Pharmacology Research & Perspectives

ObjectiveThe primary objective of this study was to explore fentanyl and fentanyl derivative distribution patterns from 2010 and 2019 across the United States (US). This study builds upon previous literature that has analyzed the trends in opioid distribution and assesses changes in opioid prescription preferences. MethodsThe amount of fentanyl base distributed in the US from 2010-2019 was obtained from the Drug Enforcement Administrations Automated Reports and Consolidated Ordering System (ARCOS). Fentanyl derivatives (sufentanil, alfentanil, remifentanil) were also analyzed using ARCOS from 2010-2017, the most recent date reported. Census data from the American Community Survey was used to correct for population. Prescriptions, units, and reimbursement of fentanyl and fentanyl citrate formulations for 2010 and 2019 were obtained from Medicaid and prescriber specialty in Medicare Part D. ResultsTotal grams of fentanyl distributed in the US from 2010 to 2019 decreased by 63%. Correspondingly, there was a 65% decrease in the milligrams per person distributed when correcting for population. From a regional perspective, Ohio had the greatest decrease (-79.3%) while Mississippi saw the smallest (-44.5%). Medicaid reimbursement in 2019 was $165 million for over eight hundred-thousand prescriptions with the majority to generic (99.7%) and injectable (77.6%) formulations. Interventional pain management and anesthesia were over-represented, and hematology/oncology under-represented for fentanyl in Medicare. ConclusionThe production and distribution of fentanyl-based substances has decreased, although not uniformly, in the US over the last decade. Additionally, the most prescribed formulations of fentanyl have transitioned away from transdermal, potentially in an effort to regulate its availability. Although impactful, the overdose deaths attributed to synthetic opioid deaths continue to increase highlighting the need for public health interventions beyond the pharmaceutical and medical communities.

BackgroundFentanyl is a synthetic opioid that is commonly given as a medication to alleviate pain. This drug can be administered through multiple routes, hence making it easy to exploit at high rates. Due to the flexibility in which it can be taken, it increases the ease of both access and use. The purpose of this study was to analyze trends in the distribution of fentanyl and its formulations across Medicaid enrollees in California and among the 3-digit registrant zip codes in California over the period of pre-pandemic (2018-2019) to the early stages of the COVID-19 pandemic (2020). MethodsUsing the Automated Reports and Consolidated Ordering System (ARCOS), the distribution of fentanyl across California was compiled from 2018 to 2020. Utilizing ARCOS, the number of individuals within the source population who lived in one of Californias many zip codes was observed. To analyze the fentanyl distribution trend, we used Google Sheets, GraphPad Prism (Version 9.3.0 [463]), and Microsoft 365 Excel. These were helpful to organize the Medicaid, ARCOS data, and as well as to create graphs. The Medicaid database was used to compile the number of fentanyl formulations prescribed from 2018 to 2020 across California. ResultsThe analyses from both databases provided insight into the difference in fentanyl distribution in California from the years 2018 to 2020. After looking further into the many 3-digit registrant zip codes as well as Medicaid enrollees, it was found that there was a decrease in the distribution of fentanyl and its formulations. Additionally, it was found that the distribution of fentanyl as a medication by business activities also decreased from 2018 to 2020. ConclusionThe results indicate that there was more fentanyl being distributed and prescribed before the pandemic (2018- 2019). On the other hand, when we considered the effects of the pandemic, during 2020, there was quite a drastic decrease in the amount of fentanyl being prescribed and distributed to those living in California and those enrolled in Medicaid.

The chronic pain and opioid addiction epidemics interact with each other, potentially exacerbating each respective condition. Despite having modest efficacy, millions of chronic pain patients in the USA continue to use opioids as their primary source of pain management. The Centers for Disease Control recommends opioid tapering to diminish the risk of opioid dependence in chronic pain patients. However, tapering, even with physician oversight, can introduce additional harm. Thus, many pain clinicians remain ambivalent about undertaking opioid tapering. Here, we surveyed attitudes on the topic from the viewpoint of chronic pain patients who have been consuming opioids over long durations. We queried 127 chronic pain patients (pain duration = 13.5 {+/-} 9.6 years) on long-term opioids (10.3 {+/-} 8.2 years), primarily consuming hydrocodone or oxycodone. Sixty-six percent of participants were "very" or "extremely" interested in participating in an opioid tapering study. Patients emphasized the importance of controlling their pain during opioid tapering, and over 50% were also worried about craving symptoms. Both the desire for tapering and the worry of pain control were more pronounced in participants with a higher magnitude of ongoing back pain. The study demonstrates that most chronic pain patients using opioids are interested in decreasing opioid consumption. Yet, they worry about losing control of their chronic pain. These results imply patient-physician strategies that may aid the engagement of both parties in opioid tapering.

