Rising cases of drug-induced pulmonary fibrosis: Analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database, 2000-2022.

PURPOSE: Pulmonary fibrosis (PF) is a severe, progressive disease, which may be caused by exposure to certain medications. METHODS: We queried the U.S. FDA Adverse Event Reporting System (FAERS) from 2000 to 2022, using the search terms "pulmonary fibrosis" and "idiopathic pulmonary fibrosis" and excluded reports with patients under the age of 18 years, and patients with unknown sex or age. Reports were sorted by generic drug names, counted, and plotted over time using a best-fit trendline based on an exponential function. RESULTS: From 2000 to 2022, there were 24 095 935 adverse drug events reported in FAERS, of which 17 520 (0.07%) were reported as PF. After excluding reports containing patients with unknown age (5255, 30%), sex (122, 0.7%), and age below 18 years old (155, 0.9%), our study included 11 988 reports. The mean age of the study sample was 66.5 ± 13.1 years, and 6248 patients (52.1%) were male. Plotting the 11 988 reports by year revealed an exponential best fit line (R2 = 0.88) with a positive slope over time. The top five drug classes associated with PF were disease modifying antirheumatic drugs (DMARDs, 39.4%), antineoplastic agents (26.4%), cardiovascular agents (12.6%), corticosteroids (4.6%), and immunosuppressive agents (4.0%). CONCLUSION: A 23-year analysis of the FAERS database revealed exponentially increasing adverse event reports of PF. Significant annual increases in reporting of PF suspected with DMARDs and antineoplastic agents were identified. Our study highlights important trends, which should be used to guide PF research related to drugs of potential importance.

High Prescribing and State-Level Variation in Z-Drug Use Among Medicare Patients.

BACKGROUND: Z-drugs are nonbenzodiazepine hypnotics used for sleep initiation and maintenance; these drugs increase the risk of fall-related injuries in older adults. The American Geriatrics Society's Beers criteria classifies Z-drugs as high-risk and strongly recommends avoiding prescribing Z-drugs to older adults due to adverse effects. The study objectives were to determine the prevalence of Z-drug prescribing among Medicare Part D patients and identify state or specialty-dependent prescribing differences. This study also aimed to determine prescribing patterns of Z-drugs to Medicare patients. METHODS: Z-drug prescription data was extracted from the Centers for Medicare and Medicaid Services State Drug Utilization Data for 2018. For all 50 states, the number of prescriptions per 100 Medicare enrollees and days-supply per prescription was determined. The percentage of total prescriptions prescribed by each specialty and the average number of prescriptions per provider within each specialty was also determined. RESULTS: Zolpidem was the most prescribed Z-drug (95.0%). Prescriptions per 100 enrollees were significantly high in Utah (28.2) and Arkansas (26.7) and significantly low in Hawaii (9.3) relative to the national average (17.5). Family medicine (32.1%), internal medicine (31.4%), and psychiatry (11.7%) made up the largest percentages of total prescriptions. The number of prescriptions per provider was significantly high among psychiatrists. DISCUSSION: Contrary to the Beers criteria, Z-drugs are prescribed to older adults at high rates.

Pronounced Regional Disparities in United States Methadone Distribution.

BACKGROUND: Methadone is an evidence-based treatment for opioid use disorder (OUD) and pain management. Methadone for OUD may be difficult for some patients to access, particularly those in rural areas. OBJECTIVE: The purpose of this study was to characterize methadone distribution patterns between 2017 and 2019 across the United States. METHODS: The US Drug Enforcement Administration's Automated Reports and Consolidated Ordering System was used to acquire the number of opioid treatment programs (OTPs) per state and methadone distribution weight in grams. Methadone distributions by weight, corrected for state population and number of OTPs, were compared from 2017 to 2019 between states, within regions, and nationally. RESULTS: The national distribution of methadone increased +12.3% for OTPs but decreased -34.6% for pain. Whereas all states saw a decrease in pain distribution, the Northeast showed a significantly smaller decrease than all other regions. Additionally, the majority of states experienced an increase in distribution for OTPs, and most states demonstrated a relatively stable or increasing number of OTPs, with an +11.5% increase nationally. The number of OTPs per 100K state population ranged from 2.1 in Rhode Island to 0.0 in Wyoming. CONCLUSION AND RELEVANCE: Although methadone distribution for OUD was increasing in the United States, the pronounced regional disparities identified warrant further consideration to improve patient access to this evidence-based pharmacotherapy, particularly in the Midwest and West regions. Greater implementation of telehealth and involvement of primary care into opioid treatment practice offer possible solutions to eliminating geographical treatment barriers.

Examination of multiple drug arrests reported to the Maine Diversion Alert Program.

