Background: Opioid use disorder (OUD) has been an increasing concern in Canada as mortality rates continue to rise. Though OUD treatments, such as methadone maintenance treatment (MMT), reduce its burden, they could potentially cause harm due to OUD’s variance in severity and presentation across individuals. It is hypothesized that genetic variants such as single nucleotide polymorphisms (SNPs) could predispose patients to respond differently to MMT. In addition, sex differences have been observed in opioid use patterns, treatment outcomes, and genetic make-up. As such, this thesis aims to identify significant SNPs associated with treatment outcomes in genome-wide association studies, and test biologically relevant SNPs with MMT outcomes of interest, while highlighting sex differences. This is achieved through a systematic review protocol, a systematic review, and a candidate gene study. Methods: A protocol was prepared for the planning of the first ever systematic review of genome-wide significant findings of medication-assisted treatment outcomes for OUD patients. The systematic review assessed the literature findings and study qualities, narratively summarizing significant associations. Next, a candidate gene study analyzed the association between SNPs in OPRM1 and CYP2B6 genes, and continued opioid use, relapse, and methadone dose within an ancestrally European sample (n=1226). Sex-stratified and sex-interaction analyses were also conducted. Results: The systematic review included 5 studies and qualitatively assessed 43 unique genetic variants. The candidate gene study showed no significant associations between the selected OPRM1 and CYP2B6 SNPs and outcomes of interest. While no significant differences between the sexes were observed, rs73568641 and rs3745274 showed near significance associations in only one sex, females, and males, respectively. Discussion: Through the study of genetic variants associated with treatment outcomes in the literature and our sample of ancestrally European individuals on MMT, we were able to highlight gaps in pharmacogenetics research and identify areas of focus for future studies. / Thesis / Master of Science (MSc) / Recently, opioid use disorder (OUD) has been declared a national crisis in Canada. OUD treatments are helpful in reducing opioid use and adverse events. However, their dosing and metabolism in patients can impact continued opioid use, relapse, or treatment dose changes. Due to the variability in response between individuals, there might be a genetic basis to treatment outcomes. This thesis explores which genetic variants reported in previous studies are involved in OUD treatment outcomes. Then, it tests select genetic variants in OPRM1 and CYP2B6 genes to see if they are linked to specific outcomes in an Ontario population and tries to identify if these associations differ by sex. No significant associations were found, though associations in males and females had near-significant results in one sex but not the other. Despite suggesting sex’s possible involvement in treatment outcomes, more research is necessary to confirm these findings.

Houseboat is the first part of a novel-in-progress set in the coastal town of Apollo, Maine during the Opioid Epidemic.

An abundance of literature has shown the five-factor model personality traits can influence current and lifetime substance use. Life satisfaction, although less clearly, has also demonstrated a significant contribution to substance use behaviors and outcomes. Still, little is known about how life satisfaction influences the relationship between personality and substance use measures pertinent to recovery like drug use refusal self-efficacy. The goal of this study is to advance the current literature on substance use by examining the mechanisms influencing the relationship between personality and life satisfaction and drug use refusal self-efficacy for a sample diagnosed with at least one substance use disorder (SUD) and/or alcohol use disorder (AUD). Data was analyzed using deidentified information from a large diverse SUD client pool (n = 348) who were recruited from the general population and from two Midwest SUD treatment centers for a larger parent study. A series of mediation and moderation analyses were tested. The relationships between both neuroticism and conscientiousness with drug use refusal self-efficacy were significantly mediated by life satisfaction. Life satisfaction significantly moderated the relationship between extraversion and drug use refusal self-efficacy. These findings suggest life satisfaction may be a novel modifiable treatment target to reduce negative effects of personality on SUD drug refusal self-efficacy, and that life satisfaction may influence and change how extraversion relates to risks among those in recovery. / M.S. / Substance misuse costs the United States healthcare system billions each year, but substance use disorder treatment reduces these costs. Unfortunately, only a small percentage of individuals seek treatment in part because it is notoriously difficult, and relapses are common. Factors like personality traits and life satisfaction influence current and lifetime substance use. The goal of this study was to advance the current literature on substance use by examining the mechanisms influencing the relationship between personality and life satisfaction and the ability for an individual to refuse drugs or alcohol (drug use refusal self-efficacy). Data was analyzed using information from a large diverse substance use disorder client pool (n = 348) who were recruited from the general population from two Midwest treatment centers. A series of mediation and moderation analyses were tested. Life satisfaction influenced the relationships between both neuroticism and conscientiousness with drug use refusal self-efficacy. The relationship between extraversion and drug use refusal self-efficacy differed based on the individual’s life satisfaction. These findings suggest modifying life satisfaction may reduce negative effects of personality on drug refusal self-efficacy, and that life satisfaction may influence and change how extraversion relates to risks among those in recovery.

