Browsing by Subject "Opioids"
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Item Astrocyte-neuron signaling in the nucleus accumbens: implications for brain reward signaling(2019-05) Corkrum, MichelleDopamine is one of the major reward signaling molecules in the brain. Dopaminergic transmission contributes to physiological states such as learning, memory encoding, movement and motivated behaviors; and, the disruption of dopamine signaling can contribute to neuropsychiatric diseases such as substance use disorders. The majority of research on reward signaling has focused on neurons; however, astrocytes are emerging as key components of brain information processing. Astrocytes are a subset of glial cell, one of the most abundant cell types in the brain. Although astrocytes are not electrically excitable, in response to brain activity, they demonstrate increases in intracellular calcium and the subsequent release of neuroactive substances, termed gliotransmitters. Therefore, my dissertation aimed to investigate the hypothesis that astrocytes respond to brain reward signaling with elevations in cytoplasmic calcium, and subsequently modulate neuronal activity in the nucleus accumbens, one of the major reward centers of the brain. Utilizing fiber photometry, I found that astrocytes in the nucleus accumbens respond to dopamine and amphetamine with cytoplasmic calcium elevations in vivo. To elucidate the cellular mechanisms of this phenomenon and the consequences of astrocyte calcium signals on neuronal activity, we conducted experiments applying multiphoton calcium imaging and whole-cell patch clamp electrophysiology in acute brain slices containing the nucleus accumbens core. We found that astrocytes respond to dopamine, amphetamine and opioids with intracellular calcium elevations and subsequently modulate neuronal activity, either through adenosine signaling in the case of dopamine and amphetamine or glutamatergic signaling in the case of opioid exposure. Furthermore, we demonstrate that astrocytes contribute to the acute psychomotor behavioral effects of amphetamine, illustrating astrocyte modulation of drug-related behaviors. Overall, the current body of work provides evidence that astrocytes actively contribute to brain reward processing via responding to dopamine and drugs of abuse with intracellular calcium increases and modulating neuronal and synaptic activity in the nucleus accumbens, one of the major nodes of the reward system.Item Bivalent Ligand MMG22 Reduces Bone Cancer Pain without Tolerance or Sedation(2022-07) Shueb, SarahPain is among the most common symptoms in cancer and approximately 90% of patients experience end-stage cancer pain. The management of cancer pain is challenging due to the significant side effects associated with opioids, and novel therapeutic approaches are needed. MMG22 is a bivalent ligand containing MOR agonist and mGluR5 antagonist pharmacophores joined by a 22-atom spacer. MMG22 exhibited extraordinary analgesia following intrathecal administration in a mouse model of bone cancer pain. Here, we assessed the effectiveness of systemic administration of MMG22 in reducing cancer pain and evaluated whether MMG22 displays side effects associated with opioids. Fibrosarcoma cells were injected into and around the calcaneus bone in C3H mice. Mechanical hyperalgesia was defined as an increase in the paw withdrawal frequencies (PWFs) evoked by the application of a von Frey monofilament (3.9 mN bending force) applied to the plantar surface of the hind paw.Subcutaneous (s.c.), intramuscular (i.m.), and oral (p.o.) administration of MMG22 produced robust dose-dependent antihyperalgesic, whose ED50 was orders of magnitude lower than morphine. Moreover, the ED50 for MMG22 decreased with disease progression. Importantly, s.c. administration of MMG22 did not produce acute (24 h) or long-term (9 days) tolerance, was not rewarding (conditioned place preference test), and did not produce naloxone-induced precipitated withdrawal or altered motor function. A possible mechanism of action of MMG22 is discussed in terms of inhibition of spinal NMDAR via antagonism of its co-receptor, mGluR5, and concomitant activation of neuronal MOR. We suggest that MMG22 may be a powerful alternative to traditional opioids for managing cancer pain.Item Effect of PV Interneurons on Opioid Withdrawal(2019) Bystrom, Lauren; Lefevre, Emilia; Pisanksi, Marc; Scheuneman, Jordan; Vijay, Sumyuktha; Rothwell, PatrickSince the opioid epidemic first started in the 1990’s, it’s societal impact has exponentially increased. With reports of 11.4 million people misusing opioids, understanding the mechanisms behind abuse and addiction is more critical to public health than ever. Our lab has previously shown that parvalbumin (PV)-fast spiking interneurons (FSI) are active during opioid withdrawal. In order to further elucidate the behavioral effect of PV activity, mice were virally injected with either Kir 2.1, a virus that turns off PV