PURPOSE: Much of the responsibility for the increasing drug overdoses in the US has been attributed to opioids but most opioid overdoses also involve another drug. The objective of this study was to identify the drugs involved in polysubstance arrests. The substances that were more likely to be found in conjunction with other substances, using the drug arrests reported to Maine's Diversion Alert Program (DAP) were examined. METHODS: Single and multiple drug arrests were quantified (N = 9,216). Multiple drug arrest percentages were compared to single drug arrest percentages to create a Multiple-to-Single Ratio (MSR) specific to each drug family and each drug to identify over (MSR > 1) and under-representation (MSR < 1). RESULTS: Over three-fifths (63.8%) of all arrests involved a single drug. Opioids accounted for over-half (53.5%) of single arrests, followed by stimulants (27.7%) and hallucinogens (7.7%). Similarly, nearly two-fifths (39.6%) of multiple arrests were for opioids, followed by stimulants (30.8%) and miscellaneous (13.0%). Miscellaneous psychoactive prescription substances (e.g. clonidine, gabapentin, cyclobenzaprine, hydroxyzine) had the highest (1.51) MSR of any drug family. Conversely, stimulants (0.63), opioids (0.42), and hallucinogens (0.35) were significantly underrepresented in polysubstance arrests. Carisoprodol (8.80), amitriptyline (6.34), and quetiapine (4.69) had the highest MSR. Bath-salts (0.34), methamphetamine (0.44), and oxycodone (0.54) had the lowest MSR. CONCLUSION: The misuse of opioids, both alone and in conjunction with another drug, deserves continued surveillance. In addition, common prescription drugs with less appreciated misuse potential, especially carisoprodol, amitriptyline, and quetiapine, require greater attention for their ability to enhance the effects of other drugs.

Opioid Mortality Following Implementation of Medical Cannabis Programs in the United States.

INTRODUCTION: The United States is in the midst of an opioid overdose epidemic. Emerging evidence suggests that medical cannabis (MC) may reduce use of opioids for pain in some individuals, with potential impacts on opioid-related overdose. However, there may be other important differences between states that did, and did not, adopt MC. METHODS: This study evaluated differences following legal MC sales on US opioid-related overdose deaths, corrected for population, from 1999 to 2017 using an interrupted time series. Comparisons by MC status were also made for Medicaid expansion and the Centers for Disease Control death certificate reporting quality (0:

Decline and Pronounced Regional Disparities in Medical Cocaine Usage in the United States.

Background: Cocaine is a stimulant and Schedule II drug used as a local anesthetic and vasoconstrictor. Objective: This descriptive study characterized medical cocaine use in the United States. Methods: Retail drug distribution data from 2002 to 2017 were extracted for each state from the Drug Enforcement Administration, which reports on medical, research, and analytical chemistry use. The percentage of buyers (pharmacies, hospitals, and providers) was obtained. Use per state, corrected for population, was determined. Available cross-sectional data on cocaine use as reported by the Medicare and Medicaid programs for 2013-2017 and electronic medical records were examined. Results: Medical cocaine use decreased by -62.5% from 2002 to 2017. Hospitals accounted for 84.9% and practitioners for 9.9% of cocaine distribution in 2017. The number of pharmacies carrying cocaine dropped by -69.4%. The percentages of hospitals, practitioners, and pharmacies that carried cocaine in 2017 were 38.4%, 2.3%, and 0.3%, respectively. There was a 7-fold difference in 2002 (South Dakota, 76.1 mg/100 persons; Delaware, 10.1 mg/100 persons). Relative to the average state in 2017, those reporting the highest values (Montana, 20.1; North Dakota, 24.1 mg/100 persons) were significantly elevated. Cocaine use within the Medicare and Medicaid programs was negligible. Cocaine use within the Geisinger system was rare from 2002 to 2007 (<4 orders/100 000 patients per year) but increased to 48.7 in 2018. Conclusion and Relevance: If these pharmacoepidemiological patterns continue, licit cocaine may soon become a historical relic. The pharmacology and pharmacotherapeutics education of health care providers may need to be adjusted accordingly.

Rise and regional disparities in buprenorphine utilization in the United States.

