 40 (44.4) 14 (45.2) Physical health score in RUTH c: 22.5 ± 13.5 24.6 ± 9.5 25.3 ± 10.3 Psychological health score in RUTH d: 10.4 ± 10.8 8.5 ± 5.8 7.7 ± 5.2 Days using alcohol e: 6.5 ± 7.0 2.5 ± 5.9 2.1 ± 5.0 Days using any opioid e: 8.3 ± 9.1 6.0 ± 7.1 4.6 ± 8.0 Days using any stimulant e: 11.3 ± 14.3 9.0 ± 9.7 12.5 ± 11.2 Dose satisfaction Yes 1 (12.5) 34 (37.8) 10 (32.3) No 7 (87.5) 54 (60) 20 (64.5) Unknown 0 2 (2.2) 1 (3.2) VAS in SALOME f: Drug Liking 55.0 ± 28.8 66.1 ± 32.0 47.8 ± 34.5 53 a. At first visit in RUTH (T0). Unstable housing is single resident occupancy hotel rooms with restrictions or couch surfing, and street housing defined as outdoor, vehicles or in public places. b. At baseline. c. OTI (Opioid Treatment Index) total health scores range from 0 to 51, higher scores suggest more physical conditions. d. MAP (Maudsley Addiction Profile) psychological health scores range from 0 to 40, higher scores indicate poorer psychological health. e. Days are in the prior 30 days of the interview. f. Visual Analog Scale (VAS) scores range from “not at all” [0] to “extremely” [100] and measures the experienced opioid drug effects. SALOME was double-blind; therefore, VAS scores are not associated with the drug, but rather their treatment allocation guess. Table 3.3 Characteristics of study participants by dose group of diacetylmorphine Characteristics Doses ≤ 150 mg n=21 Mean ± SD; n (%) Doses >150 <400 mg n=82 Mean ± SD; n (%) Doses ≥ 300 mg n=23 Mean ± SD; n (%) Age 45.3 ± 7.6 44.8 ± 9.9 45.4 ± 8.2 Gender: Woman 5 (23.8) 24 (29.3) 7 (30.4) Man 16 (76.2) 58 (70.7) 16 (69.6) Ethnicity: Indigenous 9 (42.9) 24 (29.3) 5 (21.7) Non-indigenous 12 (57.1) 58 (70.7) 18 (78.3) Stable housing a: Yes 19 (90.5) 55 (67.1) 7 (30.4)* No 2 (9.5) 27 (32.9) 15 (65.2)* Had chronic medical problems in SALOME a: Yes 9 (42.9) 46 (56.1) 13 (56.5) No 12 (57.1) 36 (43.9) 10 (43.5) Physical health score in RUTH b: 22.9 ± 11.5 24.7 ± 8.8 25.3 ± 11.6 Psychological health score in RUTH d: 7.5 ± 7.2 8.7 ± 6.1 8.6 ± 5.9 Days using alcohol e: 3.5 ± 6.6 2.2 ± 5.0 1.4 ± 3.8 Days using any opioid e: 6.0 ± 7.5 6.7 ± 8.0 3.9 ± 7.8 54 Characteristics Doses ≤ 150 mg n=21 Mean ± SD; n (%) Doses >150 <400 mg n=82 Mean ± SD; n (%) Doses ≥ 300 mg n=23 Mean ± SD; n (%) Days using any stimulant e: 7.5 ± 11.2 11.0 ± 10.3 11.4 ± 10.1 Dose satisfaction Yes 9 (42.9) 31 (37.8) 7 (30.4) No 12 (57.1) 49 (59.8) 15 (65.2) Unknown 0 2 (2.4) 1 (4.4) VAS in SALOME f: Drug Liking 60.0 ± 32.3 65.2 ± 34.1 47.3 ± 32.3 a. At first visit in RUTH (T0). Unstable housing is single resident occupancy hotel rooms with restrictions or couch surfing, and street housing defined as outdoor, vehicles or in public places. b. At baseline. c. OTI (Opioid Treatment Index) total health scores range from 0 to 51, higher scores suggest more physical conditions. d. MAP (Maudsley Addiction Profile) psychological health scores range from 0 to 40, higher scores indicate poorer psychological health. e. Days are in the prior 30 days of the interview. f. Visual Analog Scale (VAS) scores range from “not at all” [0] to “extremely” [100] and measures the experienced opioid drug effects. SALOME was double-blind; therefore, VAS scores are not associated with the drug, but rather their treatment allocation guess. (*) Indicates significance in linear trend for proportion at p < 0.05. 3.4 Discussion The present study provides evidence that mean doses of hydromorphone and diacetylmorphine vary widely amongst clients, ranging from 51 – 696 mg and 106 – 989 mg for hydromorphone and diacetylmorphine respectively per day. This demonstrates that clients use the whole range of possible dose prescriptions, thus the importance of giving program providers a guidance when prescribing. Most clients use prescriptions within the range of 75 – 150 mg and 150 – 300 mg for hydromorphone and diacetylmorphine respectively, per session. In a framework of up to three 55 sessions allowed per day, clients were prescribed an average of 2.8 and 2.7 sessions per day for hydromorphone and diacetylmorphine respectively. These findings can assist program implementation as they can provide guidance to pharmacists and prescribers by preparing syringes around the typical dosages of iOAT (which will reduce drug wastage) and forecasting of drugs to cover for almost three sessions in a day (the maximum allowed). Implementing these findings can also inform governments as they would result in a cost reduction and will support scalability. Finally, findings from this study support flexible individualized dosing (i.e., prescribing doses greater than the specified doses in clinical protocols) to match client’s needs, advocating for share-decision making. Overall doses of diacetylmorphine appear to be more stable over time compared to doses of hydromorphone that exhibited a lot of variability during the study period. The observed variability in hydromorphone could be attributed to the lower number of clients receiving this drug and to the prescription flexibilities that hydromorphone allowed. While both medications have been shown to be safe and effective, until February 2022 only hydromorphone was licensed in Canada. The prescription regulations of diacetylmorphine remain linked to prior trials, while hydromorphone, being licensed for years, can evolve with clinical practice. Now that diacetylmorphine is licensed as well, the clinical practice may evolve to provide daily total doses of up to 1200 mg (a 20% increase of the current 1000 mg/day limit). While there is no power to investigate inter-individual differences and the majority of trend test were not significant, some observational findings can be discussed for future work. Results from 56 SALOME (100) suggest that non-indigenous clients had higher doses compared to indigenous clients, which is consistent with findings from this study where one can see more non-indigenous clients in the highest dosage bracket for both drugs. This finding however, would appear counterintuitive as the opposite would be expected given the prevalence of slow metabolism in Caucasians (54). However, this difference could be attributed to an unconscious racial bias rather than a biological difference. Pain studies have found that non-indigenous clients have increased opioid prescription availability (98, 121) which could possibly be the case for iOAT prescriptions as the focus on decreasing the death rates on non-indigenous clients may divert the attention from the persistent health inequities that afflict minorities (132). For both hydromorphone and diacetylmorphine, there was a majority of males across the three dosage groups. However, for both drugs, the proportion of males compared to females is higher at the lowest dosage bracket, which could mean that females receive higher doses than males. This has been observed in sex studies of opioid prescription use where females had significantly higher use of opioids than males (133). From a biological perspective however, this finding would be contrary to what could be expected giving the increased number of µ-opioid receptors found in females (46) which could decrease the dose. Nevertheless, this result may be explained when taking age into consideration. Older participants appeared to display higher doses than the younger participants for both hydromorphone and diacetylmorphine, which could be an effect of the very small sample in the highest dosage bracket. However, if this phenomenon was to be observed in a study with enough power, the effect of the relationship between sex and metabolic differences (44), and sex with µ-57 receptor affinity (46), would be opposite to what it could be expected in relation to dose (i.e., older participants having lower doses). The number of days using illicit opioids in the previous month, although low, was higher in the lowest dosage bracket; this finding is consistent with those from SALOME (100). As clients use more illicit opioids, they would use less treatment sessions which in turn would reflect lower doses. A downward trend was also observed for the number of days using alcohol. Alcohol poses an increased risk of respiratory depression and overdose, therefore when a client presents for their dose of iOAT intoxicated by alcohol (blood concentrations that exceeds 0.05%), the iOAT dose is withheld (30), thus reflecting lower doses. The same trend (i.e., a negative association between number of days using street drugs and dose of iOAT) was observed in SALOME for stimulants (134). However, a most recent study by Palis et al. (135) found that cocaine use did not translate into less days using iOAT, and indeed this is what it was found in this study. There were no patterns observed in number of days using stimulants and dose of iOAT, emphasizing the importance of considering the heterogeneity of people accessing iOAT when delivering these treatments. Unstable housing and other psychosocial issues may result in clients missing their dose of iOAT (73) hence displaying lower doses. Nonetheless an upward significant trend for unstable housing and dose of diacetylmorphine was observed in this study (i.e., the proportion of clients reporting unstable housing increases as dose increases) which is contrary to the assumption of lower doses (explained by missed sessions) caused by unstable housing. 