PurposeWe investigated if the use of peripheral nerve blockade (PNB) was associated with a lower incidence of prescription opioid fill within 30 days post-surgery and persistent postoperative opioid use (PPOU) in patients undergoing foot and ankle surgery. MethodsWe identified adults who had undergone foot or ankle surgery between 2012 and 2018 and did or did not receive PNB in an Optums de-identified Integrated Claims-Clinical dataset (n=12,643). Pharmacy data was used to track opioid prescription fill date and supply. PPOU was defined as >90 days of continuous opioid use. Entropy balancing was used to control differences in the distribution of covariates. Log-binomial models in unweighted and weighted data estimated crude and adjusted relative risk (RR) with 95% confidence intervals (CI) for the outcomes. ResultsOne-third of the sample filled an opioid within 30 days of surgery, and among these patients, 57.3% continued use for > 90 days. Performance of PNB was associated with an increased risk for filling opioid prescriptions within 30 days post-surgery before (RR=1.40; 95%CI:1.32-1.49) and after (RR=1.31; 95%CI:1.22-1.41; p<0.0001) controlling for confounding. However, the group that received a PNB showed significantly lower risk of PPOU before (0.91; 95%CI:0.85-0.98; p=0.016) and after controlling for confounding (RR=0.92; 95%CI:0.85-0.99; p=0.029). ConclusionPerformance of PNB for patients undergoing foot and ankle surgery was associated with a 31% increased risk of any opioid prescription fill within 30 days after surgery. However, among the patients that initially filled their prescriptions, patients that received PNB had a significantly (8%) lower risk for PPOU.

BackgroundOpioid overdoses in the US have increased to unprecedented levels. Administration of the opioid antagonist naloxone can prevent overdoses. This study was conducted to reveal the pharmacoepidemiologic patterns in naloxone prescribing to Medicaid patients from 2018-2021 as well as Medicare in 2019. MethodsThe Medicaid State Drug Utilization Data File was utilized to extract information on number of prescriptions and amount prescribed of naloxone at a national and state level. States with naloxone prescription rates differing from the mean by [&ge;] 1.96 standard deviations were considered statistically significant. The Medicare Provider Utilization and Payment was also utilized to analyze prescription data from 2019. ResultsThe number of generic naloxone prescriptions per 100,000 Medicaid enrollees decreased 5.15% whereas brand naloxone prescriptions increased 245.00% from 2018-2021. There was a 33.14-fold difference in prescriptions between the highest (New Mexico = 1809.55) and lowest (South Dakota = 54.61) states in 2019. Medicare saw a 30.32-fold difference in prescriptions between the highest (New Mexico) and lowest states (also South Dakota) after correcting per 100,000 enrollees. ConclusionsThis pronounced increase in the number of naloxone prescriptions to Medicaid patients from 2018-2021 indicates a national response to this widespread public health emergency. Further research into the origins of the pronounced state-level disparities is warranted.

PurposeThe purpose of our study was to investigate dronabinol prescribing in Medicare from 2014 to 2019 by provider specialty and state. MethodsData was collected and analyzed from the Centers for Medicare & Medicaid Services databases from 2014 to 2019. The mean number of prescriptions for each area of practice, each individual year, and for 2014 to 2019 overall for the 50 United States and District of Columbia was determined. The prescriptions were separated by state and the state totals were determined. Individual states with dronabinol prescriptions [&ge;]1.96 standard deviations (SD) from the mean were identified as significant. ResultsThe total number of dronabinol prescriptions decreased 9.1% from 2014 to 2019. Dronabinol prescriptions were more concentrated in the eastern United States in 2019 than compared to 2014 [Tennessee (107.2), Kentucky (94.2), and West Virginia (87.6) (>1.96 SD)]. The largest portion of dronabinol prescriptions originated from primary care (1,736) compared to specialty areas of practice (1,233). Internal medicine (789.5), family medicine (608.8), hematology-oncology (343.3), nurse practitioners (337.3), and infectious disease (271.0) had the highest average number of dronabinol prescriptions per year (p<0.05). The areas of practice with the highest ratio of percent dronabinol prescriptions to percent Medicare utilization were infectious disease (15.8), hematology-oncology (12.2), and medical oncology (12.1). ConclusionDronabinol usage declined among Medicare patients and became more concentrated in the eastern United States. Most prescriptions originated from primary care, although after accounting for Medicare patient utilization, the highest ratios originated from infectious disease, hematology-oncology, and medical oncology.