Today, more Americans die each year because of drug overdoses than are killed in motor vehicle accidents. In fact, in 2015, more than 33,000 individuals died due to an overdose of heroin or prescription opioids. Sadly, 40-60 % of patients on current opioid addiction treatment medications relapse. Studies have shown that the addiction/abuse liability of opioids are abolished in mu opioid receptor (MOR) knock-out mice; this indicates that the addiction and abuse liability of opioids are mainly mediated through MOR. Utilizing the “message-address concept”, the our laboratory reported a novel non-peptide, reversible MOR selective ligand 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α (isoquinoline-3-carboxamido)morphinan (NAQ). Molecular modeling and mutagenesis studies revealed that the selectivity of NAQ for MOR is because of the π-π stacking of the isoquinoline ring of NAQ with W318. Therefore, other heterocyclic ring systems were explored to obtain a diverse library of compounds with similar or different molecular interactions and pharmacologic characteristics as NAQ. The newly designed compounds were indole analogs of 6α/β-naltrexamine. The compounds were synthesized and the affinity and selectivity for MOR determined using the radioligand binding assay while the functional activity at MOR was determined using the [35S]GTPγS binding assay. The indole analog of 6α-naltrexamine substituted at position 7 (compound 6) was found to be very potent and had the lowest efficacy in the [35S]GTPγS functional assay while the indole analog of 6β-naltrexamine substituted at position 2 (compound 10) was identified as a MOR agonist and had the greatest efficacy. In vivo studies were conducted using the warm-water immersion assay to find whether the synthesized compounds had antinociceptive effects and/or blocked the antinociceptive effects of morphine. Not surprisingly, compound 10 was identified as an opioid agonist while compound 6 almost completely blocked morphine’s antinociceptive effects. The opioid antagonist effect of compound 6 was found to be dose dependent with an AD50 of 2.39 mg/kg (0.46-12.47). An opioid withdrawal assay was conducted on compound 6 using morphine-pelleted mice. Compound 6 produced significantly less withdrawal symptoms at 50 mg/kg than naltrexone at 1 mg/kg. Therefore, compound 6 has the potential to be used in opioid addiction and withdrawal treatment.