58 Dose satisfaction and VAS scores are the variables that are directly related to the dose of iOAT, as they reflect client’s preferences which can influence dose (93,129,130). Drug liking has been positively associated with dose in previous studies (129,130). Nonetheless, this study found no trends neither for diacetylmorphine nor hydromorphone, based on the double-blind (SALOME) drug liking scores. The middle range dosage group for both hydromorphone and diacetylmorphine, has the highest drug liking scores, which is an effect that this study attributes to the larger sample size in this group compared to the others. VAS scores for RUTH were not reported for the dosage group analyses by clients’ characteristics, but similarly to SALOME, there were no trends for drug liking scores. 3.5 Limitations This was a population-based study; therefore, dosage was analyzed on the population level and the general conclusions reached are for the population. This study did not analyze individual doses over time. However, the NAOMI research team (74) previously explored the individual doses over time for their study participants and found that individuals have very diverse patterns, which helps the clinical teams to understand their clients. Nonetheless, studying individual doses does not provide useful information that can aid program planning as this is done on a population base, which is the reason this dissertation did not study individual doses over time. The data used in this secondary analysis was not designed to test participant’s characteristics in response to dose. In addition, time changing variables collected with the instruments (e.g., drug use patterns, health conditions) were not collected daily as the dosage, which reduces the ability to conduct analyses to test the relationship between participant’s factors and dose. Due to this 59 and to the resulting small sample size in the dosage groups, there is lack of power to conduct statistical analyses to determine if there were significant differences or trends in characteristics in response to dose. The collection of time-changing variables that match the collection of dosage data could provide a more complete picture of factors that could influence dose of iOAT. Given that study participants come from a previous clinical trial (SALOME), generalizability of findings could be a concern since participants for SALOME were chosen based on the clinical trial criteria (e.g., long-term opioid dependence, regular injection of illicit opioids, at least two prior addiction treatment episodes, among others) to demonstrate efficacy. In addition, in 2012 most people were illicit heroin users. Thus, findings from this thesis are generalizable for people who want to inject short acting opioids, specifically diacetylmorphine, who do not want other treatments (e.g., oral methadone) or for these other treatments have not been effective to them. In other words, these findings can be generalized to many more people, that the actual study population, but these findings are not for the people who inhale opioids or inject fentanyl. 3.6 Conclusion The range of safe and effective iOAT dosages is wide, which demonstrates the diversity and variability across people accessing iOAT. This supports the shared decision-making model (clients and prescribers) that allows for flexible dosing where increases in dosage are possible, if tolerated. Therefore, prescribers should titrate doses on an individual basis, but can expect stable iOAT doses over time around the mean dose which can support program planning. 60 Chapter 4: Received doses of injectable hydromorphone and diacetylmorphine: Comparing open-label to double-blind 4.1 Background Injectable hydromorphone and diacetylmorphine are both strong µ opioid receptor agonists that have similar pharmacokinetic properties (i.e., short half-lives, and less accumulation), hence produce similar clinical and subjective effects which suggests that one can substitute the other (42,129,136,137). As a consequence, and because of the advantages of hydromorphone being legally available in North America, investigators formally tested the non-inferiority of injectable hydromorphone to diacetylmorphine for the treatment of long-term opioid use disorder in the Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) (100). This randomized, double-blind study demonstrated the equivalence of hydromorphone to diacetylmorphine in terms of retention in treatment and reducing days of illicit drug use. These findings led to the offering of injectable hydromorphone and diacetylmorphine in an open-label basis in Canada. In SALOME, a double-blind clinical trial, participants expressed a preference to receive diacetylmorphine where, at baseline, 83.2% indicated they preferred this drug over hydromorphone (138). Perceived treatment guess in SALOME was measured at six-months follow-up by asking participants “what treatment do you think you are receiving” and they could answer one of the following five options: 1) heroin definitely, 2) heroin possibly, 3) hydromorphone definitely, 4) hydromorphone possibly, and 5) not sure. Regardless of treatment 61 allocation guess, the study by Oviedo-Joekes et al., (138) found that at a six-month follow-up, there were no differences regarding retention in treatment (having attended of at least 28 days in the prior month) and illicit opioid use (measured by number of days using street heroin use), but there were differences in physical and mental health scores (Maudsley Addiction Profile physical and health scores) where those who thought were receiving diacetylmorphine had better scores than those who guessed hydromorphone or were unsure. In addition, the study by Oviedo-Joekes et al., (138) identified that guessing diacetylmorphine (regardless of what actual medication they received) was associated with higher scores in terms of drug liking, good effect and drug-related high, whereas negative effects (e.g., not liking the drug, not feeling as well as they would expect) were associated with guessing hydromorphone (138). The overall findings from that study suggested that participants’ perceptions have an impact in treatment outcomes. Similarly for methadone, the most prescribed agonist treatment, studies on participants’ perceptions on methadone have been conducted to assess the impact of these perceptions on treatment outcomes. Those with negative perceptions (i.e., participants who reported dose inadequacy in terms of narcotic blockade, physical and mental opiate withdrawal syndrome, craving for heroin, heroin consumption and overdosing) reported more mental health problems, social relationship problems, legal problems, use of other drugs, among others, compared to participants with positive perceptions (i.e., participants who reported being adequately dosed). (37, 85, 86). 62 The impact of participants’ perceptions and expectations on dose received of injectable hydromorphone and diacetylmorphine is yet to be explored. Similarly for methadone no study has focused on the impact of participants’ perceptions and expectations on dose as main outcome. However, a study by Walcher et al., (91) found that daily methadone doses increased significantly over time for clients who were inadequately dosed (which could be interpreted as negative perceptions) compared to those who were adequately dosed (that could be interpreted as positive perceptions). Received daily-total doses of injectable hydromorphone and diacetylmorphine in SALOME were 261.2 mg and 506.4 mg respectively (100). The question if clients change the dose of their medication once they “know” what they are receiving is pertinent for clinical teams that use averages from a double-blind clinical trial to manage forecast or make decisions. In contrast to the double-blind doses in SALOME, the open-label doses found in this study were 294.8 mg and 455.6 mg respectively. This suggests that there may be differences in the manner participants use hydromorphone and diacetylmorphine in an open-label basis compared to how they used these drugs in a double-blind basis, given that all clients in this study are former SALOME participants. 4.2 Objectives As injectable hydromorphone and diacetylmorphine are delivered in an open-label basis in Canada, it is important to know if participants’ perceptions and expectations on hydromorphone and diacetylmorphine impact the dose received. The present study aims to determine if there are significant differences in the open-label dose received of injectable hydromorphone and 63 diacetylmorphine compared to the double-blind doses, and if differences are found, to test if participants’ perceptions and expectations can explain these differences. 