ObjectiveTo evaluate the changing pattern of the distribution of Schedule II and III opioids, stimulants, and barbiturates by advanced practice providers (APP; i.e., physician assistants and nurse practitioners) in the United States (US). DesignRetrospective study. SampleAdvanced practice providers from every US state (and DC) that directly dispense Schedule II/III drugs to patients. ProceduresControlled substances distributed by APP was obtained from the Drug Enforcement Administrations Automated Reports and Consolidated Orders System (DEAs ARCOS) for opioids (e.g., hydrocodone, fentanyl, buprenorphine), barbiturates (pentobarbital, butalbital), and stimulants (amphetamine, methylphenidate, lisdexamfetamine) from 2006-2023. Opioids were converted to their morphine milligram equivalents (MME), stimulants converted to daily doses, and barbiturates to kilograms. Opioid use by state in three selected years (2013, 2020, 2023) was further analyzed. ResultsThe total weight of controlled substances as distributed exhibited both overall and drug-specific changes since 2006. Buprenorphine accounted for only a modest amount (0.6%) in 2013 but the preponderance (94.6%) of opioids distributed by MME in 2023 nationally. Examination of the opioid MME per state and corrected for population revealed the states with the highest reported use for 2013 (Nevada), 2020 (North Dakota), and 2023 (Maine). There has been an overall modest decline in stimulant (-97.9%) and barbiturate (-64.1%) since 2010. Conclusions and Clinical RelevanceThe use of Schedule II/III drugs as distributed to APP has fluctuated yet overall increased in the past decades. Opioids by total MME have had rather small changes throughout the years, except for buprenorphine. APP direct distribution has transitioned from treating pain to Opioid Use Disorder. Future research should discover the causes underlying the yearly and state level disparities for opioid, stimulant, and barbiturate use.

IntroductionRetention in buprenorphine treatment for opioid use disorder (OUD) yields better opioid abstinence and reduces all-cause mortality for patients with OUD. Despite significant efforts have been made to expand the availability and use of buprenorphine in the United States, its retention rates remain on a low level. The current study examines discontinuation of buprenorphine with respect to concurrent initiation of other medications using real-world evidence. MethodsCase-crossover study was conducted to examine discontinuation of buprenorphine using a large-scale longitudinal health dataset including 148,306 commercially-insured individuals initiated on medications for opioid use disorder (MOUD). Odds ratios and Bonferroni adjusted p-values were calculated for medications and therapeutic classes of medications. ResultsClonidine was associated with increased discontinuation risk of buprenorphine both using the buprenorphine dataset alone (OR = 1.583 and adjusted p-value = 1.22 x 10-6) and using naltrexone as a comparison drug (OR = 2.706 and adjusted p-value = 4.11 x 10-5). Opioid medications (oxycodone, morphine and fentanyl) and methocarbamol were associated with increased discontinuation risk of buprenorphine using the buprenorphine dataset alone (adjusted p-value < 0.05), but not significant using naltrexone as a comparison drug. 6 drug therapeutic classes were associated with increased discontinuation risk of buprenorphine both using the buprenorphine dataset alone and using naltrexone as a comparison drug (adjusted p-value < 0.05). ConclusionConcurrent initiation of medications is associated with increased discontinuation risk of buprenorphine. Opioid medications are prescribed among patients on MOUD and associated with increased discontinuation risk of buprenorphine. Analgesics is associated with increased discontinuation risk of buprenorphine for patients without previous exposure of pain medications.