interneurons by turning off their K+ channels, or YFP, a fluorescent tag used as the control. These mice then underwent a Conditioned Place Aversion (CPA) assay, which is commonly used to measure a drug’s negative reinforcing properties. In the CPA mice were implanted with osmotic mini pumps that continuously delivered either morphine (opioid) or saline (control) and underwent a baseline, three conditioning days, and a test. The baseline and test exposed mice to two novel environments simultaneously and time spent on either environment was recorded. During conditioning, mice were exposed to only one environment and received injections of naloxone (opioid receptor antagonist), pairing the environment with withdrawal. Aversion was measured as decreased spent on the naloxone- paired side on the test as compared to baseline. Kir 2.1 animals showed a decreased naloxone aversion in the CPA as compared to the controls, indicating that PV-interneurons are required for learning an aversive response to withdrawal. This helps us better understand the mechanisms behind opioid abuse and addiction and can be used to develop future treatments.Item Hospital treatment for patients with opioid and methamphetamine co-use(2024) Shearer, RileyThe overdose crisis in the United States is increasingly characterized by the combined use of opioids and stimulants, with a sharp increase in the rate of deaths indicating both fentanyl and methamphetamine. Inpatient hospitalizations are a key opportunity to engage patients and initiate substance use disorder treatment. In response to rising rates of hospitalizations involving substance use, a variety of addiction services have been developed. However, it remains unclear whether these services remain effective for patients who use both opioids and methamphetamine compared to opioids alone. This dissertation uses a multi-method approach to describe hospital stays for patients who use both methamphetamine and opioids in order to inform the development and implementation of hospital-based addiction services tailored for this growing patient population. Using nationally representative data from the National Inpatient Sample we describe patient sociodemographic characteristics, health profiles, and stay outcomes associated with co-use. Next, we conducted semi-structured interviews with hospital providers to describe their experiences and perspectives caring for patients who use both opioids and stimulants. Finally, we use data from a large Midwest safety-net hospital to analyze whether the co-use of specific substances moderates the effect of being seen by an addiction consultation service on the receipt of medications for opioid use disorder. We found that patient sociodemographic and health characteristics differed for hospital stays indicating opioid use alone compared to opioid and methamphetamine co-use. A higher proportion of co-use related stays were for patients who were male and/or under 35 years old. Additionally, co-use-related stays had higher rates of co-morbid mental health (60.7%; 95% CI: 59.9-61.4%) and infectious diseases (41.5%; 95% CI: 40.8-42.2%), than opioid-related stays. Finally, we found that co-use related stays were more likely to end in patient directed discharge (10.7%; 95% CI: 10.4-11.0%) compared to opioid-related stays (8.1%; 95% CI: 7.9-8.3%). From qualitative interviews with 20 hospital-based providers we identified themes describing how opioid and stimulant co-use complicated treatment: 1) patients’ unstable circumstances impacting the treatment plan, 2) co-occurring withdrawals are difficult to identify and treat, 3) providers holding more stigmatizing views of patients with co-use, and 4) stimulant use is often “ignored” in the treatment plans. We also identified a range of potential opportunities to improve the treatment of patients with co-use in the hospital setting such as provider practice changes, healthcare system changes, and development and validation of clinical tools and stimulant use disorder treatment approaches. Finally, we found that an ACS may be an effective treatment model to support patients who use multiple substances. Among patients who were not seen by the ACS, a higher proportion of with opioid use alone (33.6%; 95% CI: 31.5-35.7) received MOUD during the hospital stay compared to those with any co-use (23.3%; 95% CI: 21.6-24.9). However, among patients seen by the ACS, the proportion that received MOUD did not vary between opioid use alone (56.2%; 95% CI: 52.2-60.2) and any co-use (57.8%; 95% CI: 55.5-60.1). We found this difference was most pronounced among patients who had opioid and methamphetamine co-use. Compared to patients without methamphetamine co-use, the increase in the proportion of admissions receiving MOUD after being seen by the ACS was 39.0 percentage points (95% CI: 31.8-39.8) higher for patients with methamphetamine co-use. Taken together these findings suggest that hospital services must account for the high rates of medical