4.3 Methods 4.3.1 Design, settings, and participants The present analysis is a retrospective longitudinal inferential study involving participants from The Research on the Utilization of Therapeutic Hydromorphone (RUTH) study who are former participants from The Study to Assess Longer-term Opioid Medication Effectiveness (SALOME) clinical trial. SALOME was a double-blind clinical trial testing the non-inferiority of injectable hydromorphone to injectable diacetylmorphine. RUTH was a longitudinal cohort study of people receiving open-label injectable diacetylmorphine or injectable hydromorphone. Treatments for SALOME and RUTH were delivered at the Providence Health Care’s Crosstown Clinic in Vancouver. The study period for this analysis includes the SALOME Phase I double-blind period (January 2012 – September 2014) and the period of August 2014 – April 2020 from the RUTH program and Crosstown Clinic Dispensation Records. 4.3.2 Crosstown Clinic Treatments Details on the delivery of treatment/medications can be found in Chapter 2 of this dissertation. Participants received individualized and adjustable doses of injectable diacetylmorphine or hydromorphone. Medications were self-administered daily, up to three times, under observation of registered nurses. Prescribed doses refer to the amount of drug in milligrams a client is prescribed by a physician or nurse after the titration period. Received doses reflect the amount of dose in milligrams that the client injects. This amount is usually lower that the prescribed amount 64 as it reflects missed sessions, and single dose adjustments made by the clients themselves or nurses due to safety concerns (e.g., intoxication of other substances). 4.3.3 Data Data for this analysis comes from the SALOME clinical database and the Crosstown clinical database. Both include the daily prescribed and received dose of injectable diacetylmorphine or hydromorphone. This analysis uses the double-blind data collected from January 2012 to September 2014 and the open-label data collected from August 2014 to April 2020. Data of days with co-prescription of oral medications (i.e., hydromorphone, methadone, morphine) and titration days (first 30 days of treatment as per SALOME protocol (118)) were removed from the analysis. Participants consented to have their Crosstown clinical data (i.e., daily dosage) linked with their records from the SALOME clinical trial (i.e., study questionnaires and daily dosage). In addition, they consented to have their RUTH questionnaire data linked to their Crosstown clinical data. Data was linked using a unique participant identifier. The questionnaires record clients’ behaviors from the previous 30 days to the day the questionnaire is performed on the following topics: socio-demographics, substance use patterns, physical and mental health, and perceptions of treatment. Questionnaires were collected at baseline and every two months for a total of 12 months and then 6 months after at 18 months. 65 4.3.4 Analysis A total of 131 participants who were receiving or had recently received double-blind injectable medications were enrolled to RUTH. For this analysis, participants were eligible if they transitioned from the double-blind phase (SALOME) and received the same medication open-label (RUTH). In other words, participants were eligible if at any point during RUTH they received the same medication that they were randomized to in SALOME. Of the 131 eligible participants for this analysis, 6 never received the same medication in the open-label period than the one they received on the double-blind period and 2 switched to oral medications, leaving a total of 123 participants to be included in the present analysis. All analyses were conducted using R (Version 1.4.1106). Descriptive statistics were used to present demographic and key characteristics such as age, gender, ethnicity, and chronic medical problems of this study population. These characteristics were chosen as they can have a clinical relationship with the dose of injectable medications, and because these fixed baseline characteristics are the ones that can be analyzed properly given that the longitudinal variables were collected in a different way than the daily dosage. Longitudinal variables that could also be associated with dosage such as physical and psychological health scores, housing, days in the previous month using alcohol, opioids or stimulants and dose satisfaction were also described. To investigate if there was a difference between the dose received of iOAT during the open-label period (RUTH) and the double-blind period (SALOME), participants were divided by the drug received and an intraindividual analysis was conducted comparing the daily-total average dose received during the open-label period to the daily-total average dose received during the double-66 blind period for eligible participants. For this purpose, a total of 439,504 injections from the open-label period were compared against 54,116 injections from the double-blind period. Daily-total doses (i.e., the total quantity in milligrams received in the three possible sessions in a day) were calculated per participant by drug received and the averages were obtained and compared using a paired t-test. Since previous studies have shown that participants have a preference for diacetylmorphine over hydromorphone when both are available (138), one hypothesizes that participants’ perceptions and expectations to receive diacetylmorphine will have an influence on the dose received. Then, assuming diacetylmorphine is the preferred drug, it was hypothesized that participants who were receiving double-blind diacetylmorphine and thought were receiving diacetylmorphine, are less likely to change their doses in an open-label basis. To test this hypothesis, a subgroup analysis was conducted (paired t-test) by blinding guess in SALOME by drug. Blinding was measured at the end of the 180-day treatment period of SALOME (100). Options were a) heroin definitely, b) heroin possibly, c) hydromorphone definitely, d) hydromorphone possibly and e) not sure. Based on these options, for the purpose of this analysis, three groups were created: 1) participants who thought were receiving diacetylmorphine, 2) participants who though were receiving hydromorphone, and 3) participants who were unsure. Participants were divided in these three groups given that some studies have suggested that the participants’ guess may have an influence on the outcomes due to their perceptions about treatment (139–141). 67 To investigate if the observed difference in dose received of iOAT during the open-label period and the double-blind period could be attributed to participants’ characteristics, pairwise comparisons were performed, using a paired t-test for binary variables (e.g., gender and chronic medical problems at baseline in SALOME) and simple linear regression for continuous variables (e.g., age and physical health scores). 4.4 Results 4.4.1 Participants’ characteristics From the 123 participants considered in this analysis, 67 participants received injectable diacetylmorphine and 56 received injectable hydromorphone in both periods (i.e., in SALOME and in RUTH). From the 56 participants that were on hydromorphone, 8 participants were removed from the analyses since these participants received daily-total doses greater that the daily-total maximum allowed dose as per protocol (500 mg) (39, 110) during the open-label period. These participants were excluded to make an adequate comparison to the double-blind period where prescriptions greater to 500 mg were not allowed. There were no participants on the diacetylmorphine group who received more than the daily-total maximum allowed per protocol (1000 mg). A total of 115 participants were included in the analyses, 67 participants on diacetylmorphine and 48 participants on hydromorphone. Participants on the DAM group were on average 45.5 (SD = 8.9) years of age, 28.4% were woman (n = 19), 31.3% self-identified as indigenous (n = 21), 71.6% reported stable housing (n = 48) and 55.2% had chronic medical problems that interfere with life at baseline in SALOME (n = 37). The average physical health score in RUTH was 24.5 (SD = 10) where total health scores 68 ranged from 0 to 51 (higher scores suggest more physical conditions), while the average psychological health score in RUTH was 8.1 (SD = 6.3) (total psychological scores ranged from 0 to 40, higher scores suggest poorer health). Average days in the prior month using alcohol, any illicit opioid and any illicit stimulant were 1.9 (SD = 4.1), 4.8 (SD = 6.5), 9.6 (SD = 10.6) respectively. Approximately half were satisfied with their dose (49.3%) over 18 months (RUTH questionnaires period) and VAS drug liking scores for SALOME (at 6 months) and RUTH (at 12 months) were 63.5 (SD = 33.3) and 77.0 (SD = 21.2) (Table 4.1). Participants on the HDM group were on average 44.8 (SD = 9.8) years of age, 25% were woman (n = 12), 31.2% self-identified as indigenous (n = 15), 70.8 % reported stable housing (n = 34), and 54.2% had chronic medical problems that interfere with life at baseline in SALOME (n = 26). The average physical health score in