BackgroundTramadol, an opioid analgesic, is liable to abuse and implicated in drug overdose deaths in the U.S. However, tramadol use and its driving factors have not been intricately examined. This study aims to evaluate the tramadol utilization trends by dosage and county, and social determinants of health (SDoH)-related factors associated with the utilization rates. MethodsThe retrospective study utilized 2015-2022 WV controlled substances monitoring program, CDC opioid dispensing rate, and County Health Ranking and Roadmaps data. Average tramadol daily dose and morphine milligram equivalent were calculated. Annual tramadol dispensing and use rate per 100 population were calculated for WV and each county. Pooled Poisson regression model was used to analyze the relationship between tramadol dispensing rate, opioid dispensing rate, and SDoH variables. ResultsTramadol dispensing rate declined by 35% (2015-2022), but varied within counties with Grant (34.10), McDowell (28.91), and Wyoming (26.67) average annual rates exceeding the overall WV rate (17.90). High tramadol dispensing rate was associated with a high percentage of the population with poor/fair health ({beta}=0.07, p=0.01), physically inactive ({beta}=0.10, p=0.0003), uninsured ({beta}=0.09, p=0.001), and elevated primary care provider (PCP) rate ({beta}=0.10, p=0.0003) and opioid dispensing rate ({beta}=0.14, p<0.0001). ConclusionOur study found heterogenous trends of tramadol dispensing rate within WV and was associated with county-wise health status, physical inactivity, insurance, PCP, and opioid dispensing rates. Considering these factors in local surveillance might improve health, and reduce disease burden, drug, and health resource utilization.

Substance use and related mental health epidemics are causing increasing suffering and death in diverse communities.1,2 Despite extensive efforts focused on developing pharmacotherapies for treating substance use disorders, there is an urgent need for radically different therapeutic approaches.3,4 Ibogaine provides an important drug prototype in this direction, as a psychoactive iboga alkaloid suggested to have the ability to interrupt opioid use in drug-dependent humans.5 However, ibogaine and its major metabolite noribogaine present considerable safety risk associated with cardiac arrhythmias.6 We introduce a new class of iboga alkaloids - "oxa-iboga" - defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds act as potent kappa opioid receptor agonists in vitro and in vivo, but exhibit atypical behavioral features compared to standard kappa psychedelics. We show that oxa-noribogaine has greater therapeutic efficacy in rat models of opioid use, and no cardiac pro-arrhythmic potential, in contrast to noribogaine. Oxa-noribogaine induces long-lasting suppression of morphine and fentanyl intake after a single dose, persistent reduction of morphine intake and reinforcing efficacy after a short treatment regimen, and suppression of morphine and fentanyl drug seeking in relapse models. Oxa-noribogaine also induces a lasting elevation of neurotrophin proteins in the ventral tegmental area and medial prefrontal cortex, consistent with targeted neuroplasticity induction and alteration of addiction-like states. As such, oxa-iboga compounds represent candidates for a novel type of pharmacotherapy for treatment of opioid use disorder.

BackgroundOpioid Use Disorder (OUD) is a debilitating condition characterized by the overuse of prescription opioid medications and the development of physical and/or psychological dependence. Consequences of this condition include chronic impairment, distress, and later life-altering health conditions such as overdose, all of which have been highlighted by the prominence of OUD in the United States in recent years. Buprenorphine is a standard OUD treatment and commonly used for pain management. Understanding changes in distribution patterns across the US is vital for continuing to improve outcomes for OUD patients. MethodsThis study analyzed changes in buprenorphine distribution among pharmacies and hospitals from 2019-2023 to determine temporal patterns and identify state level disparities. The Drug Enforcement Administrations Automated Reports and Consolidated Ordering System (ARCOS), US Census Bureau Population Estimates databases, and mortality rates (CDC WONDER) were analyzed. Data were corrected for population to identify patterns of buprenorphine distribution in the US from 2021-2022 and 2022-2023 through examining percent changes in milligrams per 100 population at national and state level. ResultsThe year-to-year percent change of national buprenorphine distribution from pharmacies has remained positive but changed from 12.2% increase from 2019-2020 to a four percent increase every year from 2020-2023. From 2021-2022, there was a +4.9% increase in total grams of buprenorphine distributed to pharmacies and a 95% CI [-5.1, 14.9], with District of Columbia, South Dakota, and Nebraska outside of the 95% CI. Distribution to hospitals increased by 10.2% [-32.3, 52.7] during 2021-2022, with Hawaii, New Hampshire and Delaware being outside of 95% CI. From 2022-2023, there was an increase of +5.7% and 95% CI [-3.5, 14.9] in pharmacy distribution, with states including Washington, Rhode Island and Kansas remaining outside of the 95% CI. Hospital distribution has decreased from twenty percent between 2019-2020 to eighteen percent between 2022-2023. Changes in mortality data from 2022-2023 showed no associations with trends in buprenorphine distribution for those years. ConclusionFollowing increases in buprenorphine distribution during the COVID pandemic, a consistent increase has continued year-over-year in most states and the country overall by both pharmacies and hospitals. Some states (e.g. Rhode Island, Georgia, Washington D.C.) have not followed this pattern. Notably, Hawaii went from the most negative percent change in hospital distribution to the most positive change in the timeframe analyzed. This may offer opportunities to analyze more specific impacts of the increased buprenorphine distribution on populations and their outcomes associated with OUD.