co-morbidities (e.g., infectious disease and psychiatric conditions) as well as unstable life circumstances (e.g., poverty, housing, and transportation instabilities) that may complicate treatment for patients with co-use. ACSs may help address some of the challenges treating patients with co-use such as identifying co-occurring intoxication and withdrawal symptoms and reducing stigmatizing views. Ongoing randomized trials should further test the impact of ACS on outcomes specifically among patients with co-use. In addition to hospital models to initiate treatment, transition strategies that support linkage to outpatient treatment must also account for the challenges associated with co-use. As these strategies continue to be refined and tested it is important that they also address barriers that patients with co-use face transitioning to community treatment.Item Impact of CDC Guidelines and Health Payer Pharmacy Coverage Changes on Opioid Prescription Trends and Pharmaceutical Opioid Marketing Spending(2021-08) Togun, AdeniyiDue to the opioid epidemic in the US, the Center for Disease Control and Prevention (CDC) in March 2016 published new guidelines for primary care providers on opioid prescribing for chronic pain. Pharmacy coverage changes were also implemented by some health payers to help modify opioid prescribing behavior. Whether these initiatives were associated with changes in opioid initiation patterns across different provider specialties is unknown. Hence, we evaluate 3 of the CDC guidelines and 2 payer pharmacy coverage changes by asking the following questions: 1a. Were fewer extended release (ER) opioids relative to immediate release (IR) opioids prescribed post-CDC guideline release and post-pharmacy coverage change when initiating opioid treatment across different provider specialties? 1b. Were fewer patients started at opioid doses of ≥50MME per day post-CDC guideline release and post-pharmacy coverage change when initiating opioid treatment across different provider specialties? 1c. Were fewer patients starting opioid prescription with benzodiazepine overlap post-CDC guideline release when initiating opioid treatment across different provider specialties? Although the CDC guidelines were recommended for primary care providers, providers often adopt evidence-based recommendations from outside of their own areas of practice, and specialist providers may also have adopted the CDC guidelines. There is a paucity of information on whether there are differences between responses to the CDC guidelines and payer policy changes on opioid initiation practices between primary care providers and specialists. Likewise, there is no documentation on rural urban differences and patient’s insurance types influence on the response to the CDC guidelines and payer policy changes. Hence, we also evaluate: - Primary care compared to specialist providers 2a. If response to the CDC guideline and payer pharmacy coverage change discouraging prescribing first-time opioids at doses ≥50MME per day differ between primary care providers and specialist providers? 2b. If response to the CDC guideline discouraging prescribing first-time opioid with benzodiazepine overlap differ between primary care providers and specialist providers? - Commercial compared to Medicare Advantage patients2c. If response to the CDC guidelines and payer pharmacy coverage change discouraging prescribing first-time opioid prescription at doses ≥50MME per day differ when prescribing to commercially insured and Medicare Advantage patients? 2d. If response to the CDC guideline on prescribing first-time opioid with benzodiazepine overlap differ when prescribing to commercially insured and Medicare Advantage patients? - Urban compared to rural primary care service areas (PCSAs)2e. If response to the CDC guidelines and payer pharmacy coverage change discouraging prescribing first-time opioid prescription at doses ≥50MME per day differ when prescribing in urban and rural PCSAs? 2f. If response to the CDC guideline discouraging prescribing first-time opioid with benzodiazepine overlap differ when prescribing in urban and rural PCSAs? Following the CDC guidelines release, the rate of opioid prescriptions decreased, and may have impacted opioid sales by pharmaceutical companies. Opioid marketing encounters with providers are one of the ways pharmaceutical companies boost the rate of prescription and sale of opioids. In response to the CDC guidelines, there is no documentation on whether pharmaceutical companies may have also made changes in their opioid marketing practices to help boost opioid prescriptions following the CDC guideline release. Hence, we also evaluate 3a) If the CDC guidelines are associated with changes in total monthly pharmaceutical opioid amount received per provider and if these changes differ when marketing to primary care compared to specialist providers, and also when marketing to urban PCSA compared to rural PCSA providers.3b) If the CDC guidelines are associated with changes in pharmaceutical opioid marketing encounters per provider per month and if these changes differ when marketing to primary care compared to specialist providers, and also when marketing to urban PCSA compared to rural PCSA providers. 