RUTH was 23.58 (SD = 9.4) and the average psychological health score was 8.8. (SD = 5.9). The average days using alcohol, opioids and stimulants in the prior month were 3.1 (SD = 6.9), 8.0 (SD = 8.3), 11.7 (SD = 10.9) respectively. Most participants were not satisfied with their dose (75%) and VAS scores for SALOME and RUTH were 59.7 (SD = 33.7) and 64.1 (SD = 29.2) (Table 4.1). For the present study, fixed characteristics of participants (i.e., age, gender, ethnicity, housing, chronic medical problems) and health scores for DAM and HDM did not seem to differ. Nonetheless, participants in HDM appeared to have more concurrent drug use (i.e., alcohol, illicit opioids, and stimulants) than DAM participants. In addition, HDM participants reported less satisfaction with their dose and lower drug liking scores than participants in DAM. 69 Table 4.1 Characteristics of study participants by drug (Double-Blind vs. Open-Label analysis) Characteristics Participants receiving DAM n=67 Mean ± SD; n (%) Participants receiving HDM n=48 Mean ± SD; n (%) Age 44.5 ± 8.9 44.7 ± 9.8 Gender: Woman 19 (28.4) 12 (25) Man 48 (71.6) 36 (75) Ethnicity: Indigenous 21 (31.3) 15 (31.3) Non-indigenous 46 (68.7) 33 (68.7) Stable housing a: Yes 48 (71.6) 34 (70.8) No 19 (28.4) 14 (29.2) Had chronic medical problems in SALOME b: Yes 37 (55.2) 30 (53.6) No 30 (44.8) 26 (46.4) Physical health score in RUTH c: 24.5 ± 10.0 23.8 ± 9.4 Psychological health score in RUTH d: 8.1 ± 6.3 8.8 ± 5.9 Days using alcohol e: 1.9 ± 4.1 3.1 ± 6.9 Days using any opioid e: 4.8 ± 6.5 8.0 ± 8.3 Days using any stimulant e: 9.6 ± 10.6 11.7 ± 10.9 Dose satisfaction Yes 33 (49.3) 10 (20.8) No 33 (49.3) 36 (75) Unknown 1 (1.4) 2 (4.2) VAS in SALOME f: n=62 n=43 Drug Liking 63.5 ± 33.3 59.7 ± 33.7 VAS in RUTH (T12) f, g: n=60 n=42 Drug Liking 77.0 ± 21.2 64.1 ± 29.2 a. At first visit in RUTH (T0). Unstable housing is single resident occupancy hotel rooms with restrictions or couch surfing, and street housing defined as outdoor, vehicles or in public places. b. At baseline. 70 c. OTI (Opioid Treatment Index) total health scores range from 0 to 51, higher scores suggest more physical conditions. d. MAP (Maudsley Addiction Profile) psychological health scores range from 0 to 40, higher scores indicate poorer psychological health. e. Days are in the prior 30 days of the interview. f. Visual Analog Scale (VAS) scores range from “not at all” [0] to “extremely” [100] and measures the experienced opioid drug effects. SALOME was double-blind; therefore, VAS scores are not associated with the drug, but rather their treatment allocation guess. g. RUTH VAS scores at 12 months (T12) correspond to the year 2017. During the open-label period (RUTH), participants on the DAM group (n= 67) received a daily-total average dose of 460.4 (SD = 186.7; range 173.6 – 948.0) mg while participants on HDM (n = 48) received 248.7 (SD = 96.8; range 55.3 – 440.2) mg. In contrast, during the double-blind period (SALOME), DAM participants received a daily-total average dose of 509.9 (SD = 190.1; range 123.9 – 890.1) mg and HDM participants received 243.8 (SD = 81.6; range 50.0 – 435.6) mg. 4.4.2 Dose: Double-blind vs Open-label When comparing the daily-total average dose received during the RUTH study period to the daily-total average dose received during SALOME for the DAM group, it was found that during the open-label period, participants received on average 49.5 mg less than during the double-blind period and this difference was significant (p <0.01; 95% CI = -12.6, -86.4) (Table 4.2). In contrast, for the HDM group, when comparing the daily-total average dose received during the RUTH study period to the daily-total average dose received during SALOME, no significant effect was noticed. (Table 4.2). Participants in the HDM group received similar amounts during the open-label and double-blind periods (p >0.05; 95% CI = -22.5, 32.3). 71 A sensitivity analysis was conducted for the HDM group (Table 4.2). The analysis was repeated including the 8 participants that received open-label doses greater than the maximum allowed as per SALOME protocol (which was different to the RUTH protocol); granting them the maximum allowed daily-total dose as per SALOME protocol plus one to identify those observations, i.e., 501 mg/day. This analysis (n=56) resulted in a daily-total average dose received during the RUTH study period of 284.8 mg (SD = 126.3) compared to a daily-total average dose in SALOME of 267.4 mg (SD = 99.9). Thus, during the open-label period these participants received only 17.4 mg more than during the double-blind period; this difference was not significant (p >0.05; 95% CI = -8.7, 43.4). The previous analyses by drug group were repeated using the daily-total average dose prescribed, and similar results were observed. Table 4.2 Double-blind and open-label daily-total doses in milligrams and dose difference in milligrams by drug Group SALOME dose in mg RUTH dose in mg Difference in mg (RUTH – SALOME) DAM (n=67) 509.9 ± 190.1 460.4 ± 186.7 -49.5 (-86.4, -12.6)* HDM (n=48) 243.8 ± 81.6 248.7 ± 96.8 4.9 (-22.5, 32.3) HDM sensitivity analysis (n=56) 267.4 ± 99.9 284.8 ± 126.3 17.4 (-8.7, 44.4) DAM: diacetylmorphine; HDM: hydromorphone; mg: milligrams Data shown are mean ± standard deviation and 95% confidence interval. (*) Indicates the difference in dose received within groups is significant at p < 0.05. Differences within groups calculated using t-test. 72 4.4.3 DAM dose difference by blinding guess To explain the observed difference in DAM dose received between the open and the double-blind period, analyses of the medication guesses were conducted. For this analysis, participants who were receiving DAM during both the RUTH and SALOME study periods (n=67) were divided into three groups according to their SALOME treatment allocation guesses: 1) participants who thought were receiving diacetylmorphine (n= 23), 2) participants who thought were receiving hydromorphone (n=30), and 3) participants who were unsure (n=14). Although there was no power (calculated power was 20%) the differences in dose by blinding guess were clear. Participants receiving double-blind DAM on the trial who thought that they were in that medication (group 1) received an open-label daily-total average DAM dose of 512.8 (SD = 198.9; range 218.2 – 948.0) mg compared to a double-blind daily-total average DAM dose of 535.8 (SD = 163.2; range 309.8 – 879.9) mg. This observed non-significant decrease in dose of 22.9 (p >0.05; 95% CI = -82.9, 36.2) mg less received during the open-label period, supports the hypothesis that participants who were receiving double-blind diacetylmorphine and thought they were receiving diacetylmorphine, are less likely to change their doses in an open-label basis (Table 4.3). In contrast, amongst participants in the second group (i.e., those who were receiving double-blind DAM but thought they were receiving HDM), there was a significant decrease in the daily-total average dose received during the RUTH study period (450.4 ± 170.9; range 192.1 – 785.7 mg) compared to SALOME (528.7 ± 187.9; range 123.9 – 890.1 mg) (Table 4.3). The resulting 73 difference was of 78.3 mg less received during RUTH compared to SALOME (p<0.01; 95% CI = -134.3, -22.4). Among participants in the third group (i.e., unsure), there were no significant differences in doses received while in the RUTH study period compared to the SALOME study period (i.e., no differences in open-label dose received vs. double-blind dose received). Table 4.3 DAM dose and dose difference in milligrams for participants receiving DAM in SALOME and DAM in RUTH by blinding guess Group SALOME DAM dose in mg RUTH DAM dose in mg Difference in mg (RUTH – SALOME) Guessed DAM (n=23) 535.8 ± 163.2 512.8 ± 198.9 -22.9 (-82.1, 36.2) Guessed HDM (n=30) 528.7 ± 187.9 450.4 ± 170.9 -78.3 (-134.3, -22.4)* Guessed unsure (n=14) 427.1 ± 224.1 395.6 ± 187.8 -31.5 (-132.9, 70.0) DAM: diacetylmorphine; mg: milligrams Data shown are mean ± standard deviation and 95% confidence interval. (*) Indicates the difference in dose received within groups is significant at p < 0.05. Prescriber may have different prescription practices or preferences. Therefore, to discard the possibility that the observed differences were attributed to differences in prescription practices between providers at the Crosstown clinic, the dose differences were categorized as increase or decrease, and a Fischer’s exact test was conducted (p > 0.5) which indicated that the observed difference in dose was not associated to prescribers. 