Compared to most ATP-site kinase inhibitors, small molecules that target an allosteric pocket have the potential for improved selectivity due to the often observed lower structural similarity at these distal sites. Despite their promise, relatively few examples of structurally confirmed, high-affinity allosteric kinase inhibitors exist. Cyclin-dependent kinase 2 (CDK2) is a target for many therapeutic indications, including non-hormonal contraception.1 However, an inhibitor against this kinase with exquisite selectivity has not reached the market because of the structural similarity between CDKs.1-2 In this paper, we describe the development and mechanism of action of new type III inhibitors that bind CDK2 with nanomolar affinity, making them the highest affinity, structurally confirmed allosteric CDK inhibitors reported. Notably, these anthranilic acid inhibitors exhibit a strong negative cooperative relationship with cyclin binding, which remains an underexplored mechanism for CDK2 inhibition. Furthermore, the binding profile of these compounds in both biophysical and cellular assays demonstrate the promise of this series for further development into a therapeutic selective for CDK2 over highly similar kinases like CDK1. The potential of these inhibitors as efficacious contraceptive agents is seen by incubation with mouse testicular explants, where they recapitulate Cdk2-/- and Spdya-/- phenotypes.

IntroductionThe Adequacy of Opioid Consumption (AOC) Index uses the human development index (HDI) to benchmark pain management. This does not account for health system factors such as the anesthesia workforce and can misrepresent high consumption as better. We improved the AOC index by adjusting it for physician anesthesia provider (PAP) density to provide a better indicator for pain management and perioperative care. MethodsCountry-level mean opioid consumption in milligrams per capita (mg/capita) for 2017-2021 (five-year arithmetic mean) was obtained from the International Narcotics Control Board Annual Report 2022. For parsimonious analysis, we included 11 opioids and analogs present in the WHO Model List of Essential Medicines 2023. Projections for PAP density per 100,000 people for 2019 were based on the World Federation of Society of Anaesthesiologists Survey (2015-16) and physician density estimates (2015-2019) derived from the Institute for Health Metrics and Evaluation. A generalized linear regression model for 137 countries was run with mean essential opioid analgesic consumption as the dependent variable and PAP density and HDI (2019) were independent variables to get PAP-adjusted consumption values. The arithmetic mean of PAP-adjusted consumption values of the top 20 countries was used as the adequacy threshold. PAP-adjusted AOC index was calculated as the ratio of the countrys adjusted essential opioid analgesic consumption to the threshold multiplied by 100. ResultsPAP-adjusted AOC index values ranged from 129.14 for Switzerland to 0.23 for Mali. Merely 7.3% of countries had a high AOC. About 5.97 billion people are estimated to be living in regions of low to extremely low PAP-adjusted AOC which are mainly situated in low and middle-income countries in the global south. ConclusionIn this comprehensive up-to-date global analysis, we find that most low- and lower-middle-income countries lack access to essential opioid analgesics. These point to the need for investing in the anesthesia workforce and ensuring access to opioid analgesics in tandem. O_TEXTBOXO_TEXTBOXNOResearch in contextC_TEXTBOXNO Evidence before this studyBefore undertaking the analysis, a rapid review of the literature was conducted to assess existing evidence on global opioid analgesic consumption and adequacy. Relevant publications included comparing opioid consumption for varying numbers of countries using data from the International Narcotics Control Board (INCB), IQVIA MIDAS database, the Organisation for Economic Cooperation and Development, and the European Monitoring Centre for Drugs and Drug Addiction. Three studies quantified the adequacy of opioid consumption between 2006-2015 using ACM and AOC indices. The added value of this studyOur study provides the latest available data for essential opioid analgesic consumption (190 countries) and adequacy (137 countries) between 2017-2021. We only include opioids and their analogs enlisted in the WHO list of Essential Drugs and use a modified AOC index which is adjusted for Physician Anesthesia Provider (PAP) density. This makes our index specific for anesthesia and perioperative pain management. Adjusting for PAP density normalizes the distribution of AOC by bringing higher and lower extremes closer to the mean adjusted consumption and thus accounts for opioid overconsumption values in developed countries. Implications of all the available evidencePAP-adjusted AOC can be used as an indicator to assess regional disparities in access to anesthesia and pain management. AOC has already been used as one of the indicators to measure access to anesthesia and pain management in the South Asian Region. Its national and sub-national mapping can help identify unmet needs and aid in drafting tailored healthcare policies and plans. Further research should be focused on adjusting the AOC based on other health system indicators like surgical rate and burden of disease, and also explore more global indicators for anesthesia care which would aid in tracking its process in global healthcare development. C_TEXTBOX