Background – An increase in opioid prescribing has led to an increase in opioid overdoses.1,2 No study has estimated the incremental costs subsequent to an opioid overdose event in prescription opioid users, or the prevalence and costs of overdose events in family members of prescription opioid users and in overdose victims with no identifiable source of prescription opioid. The latter group will be referred to as “others”. Objectives – The first objective of this study was to estimate the prevalence of opioid overdoses in aforementioned groups. The second objective was to estimate the incremental costs and resource utilization associated with opioid overdoses in these groups. Methods – This study is a retrospective analysis using claims data from SelectHealth, a not-for-profit health insurance organization in Utah and southern Idaho. We estimated the prevalence of opioid overdoses in the sample population, as well as in each group, by year. For the cost estimation we collapsed family members and others into one category – “non-medical users”. To estimate costs we used an incremental cost approach whereby we used propensity scores to match cases (patients who suffered from an opioid overdose) to appropriate controls (patients who did not suffer from an opioid overdose) and estimated the direct medical costs incurred in each group in the year following an overdose. Generalized Linear Models were used to estimate incremental costs and resource utilization. Sensitivity analyses were conducted to measure the robustness of the estimates. Results – The prevalence of opioid overdoses increased by 84.8% in prescription opioid users (from 55.6 per 100,000 in 2011 to 102.8 per 100,000 in 2014), increased by 37.9% in family members of prescription opioid users (from 5.9 per 100,000 in 2011 to 8.2 per 100,000 in 2014) and increased by 179.9% in others (from 8.2 per 100,000 in 2011 to 23.1 per 100,000 in 2014). The prevalence of opioid overdoses in acute users increased by 14.7% (from 43.8 per 100,000 in 2011 to 50.3 per 100,000 in 2014) as compared to 165.9% in chronic users (from 187.0 per 100,000 in 2011 to 497.3 per 100,000 in 2014). The incremental direct medical costs per patient per year were estimated to be $65,277 (p-value<0.05) in prescription opioid users who suffered from an overdose and $41,102 (p-value<0.05) in non-medical users who suffered from an overdose. Overdose-specific costs were estimated to be $12,111 for prescription opioid users and $11,070 in non-users. Conclusions – Our study found that the prevalence of opioid overdoses increased steadily from 2011 to 2014 in the sample population. The prevalence of overdoses was much higher in chronic opioid users as compared to acute users. Differences between overdose-specific costs and total incremental costs may suggest that overdoses are associated with substantial costs in addition to costs for the initial treatment of the overdose. While the cost to payers due to overdoses in prescription opioid users is substantial, payers also incur costs from diversion of opioids.

Bakgrund: Användningen av höga doser av opioider under generell anestesi är numera mycket vanligt. Biverkningar orsakade av opioider är väl känt inom anestesin och sjukvården och senare evidens tyder på att opioider även kan bidra till smärtutveckling. Av denna anledning har studier de senaste 20 åren ifrågasatt användningen av opioider och intresset för att minska opioidbehovet och utveckla opioidfria metoder för anestesi har växt. Syfte: Att beskriva opioidfri analgesi i generell anestesi, och hur detta påverkar den perioperativa smärtupplevelsen, jämfört med patienter i generell anestesi som fått traditionell smärtlindring med opioider. Metod: En litteraturöversikt med systematisk ansats. Artikelsökningen genomfördes i PubMed, Cinahl och Scopus. Resultatet sammanställdes utifrån 15 granskade artiklar med kvantitativ design. Resultat: Litteraturöversikten visar att det finns ett stort antal läkemedel som kan användas inom opioidfri anestesi, samt deras för- och nackdelar för smärtupplevelsen jämfört opioider. De protokoll som användes vid opioidbaserad anestesi eller för opioidsparande anestesi är inte standardiserade och därför är det inte möjligt att syntetisera resultatet och ställa olika metoder mot varandra i denna litteraturöversikt. De flesta artiklar visade att det går att minska intraoperativt och postoperativt opioidbehov för patienter och ändå erbjuda likvärdig smärtlindring. De patienter som fick en opioidfri eller opioidsparande anestesi hade inte en försämrad perioperativ smärtupplevelse. Den mängd metoder som beskrevs indikerar att analgesi kan anpassas efter patientens individuella förutsättningar. Slutsats: Litteraturöversikten visade att olika läkemedel och metoder kan användas för att ge analgesi till patienten vid opioidfri anestesi samt dess effekt på smärtupplevelsen kontra opioider. De flesta alternativa läkemedel som används i artiklarna gav ett mer gynnsamt eller likvärdigt utfall för patienten. Genom utveckling av fler metoder för analgesi under anestesi kan anestesin i större omfattning utgå från individens behov och förutsättningar, vilket bidrar till en mer personcentrerad vård. Litteraturöversiktens resultat visar på en stor spridning och det är därför svårt att bedöma vilka läkemedel som är bäst lämpade. Det krävs således mer forskning inom detta ämne för att möjliggöra jämförelser och utarbeta protokoll som gör opioidfri anestesi till etablerad och säker metod för patienten. / Background: High dose opioids during general anesthesia are frequently used. The side effects caused by opioids are well known in anesthesia and healthcare and recent evidence implies opioides can contribute to the development of pain. For this reason, studies over the past 20 years have questioned the use of opioids and an interest has grown in reducing the need of opioids and developing opioid-free methods for anesthesia. Aim: To describe opioid-free analgesia in general anesthesia, and how this affects the perioperative pain experience, compared to patients in general anesthesia who have received traditional opioid-based pain relief. Method: A literature study with systematic approach. The article search was performed in PubMed, Cinahl and Scopus. The result was compiled based on 15 reviewed articles with quantitative design. Result: The literature review shows that there are a large number of drugs that can be used in opioid-free anesthesia and the advantages and disadvantages of these drugs versus opioids. The protocols used for opioid-based anesthesia or for opioid-saving anesthesia are not standardized and therefore it is not possible to synthesize the results or set different methods against each other in this review. Most articles found that it is possible to reduce the intraoperative and postoperative need of opioid for patients and still offer equivalent pain relief. The patients receiving opioid-free or opioid-sparing anesthesia did not suffer a worsened pain-related experience. The amount of methods described indicates that the analgesia can be customized accordingly to the patient's individual circumstances. Conclusion: The literature review described various drugs and methods that can be used to give analgesia to the patient during opioid-free anesthesia and the effect on the pain-related experience. Most of the alternative drugs used in the articles gave a more favorable or equivalent outcome for the patient. By developing more methods for analgesia during anesthesia, it is in a greater extent possible to adjust the anesthesia depending on the individuals needs, which contributes to a more person-centered care. The result shows a wide spread and it is therefore difficult to assess which drugs are best suited. Thus, more research is required in this subject to prepare protocols that make opioid-free anesthesia an established and safe method for the patient.