74 4.4.4 DAM dose difference by client-characteristic To further explore the difference in dose received of diacetylmorphine during the open-label period compared to the double-blind period, analyses of participants characteristics were conducted (Table 4.4). Table 4.4 DAM dose difference in milligrams for participants receiving DAM in SALOME and DAM in RUTH by client-characteristic Groups/Factors Difference in mg (RUTH - SALOME) Age -2.37 (-6.54, 1.79) Males (n=48) -49.95 (-92.29, -7.62)* Females (n=19) -48.48 (-129.67, 32.71) Stable housing a: -36.67 (-116.77, 161.34) Had chronic medical problems in SALOME a: Yes (n=37) -55.05 (-108.22, -1.92)* No (n=30) -42.70 (-96.07, 10.67) Physical health score in SALOME b: -3.56 (-7.39, 0.26) Physical health score in RUTH b: -3.06 (-6.72, 0.60) Psychological health score in RUTH b: -1.19 (-7.13, 4.75) Days using alcohol e: 2.43 (-6.74, 11.60) Days using any opioid e: -8.84 (-14.18, -3.50)* Days using any stimulant e: -2.32 (-5.80, 1.17) Dose satisfaction Yes (n=33) -48.34 (-107.77, 11.08) No (n=33) -52.65 (-101.5, -3.8)* Unknown NA DAM: diacetylmorphine; mg: milligrams a. At first visit in RUTH (T0). Stable housing was not significant after adjusting by number of attended sessions. b. OTI (Opioid Treatment Index) total health scores range from 0 to 51, higher scores suggest more physical conditions. (*) Indicates the difference in DAM dose received in RUTH and SALOME within groups is significant at p<0.05. Linear regression models were used to estimate the mean differences and 95% CIs. 75 First, by separating the participants in the DAM group (n=67) by gender a significant negative difference (p<0.05; 95% CI = -92.3, -7.6) of 50 mg less received during the RUTH study period was observed in the males group. However, when compared to the non-significant negative difference of 48.5 mg less received during the RUTH study period for females (p>0.05; 95% CI = -129.7, 32.7), one discerns that the observed difference in both groups is similar (Table 4.4). Thus, the lack of significance in the female group can be attributed to lack of power due to the small sample size. For chronic medical problems, both participants who exhibited chronic medical problems that interfere with life at baseline in SALOME and those who did not, experienced a decrease in dose received during the RUTH study period, but the difference was significant for the first group and not for the second. DAM participants who had chronic medical problems (n=37) had a significant difference in daily-total average dose received of 55.1 mg less during RUTH (p<0.05; 95% CI = -108.2, -1.9). In contrast, those participants who did not have chronic medical problems (n=30) had a non-significant (p>0.05; 95% CI = -96.1, 10.7) difference of 42.7 mg less received during the RUTH study period. The difference in dose received between the group who had chronic medical problems and those who did not was only 12.4 mg. Days using illicit opioids in the prior month, although low, was significantly associated with a negative daily-total dose difference of 8.8 mg, on average, received during the RUTH study period (p<0.05; 95% CI = -108.2, -1.9). This is the anticipated effect of using illicit opioids given that as illicit opioid use increases, received doses of iOAT medication decrease due to single 76 dose adjustments made by the clients themselves or nurses due to safety concerns (i.e., intoxication of other substances including illicit opioids) and missed sessions. For dose satisfaction, a significant negative difference (p<0.05; 95% CI = -101.5, -3.8) of 52.7 mg less received during the RUTH study period was observed for those who were not satisfied with their drug. Nonetheless, the difference in those who were satisfied with their drug, although not significant (p>0.05; 95% CI = -107.77, 11.08), is comparable (48.3 mg less). Thus, the significant effect of this variable on dose difference could be disregarded. Neither age, physical and psychological health scores, nor days using alcohol and stimulants were significantly associated with the difference in daily-total average DAM dose received during the two study periods. Drug liking in SALOME, which was blinded, was not associated to the medication (i.e., DAM or HDM) but rather to blinding guess (i.e., the treatment participants thought were receiving). Therefore, drug liking effect for both drugs is similar. Nevertheless, drug liking association to difference in DAM dose received was analyzed and no significant associations were found. Drug liking scores for RUTH were not analyzed given that the time points at which they were collected (see section 3.2.3 for details) do not capture the transition from the double-blind period to the open-label period (2014) neither the introduction of open-label diacetylmorphine at the Crosstown clinic (2015). 77 4.4.5 Potency Ratio To continue exploring potential explanations of differences in received doses when people switch opioids, potency ratio is another area of interest. When offering iOAT, one finds a paucity of data on conversion ratios for switching between these two substitution treatments (42,142). Current potency ratios have been derived from randomized clinical trials (100,142), and a potency ratio of 2:1 diacetylmorphine to hydromorphone, which is currently being used in clinical practice, was derived from these studies. Nonetheless, potency ratios have not been re-assessed in an open-label fashion which is the current regimen under which treatments are being delivered. Thus, to determine the potency ratio of diacetylmorphine to hydromorphone open-label, the same number of injections that were used in Chapter 3 (i.e., 587, 361 prescribed injections and 450, 915 received injections), were used to calculate the potency ratios. The average daily-total doses of prescribed and received diacetylmorphine and hydromorphone were calculated, along with percentile ranks of 10, 25, 50, 75 and 90 to show potency ratios at different dose ranges. Potency ratios were calculated for the whole study period (August 2014 to April 2020). Prescribed and received doses of hydromorphone for participants who received doses outside of protocol, were imputed with the maximum daily-total allowed plus one of hydromorphone as per protocol (i.e., 501 mg a day). 78 4.4.5.1 Open-label potency ratio The average daily-total prescribed doses of diacetylmorphine and hydromorphone were 524.3 mg and 333.7 mg respectively, while the corresponding daily-total received doses were 455.6 mg and 286.9 mg. The potency ratio between diacetylmorphine and hydromorphone was different across dose ranges (Table 4.5), ranging from 1.3:1 to 1.7:1 for dose prescribed and from 1.4:1 to 1.6:1 for dose received. The potency ratio for the mean prescribed and received doses was 1.6:1 diacetylmorphine to hydromorphone (Table 4.5). Table 4.5 Potency ratios between hydromorphone and diacetylmorphine Outcome Statistics Hydromorphone Diacetylmorphine Ratio Dose Prescribed Clients 127 123 10th percentile 203.1 265.1 1.3 25th percentile 254.0 361.0 1.4 50th percentile 317.8 501.0 1.6 75th percentile 419.4 651.0 1.6 90th percentile 501.0 826.9 1.7 Mean 333.7 524.3 1.6 Dose Received 10th percentile 156.4 220.3 1.4 25th percentile 196.3 294.0 1.5 79 Outcome Statistics Hydromorphone Diacetylmorphine Ratio 50th percentile 273.1 431.2 1.6 75th percentile 370.2 589.0 1.6 90th percentile 480.4 730.8 1.5 Mean 286.9 455.6 1.6 Potency ratios between diacetylmorphine and hydromorphone open-label are in the range of 1.3:1 and 1.6:1. Lower potency ratios were observed on the lower dosage percentiles and stabilizes at around 1:6:1 starting at medium dosages (i.e., 270 mg for hydromorphone and 430 mg for diacetylmorphine). This observed potency ratios for diacetylmorphine to hydromorphone are lower than the observed potency ratio of 2:1 in previous clinical trials (93, 133). 4.4.5.2 Switching opioids In addition to equipotencies, guidance on the process of switching between injectable medications are needed. For treatment to be effective, it needs to be individualized to meet each client’s needs and expectations, and in order to do so, it is imperative to know the client’s motivation for switching and their goals (143), along with an evaluation of the client’s physical health to ensure safety (39, 134). As per clinical expertise of Dr. Scott MacDonald and the Providence Health Care’s Crosstown Clinic, to switch from hydromorphone to diacetylmorphine, and vice versa, the same general approach as the induction protocol outlined in Chapter 2 and described in detail by Oviedo-80 Joekes et al. (101) is followed, but the induction time of 3 days is attempted to be reduced to within a day, given that the goal is to have the client reach a safe and effective dose as quickly as possible. Prior to proceeding with the switch, the reason for switching opioids needs to be assessed. Given that diacetylmorphine is the preferred drug (138), some clients who are stable on hydromorphone may wish to switch to diacetylmorphine, nonetheless, diacetylmorphine may not be the proper medication for everyone. Drug intolerances could occur; therefore, the switch may not be clinically recommended in some cases, for example in clients with concurrent use of alcohol. It is important to discuss these possible drug intolerances with the clients to support the decision to remain (or move) to the less desirable medication (hydromorphone). If the decision is taken to proceed with the switch, it is imperative to discuss with the client the approach they desire to take for switching medications