BackgroundPast research has identified pronounced regional disparities in use of different opioids but less is known for codeine. The primary objective of this study was to analyze the trends of distribution of prescriptions containing codeine in the United States (US) from 2010 to 2019. In addition, this study aimed to identify regional disparities in prescribed milligrams of codeine per person in 2019 and identify any unusual states. MethodsThe distribution of codeine via pharmacies, hospitals, and practitioners in kilograms was obtained from the Drug Enforcement Administrations Automated Reports and Consolidated Ordering System (ARCOS) from 2010 to 2019. In addition, the number of prescriptions of codeine per 1,000 Medicaid enrollees was obtained from the State Drug Utilization Database. ResultsThe total grams of codeine decreased (-25.0%) through all distributors from 2010 to 2019. The largest increase in total grams of codeine distributed between two consecutive years (2014 to 2015) was +28.9%. For a given distributor type, the largest decrease from 2010 to 2019 was hospitals (-89.6%). In 2019, the total mg of codeine per person distributed in Texas (11.46) was significantly higher relative to the national average (3.06, 1.88 SD). Codeine prescriptions to Medicaid patients peeked in the third quarter of 2016. ConclusionThe peak of prescription codeine in 2011 was consistent with the overall peak in prescription opioids, with a subsequent decrease over the decade. This could be explained by relatively recent recommendations regarding the therapeutic use of codeine and how other antitussive agents may be of better use. The precipitous rise of codeine in Texas that we observed has been recognized in prior studies. These state-level disparities warrant further attention by opioid stewardship committees.

BackgroundA growing body of literature suggests that intraoperative opioid administration can lead to both increased post-operative pain and opioid requirements. However, there has been minimal data regarding the effects of the intraoperative administration of intermediate duration opioids such as hydromorphone on post-operative outcomes. Causal inference using observational studies is often hampered by unmeasured confounding, where classical adjustment techniques, such as multivariable regression, are insufficient. Instrumental variable analysis is able to generate unbiased causal effect estimates in the presence of unmeasured confounding, assuming a valid instrumental variable can be found. We previously demonstrated, using a natural experiment, how hydromorphone presentation dose, i.e. the unit dose provided to the clinician, affects intraoperative administration dose, with the switch from a 2-mg to a 1-mg vial associated with decreased administration. As the change in hydromorphone presentation dose was unrelated to any external factors, presentation dose could serve as an instrumental variable to estimate the effect of intraoperative hydromorphone administration dose on post-operative outcomes. MethodsIn this observational study with 6,751 patients, an instrumental variable analysis was employed to estimate the causal effect of an increased intraoperative administration dose of hydromorphone on post-operative pain and opioid administration. The study population included patients who received intraoperative hydromorphone as part of an anesthetic at the University of California, Los Angeles, from October 2016 to November 2018. Before July 2017, hydromorphone was available as a 2-mg unit dose. From July 1, 2017 to November 20, 2017, hydromorphone was only available in a 1-mg unit dose. A two-stage least squares regression analysis was performed to estimate the effect of intraoperative hydromorphone administration dose on post-operative pain scores and opioid administration. ResultsAn increase in hydromorphone administration caused a statistically significant decrease in Post-Anesthesia Care Unit pain scores as well as maximum and mean pain scores on post-operative days one and two, without a statistically significant effect on post-operative opioid administration. Various sensitivity analyses support the validity of the instrumental variable assumptions and suggest that the results are robust against violations of these assumptions. ConclusionsThe results of this study suggests that the intraoperative administration of intermediate duration opioids do not cause the same effects as short acting opioids with respect to post-operative pain. Instrumental variables, when identified, can be invaluable in estimating causal effects using observation data whereby unmeasured confounding is likely present.