Pain assessment and management is a fundamental part of nursing care. Opioids are 1 of the interventions utilized to manage pain within the hospital setting and have a known adverse effect called opioid-induced sedation and respiratory depression (OSRD). The purpose of this quantitative study was to create a prediction model with the known risk factors present on admission, to determine how well they predict OSRD. This served as a first step in the creation of a risk screen tool, supported by the cognitive continuum theory, in understanding the judgment and decision-making process to provide safe care. The combination of factors that most accurately predicted the risk of OSRD in patients on admission to an acute care healthcare institution was determined through a retrospective case control analysis. Risk factors present on admission of a case group of 100 patients who had succumbed to OSRD after an opioid administration were matched and compared to a control group of 100 who did not. A binary logistic regression analysis was used to determine how well age, body mass index, obstructive sleep apnea, pulmonary disease, respiratory disease, renal failure, and no opioid use (i.e., being opioid na�ve) predicted OSRD. The presence of pulmonary disease, renal disease, cardiac disease, diabetes, and being opioid na�ve most accurately predicted OSRD. Although only pulmonary disease and renal disease were statistically significant, the final model included other factors that increase the odds of OSRD, which are encompassed in the proposed tool for future research. Through understanding the factors that predict OSRD, a screening tool was created that could save lives in hospital institutions and lead to positive social change by supporting clinical decision making and care.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 140-150).

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

The Argus Commission identified three major federal priorities related to health care, including the precision medicine initiative, the Cancer Moonshot and the opioid abuse epidemic. Current activities at the federal level were summarized and an analysis of activities within the profession, and academic pharmacy specifically, was prepared. The implications for pharmacy education, research and practice are compelling in all three areas. Recommendations, suggestions and two policy statements aim to optimize the attention to these priorities by the academy. Further, aligning the AACP Strategic Engagement agenda with the opportunities and threats acknowledged in the analysis is essential.