and reassure them that they always have the option to revert to something that works for them. There are two general approaches for switching opioids that, for the purpose of this dissertation, are considered a cautious and aggressive approach (Table 4.6). Overall, the cautious approach is desired for those clients who have other health conditions (e.g., chronic obstructive pulmonary disease) or clients who use other drugs (e.g., benzodiazepines, alcohol). For clients on the cautious approach, via share-decision making, a reduction of 30% to the corresponding dose, if a potency ratio of 2:1 would be followed, is administered as initial dose (e.g., if a client is receiving 100 mg of hydromorphone and is switching to diacetylmorphine, the corresponding dose of diacetylmorphine is 200 mg, and with the reduction of 30% the initial dose is 140 mg 81 (Table 4.7)). After the first dose, increments of 15% per dose, if tolerated and needed, can be done during the first day. Increments of 10% can be done during the second day, until a maximum of 10% over the corresponding diacetylmorphine dose following a 2:1 potency ratio (in the previous example, the maximum would be 220 mg). This is performed over a 2-day period. The aggressive approach follows the same principle as the cautious approach previously outlined, but the initial dose is reduced only 20%, the second increment is 25% and the final increment would be 10% over the corresponding dose (following a potency ratio of 2:1) (Table 4.6). Under this approach, a client is switched within a day. Table 4.6 Switching protocol for iOAT Induction doses for switching opioids HDM to DAM cautious and [aggressive] Day 1 Dose 1: Give 30% [20%] less of the corresponding dose of DAM. Observe for 15 minutes, if patient is fit to, they can leave and return at the next dosing in 3 hours. Dose 2: If needed, give 15% [25%] more of amount administered in Dose 1. Observe for 15 minutes. Have patient leave and return at the next dosing window. Dose 3: If needed, give 15% [10%] more of amount administered in Dose 2. Observe for 15 minutes. Have patient leave and return the next day. Day 2a Dose 1: If needed, give 10% more of the amount administered at Dose 3, Day 1. Wait 15 minutes, if patient is fit to leave can do so and return at the next dosing window. Dose 2: If needed, give 10% more of the amount administered in Dose 2. a. Day 2 only contains information for cautious approach, given that following the aggressive approach, the target dose is reached in Day 1. 82 Table 4.7 Example of cautious and aggressive approach for opioid rotation Switching a client who receives 100 mg of HDM to 200 mg DAM (2:1 potency ratio) Cautious Aggressive Day 1 Dose 1: 140 mg DAM Dose 1: 160 mg DAM Dose 2: 160 mg DAM Dose 2: 200 mg DAM Dose 3: 180 mg DAM Dose 3: 220 mg DAM Day 2 Dose 1: 200 mg DAM Dose 2: 220 mg DAM As seen in Table 4.5, the potency ratio of 2:1 hydromorphone to diacetylmorphine is no longer maintained, therefore, to switch between these two medications the potency ratios outlined in Table 4.5 can serve as guidance to determine the initial reduction (or increment) of a dose when switching opioids (i.e., a potency ratio of 1.4 is equivalent to a reduction of 30% whereas a potency ratio of 1.6 corresponds to a reduction of 20%). However, as with the experience of switching opioids for substitution treatment with methadone, the process of switching between these injectable medications is an individualized process that requires caution and shared-decision making to determine the approach to be followed (i.e., cautious, or aggressive) regardless of the dose the client is receiving. Clients respond different to opioids, although diacetylmorphine and hydromorphone have similar characteristics, there are interindividual differences (as outlined in section 1.5 of this dissertation) that will cause a different response to these opioids (144), independently of the potency ratio, that should be considered when deciding, via shared-decision, the approach (i.e., cautious or aggressive) to take. Nonetheless, it is important to provide sufficient doses that will 83 suppress withdrawal, which is the reason many clients and prescribers may choose an aggressive approach. 4.5 Discussion The present analysis demonstrated that there was a statistically significant reduction in the received dose of diacetylmorphine between the double-blind and open-label period, which could be attributed to participants’ perceptions and expectations of the medication. As iOAT is expanding across Canada (2), understanding the implications of clients’ medications expectations and preferences on the drugs being offered can further guide program providers in terms of program planning and prescription practices. The significant decrease in dose received of diacetylmorphine came from the group of participants who guessed they were receiving double-blind hydromorphone, whereas those who guessed they were receiving double-blind diacetylmorphine continued to have similar open-label doses. A study by Dunn et al. (129) found that blinded participants that guessed were being administered diacetylmorphine, reported higher scores in drug liking and good effect compared to when they guessed hydromorphone, even though they were receiving a placebo dose (i.e., 0 mg of diacetylmorphine or hydromorphone), which can explain the findings of this analysis. As participants perceptions were positive (i.e., good effect, drug liking) during SALOME, these participants guessed were receiving diacetylmorphine, hence when offered open-label 84 diacetylmorphine, they maintained the doses they received double-blind, as there is no perceived change for these participants and their expectations had already been met. In contrast, participants who received double-blind diacetylmorphine, but had negative perceptions (i.e., not liking the drug, side effects) guessed they were receiving double-blind hydromorphone (i.e., the less preferred drug, the one they had inferior expectations). In that same study by Dunn et al. (129) it was found that by increasing the dose of the medication the scores for drug liking and good effect increased, which this study attributes as the reason participants increased their doses of hydromorphone in RUTH, thus they would obtain the desired effects (i.e., higher drug liking and good effect) as if they were receiving diacetylmorphine. When participants are matched to their preferred treatments, they tend to decrease their drug consumption (145). Thus, when offered open-label diacetylmorphine, their expectations are met as they are receiving the preferred drug, which leads them to decrease the received dose of diacetylmorphine. Thus, iOAT programs should advocate for clients’ autonomy when choosing their preferred the medication, given that it plays an important role in their treatment. This study demonstrated that when clients receive their “preferred” medication (either by perception (blinded) or reality (open-label)), they self-regulate in regard to their dose by decreasing it if they receive their preferred treatment, and increasing it if not. In addition, when clients received their preferred drug open-label, both diacetylmorphine and hydromorphone showed high drug liking scores, although most clients prefer diacetylmorphine. This is relevant for prescribers and governments given that knowing the preferred drug that clients will use, can 85 result in cost reductions since, contrary to people’s assumption, this study found that when clients receive their preferred drug (i.e., diacetylmorphine) they decrease their doses. For hydromorphone though, this study found open-label increases in dosage. However, this could potentially be explained by the potency ratio, although not verifiable by the analyses in this study, since it is plausible that if hydromorphone would have been prescribed open-label in a potency ratio of 1.6:1 that was observed in this study, perhaps double-blind and open-label doses would have been similar. The open-label potency ratio of diacetylmorphine to hydromorphone observed in this study are lower than the expected potency ratio of 2:1 that was observed in the SALOME clinical trial which was already lower than the NAOMI clinical trial potency ratio of 3:1 (146). Potency-ratios for diacetylmorphine to other opioids, including methadone and hydromorphone, do not follow a linear relationship (102); this study found that potency ratios are different across dosages, where the middle dosages have the highest potency ratios. Potency ratios are a guidance tool for prescribers, in other words, potency ratios provide an estimate only which should be discussed by prescribers with the client. Nonetheless, the average open-label potency ratio found on this dissertation should be integrated to clinical practice, since prescribers following a 2:1 diacetylmorphine to hydromorphone potency ratio, may be underestimating the dose of hydromorphone a client should receive. Thus these findings may aid the conversations between the clinical teams and the clients and therefore, the shared-decision making process for determining dosages. 