ObjectiveUnderstanding opioid use and distribution trends by geographic area is critical in addressing the ongoing opioid epidemic in the United States. This study is a county level analysis of oxycodone and hydrocodone use in Delaware, Maryland, and Virginia between 2006-2014. Materials and MethodsA retrospective analysis of oxycodone and hydrocodone distributed as collected by the Drug Enforcement Administrations (DEA) Washington Post Automation of Reports and Consolidated Orders System (ARCOS) in Delaware, Maryland, and Virginia. Raw drug weights in each county were adjusted to "daily average dose" (grams/county population/365). Purchasing data collected from ARCOS was used to compare distribution trends during this period. ResultsThere was a 57.59% in the weight of oxycodone and hydrocodone between 2006-2014. Oxycodone prescriptions increased by 75.50% and hydrocodone by 11.05%. Oxycodone increased across all three states between 2006-2010 and declined until 2014. Hydrocodone also increased but to a lesser extent than oxycodone. There was substantial variability in daily average dose of both opioids at the county level in all states. Pharmacies accounted for largest portion of oxycodone (69.17%) and hydrocodone (75.27%) purchased in the region. Hospitals accounted for 26.67% of oxycodone and 22.76% hydrocodone purchased. Practitioners and mid-level providers did not significantly contribute to this increase. ConclusionIn the states of Maryland, Delaware, and Virginia, the distribution of the prescription opioids oxycodone and hydrocodone increased by 57.59%. Daily average dose increased between 2006-2010 in all three states followed by a decline until 2014. Variability in daily average dose by county highlights the relationship between geography and likelihood of receiving high dose opioids. It may further allude to effects of targeted distribution by pharmaceutical manufacturers and prescribing habits of geographically distinct healthcare entities. Relationships between location and opioid usage should continue to be investigated to promote rational use of controlled substances.

AT-527, an orally administered double prodrug of a guanosine nucleotide analog, has been shown previously to be highly efficacious and well tolerated in HCV-infected subjects. Herein we report the potent in vitro activity of AT-511, the free base form of AT-527, against several coronaviruses, including SARS-CoV-2, the causative agent of COVID-19. In normal human airway epithelial (HAE) cell preparations, the average concentration of AT-511 required to inhibit replication of SARS-CoV-2 by 90% (EC90) was 0.5 {micro}M, very similar to the EC90 for AT-511 against HCoV-229E, HCoV-OC43 and SARS-CoV in Huh-7 cells. No cytotoxicity was observed for AT-511 in any of the antiviral assays up to the highest concentration tested (100 {micro}M). Surprisingly, AT-511 was 30-fold less active against MERS-CoV. This differential activity may provide a clue to the apparent unique mechanism of action of the guanosine triphosphate analog formed from AT-527.