3c) If the CDC guidelines are associated with changes in pharmaceutical opioid marketing spending per encounter and if these changes differ when marketing to primary care compared to specialist providers, and also when marketing to urban PCSA compared to rural PCSA providers. To answer the first two group of questions (1a-1c, 2a-2c), we used claims data from OptumLabs® Data Warehouse between January 2014 and December 2018. Subjects were continuously enrolled opioid naïve patients ≥18 years old who had at least one chronic pain condition diagnosis within 2 weeks before their first (first-time) opioid prescription. We used multiple treatment period segmented regression discontinuity analysis to answer first two group of questions. To answers the third group of questions (3a-3c), we used data from the open payment database from CMS between August 2013 and December 2017. We used single and multiple groups interrupted time series analysis to answers the third group of questions.We found the CDC guidelines were not associated with any change in the rate of first-time prescriptions of extended-release opioids. However, a January 2017 payer pharmacy coverage change requiring prior authorization and provider attestation before initiating long-acting opioids instead of immediate release opioids was associated with a reduction in the rate of first-time extended-release opioid prescription by 22 in every 100,000 prescriptions [CI -40.04 to -2.92, P=0.013]. The CDC guidelines were associated with an immediate decline in level of first-time opioid prescription at doses ≥50MME per day by 74 in every 10,000 prescriptions [CI -124.86 to -23.13, P=0.004], and an increased rate of decline by 14 in every 10,000 prescriptions [CI -17.07 to -10.21, P<0.001]. These associations varied across different provider types and specialties. The March 2018 payer coverage change was associated with an immediate reduction in level of first-time opioid prescriptions at doses ≥50MME per day across all specialties. The CDC guidelines were also associated with a reduction in the rate of first-time opioid prescription overlap with benzodiazepines among family medicine, internal medicine, surgeons, emergency medicine providers, and providers with unknown specialty by 6, 5, 3, 11, and 9 in every 10,000 prescriptions monthly respectively [CI -9.48 to 02.73, -9.86 to -0.35, -5.40 to -0.38, -17.26 to -5.61 and -11.96 to -6.25 respectively, P<0.001, P=0.035, P=0.024, P<0.001 and P<0.001]. We found a larger decline in the rate of prescribing first-time opioid dose ≥50MME per day and first-time opioid prescription with benzodiazepine overlap following the CDC guidelines release among specialist providers than primary care providers. Prescribing first-time opioid fills at doses ≥50MME per day declined following the CDC guidelines release and payer coverage change, and the decline was more significant among specialist providers than PC providers and in rural PCSAs than Urban PCSAs. Also, following the CDC guidelines release the decline was more significant among MA patients however following the payer coverage change the decline was more significant among commercially insured patients. Decline in first-time opioid fill with benzodiazepine overlap did not differ between provider and insurance types and rural and urban PCSAs. Following the CDC guideline release, the monthly number of marketing encounters per physician and total monthly amount received per physician decreased. However, the amount spent at each marketing encounter increased. The CDC guideline release was associated with an immediate increase in level of opioid marketing spending per encounter by $0.59 (CI, $0.51 to $0.68, P< 0.001) and an over-time increase in rate of spending per encounter of $0.04 per month (CI, $0.03 to $0.05, P< 0.001). Physicians who received higher amounts per encounter also received a higher frequency of encounters. Following the CDC guideline, the immediate increase in level was greater when marketing to specialists than primary care physicians by $32 (CI, $0.16 to $0. 