86 Health problems are relevant to explain differences in dose received, as well as potency ratios of injectable opioid and injectable opioid rotation. Prolonged used of diacetylmorphine can be associated with neurotoxicity (147), nephrotoxicity (148), lung toxicity (149), among others, which can be an indication to switch to hydromorphone. Thus, for participants who had chronic medical problems in SALOME, to prevent further exacerbation of these conditions over the years, via share-decision making, participants and the clinical team could have chosen to either reduce the dose of diacetylmorphine while in RUTH, reflecting the significant decrease in the dose received of diacetylmorphine for these participants, or they could have opted to switch to hydromorphone (potentially following a cautious approach as explain in section 4.4.5.2). Although this study found that differences in doses were not associated with individual prescribers’ practices, this might not be the case for other settings given that the Crosstown clinic follows a client-centered approach, therefore, it was expected to find no associations between dosages and prescribers. Nonetheless, other iOAT settings across Canada may operate differently (2), then perhaps associations between dosage and prescribers might be found. Therefore, is important to consider prescribers preferences and expectations as these might influence dosage and medication choice. Adverse events (AEs) were also hypothesized that could explain the differences in dose received given that when AEs happen, the prescriber may lower the dose for safety concerns, but this is independent of the drug (i.e., diacetylmorphine or hydromorphone) in an open-label basis, and during the double-blind period, prescribers were blinded and prescribing in DAM equivalents, 87 therefore AEs cannot explain the differences in dose by drug during the open-label and double-blind periods. In addition, the collection of AEs for the open-label study period was with the RUTH instruments that cover only 18-months, and the AEs collection was not as detailed as during SALOME. Finally, previous studies on AEs have found that people who experience more AEs do not receive lower doses(150). 4.6 Limitations The main limitation of this study is that it uses blinding guess as a proxy for preferences and expectations measures (i.e., drug liking, good effect), instead of the Visual Analog Scale (VAS) that directly asked the perceived drug liking and drug effects on a 100-point scale. However, this variable was only measured once in SALOME (at the beginning of the study) and as previously mentioned, the time points at which it was measured in RUTH are not informative for this analysis. That is why this study deemed blinding guess, that was measured at 6 months in SALOME (i.e., at the end of the blinded period), as a more appropriate measure. Further studies could implement the use of the VAS periodically to match with dosage data and transitions. Additionally, the data used in this secondary analysis was not designed to test participant’s differences (e.g., age, sex, physical conditions) in response to dose, which results in a lack of power to conduct proper statistical analyses to determine if the observed DAM dose differences are a product of differences in participants’ characteristics. 88 4.7 Conclusion This study suggests that clients’ perceptions and expectations of the administered treatment influence the quantity of drug received. Knowing the client’s preferences and expectations a priori should be considered and integrated to prescription guidelines to further direct prescription practices. Open-label potency ratios should also be considered in iOAT programs to guide prescription practices and should be integrated to opioid rotation protocols. 89 Chapter 5: Conclusion 5.1 Summary of findings Opioid use disorder continues to be a major Public Health concern in Canada that has been aggravated by the current COVID-19 pandemic. This opioid overdose crisis is a complex and multifaceted problem, but reaching, engaging, and maintaining people in treatment is an important step towards its mitigation. The scale-up of programs that offer treatment with injectable opioid agonist treatments is crucial to reach people and maintain them in treatment. Thus, identifying the typical doses of injectable hydromorphone and diacetylmorphine to be prescribed is meaningful to program providers as it can aid forecasting of resources (e.g., drugs and medical supplies) but also for prescribers and users of these medications, as it can support the shared decision-making process when choosing the medication and its dosage. The main objective of this thesis was to determine the typical doses of injectable diacetylmorphine and hydromorphone. The three specific objectives were: 1) to describe prescribed and received doses of injectable diacetylmorphine and hydromorphone and identify potential dosage cohorts; 2) to determine if there were differences in dose received of injectable diacetylmorphine and hydromorphone between open-label compared to double-blind; and 3) to identify the potency ratio of injectable diacetylmorphine and hydromorphone in an open-label basis. For this purpose, three different analyses were conducted to address each objective, using data from the dispensation records from the Crosstown clinic and the SALOME clinical trial. 90 5.1.1 Typical doses of injectable hydromorphone and diacetylmorphine As previously presented in Chapter 3 “Typical doses of injectable hydromorphone and diacetylmorphine” found that individual doses of hydromorphone and diacetylmorphine vary widely amongst clients. However, this study was the first, it is believed, to properly study the dose of these medications as the main outcome. This dissertation demonstrates the clients use of the whole range of possible prescriptions and speaks of the importance of providing guidance when prescribing. This study found that the average session prescription of hydromorphone was 125 mg, and most clients receive prescriptions in the range of 75 – 150 mg. The average prescription of diacetylmorphine was 225 mg per session, with most clients in the range of 150 – 380 mg. Although there was variation over time in doses of these medications, overall, there was a stable trend in iOAT doses which can support program planning. There were no noteworthy observed differences in dose of hydromorphone as a result of participants’ characteristics. The observed not significant trends, likely due to lack of power, were that clients on the third range of dosages tend to be older, tend to use less illicit opioids and alcohol and more stimulants and the proportion of females increases as dosage increases while the opposite was observed for ethnicity (as dose increases the proportion of indigenous clients decreases). For diacetylmorphine dose, similar patterns for ethnicity, and other drug use were observed, with the addition that clients on the third dosage group tend to have less stable housing and satisfaction with their dose. The only statistically significant trend was the housing trend for diacetylmorphine. Nonetheless, regardless of the lack of power due to the small sample size of the dosage groups, there is no reason to believe that participants’ characteristics influence dose of iOAT, since doses are individualized. 91 5.1.2 Received doses of injectable hydromorphone and diacetylmorphine: comparing open-label to double-blind With the results from Chapter 3, it became evident that there was a difference in how the clients used the drugs open-label, in terms of dosages, in comparison to how they used these same drugs in a double-blind basis. Then, it became evident that there was a need to understand if clients changed their dosages once they were aware of the medication they were receiving, given that currently program providers forecast and make program decisions based on the average dosages observed in the double-blind clinical trial SALOME. In addition, current prescriptions follow a potency ratio of 2:1 hydromorphone to diacetylmorphine that was also obtained from the SALOME clinical trial. Thus, Chapter 4 “Received doses of injectable hydromorphone and diacetylmorphine: comparing open-label to double-blind” studied the differences in the open-label dose received of injectable hydromorphone and diacetylmorphine compared to the double-blind doses. It was hypothesized that participants’ perceptions and expectations to receive diacetylmorphine had an influence in dose received. Thus, it was assumed that diacetylmorphine was the preferred drug; in this manner, the participants who were receiving double-blind diacetylmorphine and thought they were receiving diacetylmorphine were less likely to change their doses in an open-label basis. This hypothesis was confirmed by this study with clients receiving on average only 23 mg less of open-label diacetylmorphine. In contrast, clients who thought they were receiving double-blind hydromorphone, received 78 mg less of open-label diacetylmorphine. 