BackgroundLong-acting injectable buprenorphine (LAIB) has been positioned as a potentially transformative option for opioid use disorder (OUD), in part because patient experiences reported in qualitative studies emphasize reduced daily burden, increased "freedom," reduced stigma, and fewer pressures related to diversion--while also noting barriers such as insufficient information, early adverse experiences, and concerns about coercion. MethodsWe conducted a cross-sectional online survey of adults recruited from the Behavioral Health Research Panel (BHRP). Eligibility included age [&ge;]18, English literacy, and OUD diagnosis or problematic opioid use within the past 5 years. Survey content assessed buprenorphine experience, knowledge and attitudes toward LAIB, attribute preferences, and open-text feedback. Descriptive statistics were generated; analyses were stratified by buprenorphine experience (experienced vs naive). ResultsAmong 105 participants, 82.9% reported prior buprenorphine use, and 17.1% were buprenorphine-naive. Overall, 53.3% preferred a long-acting injection regimen (weekly/monthly/3-monthly) versus 46.7% preferring a daily oral tablet/film. Convenience and adherence-related themes (e.g., not missing doses, fewer visits) drove LAIB preference, while oral-route preference and concerns about side effects and safety were prominent among those favoring oral formulations. ConclusionsIn this national convenience sample, preferences were nearly evenly split between daily oral and long-acting injectable buprenorphine regimens, with a slight overall preference for LAIB. Findings align with the qualitative literature, emphasizing the practical and psychosocial benefits of LAIB, alongside persistent needs for improved education, shared decision-making, and attention to tolerability, safety perceptions, and cost/coverage barriers.

BackgroundOpioid-related mortality has been on a sharp rise in the decade. This study aims to provide insight into the difference in mortality between white and black population in various census regions of the United States between 1999-2020. MethodsThe data was extracted from multiple cause of death files from CDC Wonder database. The International Classification of Disease (ICD-10) codes used to extract data include F11 (mental and behavioral disorders due to use of opioids); T40.0 (Opium); T40.1 (Heroin); T40.2 (Other opioids); T40.3 (Methadone); T40.4 (Other synthetic narcotics). The regression analysis was conducted using Joinpoint statistical software. ResultsThe black population in the Midwest census region showed the highest age-adjusted mortality in the year 2020 (46.14 per 100,000). This was followed by the black (32.71 per 100,000) and white population (30.5 per 100,000) in the northeast census regions respectively. Overall, the opioid-related mortality followed a similar trend across all census regions. Except south census region where age-adjusted mortality was comparable between the black and white populations, blacks had higher opioid-related mortality in all other census regions. ConclusionThis study provides concise evidence of inequality in opioid-related deaths among various US census regions. Policy changes focused to certain regions are required to significantly address the underlying factors related to disparities in opioid-related mortality among the black population.

BackgroundHealth care inequity includes the lack of adequate representation of various populations in clinical trials. Government, academic and industry organizations have highlighted these issues and committed to actions to improve. In order to assess the current status and future success of these initiatives a quantitative objective measure to assess the state of clinical trial diversity is needed. MethodsFDA review documents for all novel drug approvals from January 2022 through February 16, 2023 were assessed using a scorecard that considers diversity across different demographic subgroups including age (>65 yo), sex (female), race (Black and Asian) and ethnicity (Hispanic/Latino). The scorecard assigns each drug a letter grade, between A and F, for each subgroup (and overall) based on 1) the percent of each sub-population included in the trials and grades relative to the percent of the US population, 2) the number of participants from each subpopulation that received the novel new drug in the trials, 3) the incidence or prevalence of the disease/condition in each of the sub-populations. ResultsThe FDA approved 43 novel new drugs for 44 indications (one drug was simultaneously approved for two indications). The three drugs with A Grades reflecting the best diversity in their registration trials were tapinarof (Vtama from Dermavant), daprodustat (Jesduvroq from GlaxoSmithKline) and eflapegrastim (Rolvedon from Spectrum Pharmaceuticals.) There was good representation of elderly and females with only two drugs receiving a D grade in either of these sub-populations. In contrast, Black and Hispanic representation was often inadequate with 4 drugs receiving F grades. There were 9 drugs (20%) where there were no Black participants receiving the novel new drug and an additional 14 approvals where there were <10 Black participants receiving the novel drug. The median number of Black participants receiving the investigational drug was 9. In the Hispanic/Latino population there were 2 approvals with no Hispanic participants receiving the novel drug and 14 approvals where there were < 10 Hispanic participants receiving the drug. The median number of Hispanic participants receiving the novel drug was 12.5. ConclusionsThis newly developed scorecard provides an objective quantitative approach to assess the current state of diversity in clinical trials supporting new drug approvals. Substantial improvement in racial and ethnic representation is needed. Meaningful change will require actions and cooperation amongst all stakeholders to address this multifaceted issue and will take commitment, perseverance, and appropriate incentives.