48, P=0.031), while increase in rate of spending per encounter was less among specialists compared to primary care physicians by $0.02 per month (CI, -$0.04 to -$0.01). The immediate increase in level was greater when marketing in urban PCSAs than rural PCSAs by $0.26 (CI, $0.05 to $0.46, P<0.001), while increase in rate of spending per encounter was less in urban PCSAs compared to rural PCSAs by $0.02 per month (CI, -$0.04 to -$0.001). Conclusion and Relevance: Some specialist providers also adopted the CDC guidelines. The CDC guidelines were associated with a reduction in some high-risk first-time opioid prescriptions. Payer pharmacy coverage changes were associated with such reductions, both in situations where the CDC guidelines did and did not show any associated reductions. Responses to the CDC guideline and payer pharmacy coverage changes differ between primary care and specialist providers, providers in urban and rural PCSAs and prescribing to Medicare Advantage and commercially insured patients. Understanding factors that may influence guideline adoption, such as provider specialties, patient insurance types, and location in urban or rural PCSAs is important and can help inform future opioid guidelines. The CD guideline release were associated with changes in pharmaceutical opioid marketing practices. Following the CDC guidelines, pharmaceuticals reduced their total spending per physician and number of marketing encounters to physicians but increased the value of food and beverages served at each encounter subsequently. The associated increase in the amount spent per opioid marketing encounter was more significant to specialists than primary care physicians and in urban than rural PCSAs. It is important to continue ongoing education for physicians to increase their awareness of pharmaceutical opioid marketing practices.Item Pain relief of cannabinoids in the KATP pathway and its connections to the opioid pathway in mice(2019) Messerschmidt, Lauren; Klein, AmandaOpioids are known to be addictive drugs, and long term use may lead to overdose or death. To combat the opioid epidemic, different therapies should be developed and used for pain management. One potential alternative to prescription opioids is cannabis. The science of cannabinoids, the chemical compounds in cannabis, is relatively new research. There are two primary cannabinoid receptors: CB1 and CB2, both being G protein coupled receptors (Pertwee, 2006). The receptors are especially sensitive to THC and cannabidiol, both components in cannabis, which are thought to aid in pain relief. The hypothesized pathway begins with a cannabinoid binding to its receptor, which inhibits adenylyl cyclase. Adenylyl cyclase is responsible for producing cyclic adenylyl phosphate (cAMP) from ATP. Inhibiting adenylyl cyclase decreases the concentration of cAMP, resulting in the opening of ATP sensitive potassium channel opening (K ATP channels, Pertwee, 2006). This aligns with an accepted pathway for opioid signal transduction (Figure 2), and it is possible cannabinoids and opioids affect the same downstream potassium channels. In this research, experimentation of mice was used to observe the potassium channel connections between the opioid and cannabinoid pathways. This was the starting point in finding a potentially safer therapy than opioids but with similar pain relief efficacy.Item Responding to the Opioid Epidemic in Minnesota(Resilient Communities Project (RCP), University of Minnesota, 2020) Heimisdottir, Dagny; Paulus, Sarah; Rose, Tim; Wu, Emma; Yawakie, BenjaminThis project was completed as part of a partnership between the League of Minnesota Cities and the University of Minnesota’s Resilient Communities Project (http://www.rcp.umn.edu). The goal of this project was to develop a deeper understanding of the role “at-home” drug disposal products may play in combating the opioid crisis, and that cities may play in administering and promoting drug disposal methods. League of Minnesota Cities project lead Rachel Walker collaborated with graduate and postdoctoral students in the RCP Fellows Program to conduct a literature review, develop a logic model, design and administer a follow-up online survey to city officials who received drug disposal bags, create interview guides for city officials and the drug disposal bag company, and interview a legislative representative with experience leading efforts to address the opioid crisis. A final student report and presentation are available. A videorecording of the students' final presentation is also available at https://vimeo.com/418526530.Item Responding to the Opioid Epidemic: Identifying Actionable Approaches for Cities in Minnesota(Resilient Communities Project (RCP), University of Minnesota, 2020) Daly, Mara; Schmaltz, Kaitlyn; Walter, AshleighThis project was completed as part of a partnership between the League of Minnesota Cities and the University of Minnesota’s Resilient Communities Project (http://www.rcp.umn.edu). The goal of this project was to identify the role cities should play in addressing the opioid epidemic. League of Minnesota Cities project lead Luke Fischer collaborated with students in Dr. Greg Lindsay’s course, PA 8081: Planning and Public Affairs Capstone, to identify cities both nationally and in Minnesota that are coordinating effective opioid response programs, and to determine themes across different programs that practitioners may consider in crafting similar response measures. A final student report, a visual report, and a presentation is available. A videorecording of the students' final presentation is also available at https://vimeo.com/418512328.