92 It was also hypothesized that that prescribers’ preferences could explain the differences in the open-label dose received, however no associations were found. Another hypothesis was that the adverse events (AEs) could also explain the differences in dose received between the open-label and double-blind period, unfortunately, the AEs variable was not collected in detail during the open-label period compared to the double-blind period, and previous studies found no relationship between dosage and AEs. Therefore, these hypotheses were dismissed. With respect to participants’ characteristics, there were significant differences observed in dose received of open-label diacetylmorphine and double-blind diacetylmorphine. Significant decreases in open-label dose received were observed by gender, for males, by dose satisfaction, for those unsatisfied and by chronic medical problems. However, given that these differences were very similar to that observed in the comparator group (i.e., females, satisfied, no medical problems), the effects of gender and dose satisfaction on dose difference were dismissed. There was a significant decrease in open-label dose received attributed to illicit opioid use that cause dose adjustments and missed sessions. There were no notable differences in terms of age, physical and psychological health, and days using alcohol and stimulants. The potency ratio between hydromorphone and diacetylmorphine open-label was examined as well. This study found different potency ratios depending on the dose ranges, varying form 1.3:1 to 1.6:1, where the lower ratios corresponded to lower dose ranges. The potency ratio for both mean prescribed and received doses was 1.6:1 hydromorphone to diacetylmorphine. This potency ratio is lower than the potency ratio of 2:1 observed in previous clinical trials. This is a relevant finding for the clinical teams that it should be considered when switching between 93 injectable opioids, as the currently used potency ratio of 2:1 is no longer maintained in an open-label fashion. 5.2 Limitations The overall limitation that was found across this dissertation is that all analyses conducted were secondary analyses of data that was not originally collected to study dose as an outcome neither to test participant’s characteristics such as age, gender, ethnicity, physical health, and drug use in response to dose. The collection of instruments, that went from 2016 to 2017, does not match the collection of the dosage which was collected daily throughout the study period from 2014 to 2020. This mismatch limited the availability of variables, and when variables were available there was a lot of missing information, therefore it was difficult to match the available variables to client’s dosages since client’s could switch between diacetylmorphine and hydromorphone at any time for personal reasons (e.g., one’s desire, due to medical concern’s, among others) or due to external reasons (e.g., shortage of diacetylmorphine at the Crosstown clinic due to political changes), thus the questionnaires did not reflect accurately participant’s experiences in relation to dosage. This limited the ability to conduct proper statistical analyses, and therefore the findings of this thesis are mostly descriptive. Findings from this dissertation allows one to determine typical doses of iOAT and demonstrates that these are stable over time. Nonetheless, due to the limitations in data for participants’ characteristics, it did not allow one to properly determine if there were any characteristics (e.g., age, sex, physical health, drug use) that influenced iOAT dose, beyond the inter-individual differences. Participants’ characteristics were collected at baseline and at selected timepoints 94 only for two years, whereas dosage was collected daily for the 6-year study period. These differences also limited the ability to determine if there were any systematic differences between participants in the different dose range groups. Analyses could have been conducted taking the current dosage at the time point when the time-changing variables (i.e., physical health, drug use) were collected, however a lot of information from the dosage would have been lost. The main objective of this dissertation was to determine typical doses of iOAT, not to test participants’ characteristics in response to dose. Therefore, it was deemed unnecessary to conduct these analyses given that results from these would not provide more meaningful information that the descriptive results had already provided. Another limitation pertaining the use of secondary data for this dissertation was the inadequacy of the available variables to determine if preferences and expectations on the drug explained the observed differences in dose received open-label versus doble-blind. Previous studies informed of the patient preferences towards diacetylmorphine and how these preferences were related to blinding guess and drug effects (i.e., drug liking and good effect, for example) which allows one to conduct analyses with blinding guess as a proxy of preferences. However, the implementation of the Visual Analog Scale during the study period would have yielded more accurate results. A larger sample size to test differences in fixed variables such as age, gender, and ethnicity, as well as collection of time-changing variables at more frequent time points, and for a longer period would have provided a more complete picture of factors that could influence iOAT dosage. This larger sample size and additional collection of time-changing variables would have 95 also allowed to test if the differences in open-label diacetylmorphine dose compared to the double-blind dose were a result of these characteristics, rather than preferences. 5.3 Significance and implications This is the first study to one’s knowledge to examine the dose of injectable opioid agonist treatments with hydromorphone and diacetylmorphine as a main outcome. Thus, this research makes a unique and significant contribution towards policymakers, researchers, clinicians, program providers and users of these treatments. These typical doses of iOAT as well as the potency ratio can inform clinicians and program providers across Canada to optimally implement these treatments. Program providers can now have guidance and confidence to more accurately forecast resources (e.g., quantity of drug) in an open-label setting which could allow reduction in cost of treatment implementations. In addition, information on these typical doses of iOAT can provide a sense of reassurance and calmness to stakeholders (namely policymakers and clinicians). This research analyzed over half a million injections, demonstrating that iOAT doses stabilize over time (i.e., it does not continue to rise indeterminably as the common misconception suggests), and previous studies have demonstrated their safety and effectiveness. In other words, this study adds confidence regarding dosage of iOAT for stakeholders. This study found typical doses of iOAT; however no significant predictors of dose were found. Nonetheless, that is also an important and informative finding of this research. Having no 96 predictors of dose confirms the current clinical practice where doses must be titrated individually based on each client’s needs until reaching an individual effective dose for the client, via shared decision making where typical doses can assist. Future research could be designed to find factors such as age, physical health and other drug use which could influence the dose of iOAT based on the findings from this research. If any factor is found, it could further aid to a more accurate forecast of resources, and a more informed share decision-making when determining the dose. It could also lead to implementation on programs aimed to reduce other drugs use (e.g., stimulants), or prevention and treatment of certain health conditions, which may lead to an overall improvement in health outcomes. 5.4 Conclusion Overall, this dissertation provides the first ever evidence on typical dosages of injectable opioid agonist treatments with hydromorphone and diacetylmorphine on an open-label basis. The intent demonstrates the use of the whole range of prescriptions, stable over time, which indicate the diversity of people accessing iOAT. These findings contribute to the expansion of iOAT programs across Canada and to encourage researchers, clinicians, and policymakers to scale up these treatments. 97 Bibliography 1. Gartry CC, Oviedo-Joekes E, Laliberte N, Schechter MT. NAOMI: The trials and tribulations of implementing a heroin assisted treatment study in North America. Harm Reduct J [Internet]. 2009;6:2. Available from: 19159475 2. 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Thesis/Dissertation
eng
Population and Public Health
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Oviedo-Joekes, Eugenia
Determining typical doses of injectable diacetylmorphine and hydromorphone for the treatment of opioid use disorder
Text