PURPOSE: Buprenorphine is an opioid partial agonist used to treat opioid use disorder. While several policy changes have attempted to increase buprenorphine availability, access remains well below optimal levels. This study characterized how buprenorphine utilization in the United States has changed over time and whether there are regional disparities in distribution of the medication. METHODS: The amount of buprenorphine distributed from 2007 to 2017 was obtained from the Drug Enforcement Administration's Automated Reports and Consolidated Ordering System. Data were expressed as the percent change and milligrams per person in each state. The formulations and cost for prescriptions covered by Medicaid (2008 to 2018) were also examined. RESULTS: Buprenorphine distributed to pharmacies increased about 7-fold (476.8 to 3179.9 kg) while the quantities distributed to hospitals grew 5-fold (18.6 to 97.6 kg) nationally from 2007 to 2017. Buprenorphine distribution per person was almost 20-fold higher in Vermont (40.4 mg/person) relative to South Dakota (2.1 mg/person). There was a strong association between the number of physicians authorized to prescribe buprenorphine and distribution per state (r[49] = +0.94, P < .0005). The buprenorphine/naloxone sublingual film (Suboxone) was the predominant formulation (92.6% of 0.31 million Medicaid prescriptions) in 2008 but accounted for less than three-fifth (57.3% of 6.56 million prescriptions) in 2018. CONCLUSIONS: Although buprenorphine availability has substantially increased over the last decade, distribution was very nonhomogeneous across the United States.

Trends in the medical supply of fentanyl and fentanyl analogues: United States, 2006 to 2017.

Fentanyl is an important opioid for pain management, but also has exceptional potential for misuse. Seven states have implemented opioid prescribing laws. The objectives of this study were to: 1) characterize the temporal pattern of fentanyl, fentanyl analogue, and other opioid use over the past decade, and 2) determine whether opioid prescribing laws impacted fentanyl use in the US. Drug weights were obtained from the US Automated Reports of Consolidated Orders System (June 2018), a comprehensive publically available resource, from 2006 to 2017 for fentanyl, sufentanil, remifentanil, alfentanil, other prescription opioids, and analyzed by presence of a state opioid prescribing law. Fentanyl, corrected for population, was reduced from 2016 to 2017 (-17.9%) and these decreases significantly exceeded the changes in hydrocodone (-12.3%), oxycodone (-10.1%), morphine (-13.3%), or codeine (-8.8%). Fentanyl showed a particularly large decline in Maine, a state with a strong opioid prescribing law. There was a 3.5 fold difference in fentanyl (µg per capita) in Alaska (488.2) relative to Oregon (1718.4). Hospital use of remifentanil and sufentanil tripled from 2006 to 2017. Although all states experienced a 2016 to 2017 decline in fentanyl, and this reduction was larger than many other prescription opioids, the rate of decline varied over three-fold between states. Strong state laws may account for a portion of the variance in fentanyl and other opioid reductions. The population health risks of fentanyl and fentanyl analogues warrants ongoing vigilance.

Using Controlled Substance Receipt Patterns to Predict Prescription Overdose Death.

BACKGROUND: This study evaluates complete state data from controlled substance prescribing trends in the prescription monitoring program (PMP) database and their association with the risk of prescription drug overdose death. SUMMARY: Maine PMP records of individuals who died of prescription overdose deaths between 2006 and 2010 were selected (n = 690). For each subject, an age, gender, and residence matched cohort of PMP users in a 50: 1 ratio was identified (n = 34,500). Key Messages: Prescription opioids contributed to 480 of 690 prescription deaths, many co-ingestions were noted, and OR for overdose death increased with milligram of morphine equivalent (MME)/day >100. The majority who were prescribed MME >100 per day received a prescription within 90 days of overdose matching the toxicology cause of death. CONCLUSIONS: Medication profiles available through state PMP can identify dosing of prescriptions associated with drug overdose death.

Pronounced State-Level Disparities in Medicaid Prescribing of Buprenorphine for Opioid Use Disorder (2019-2020).

OBJECTIVE: The purpose of this study was to analyze buprenorphine prescribing across states in Medicaid patients during 2019-2020. METHOD: Buprenorphine prescriptions per Medicaid enrollee per state were calculated for 2019 and 2020. Data analysis was conducted with buprenorphine formulations that are approved by the U.S. Food & Drug Administration for opioid use disorder (OUD; including generic and brand name formulations of buprenorphine mono product and buprenorphine/naloxone combination products) using Microsoft Excel. The totals of mono product buprenorphine were divided over the total of combination buprenorphine/naloxone in 2019 and 2020 to obtain the ratio of mono/combo. Formulations of buprenorphine indicated for pain were excluded. States outside 95% confidence intervals (1.96 standard deviations above and below the mean) were considered statistically significant. RESULTS: The overall change in buprenorphine prescribing between 2019 and 2020 was modest (+3.6%) but highly variable, with more than a 10% increase in 17 states (Iowa = +100.5%, p < .05) but more than a 10% decrease in 9 states (Alabama = -68.5%, p < .05). Total amount reimbursed in 2019 increased (+9.9%) to $1.42 billion in 2020. Branded formulations accounted for two fifths (39.5%) of prescribing but more than two thirds (66.8%) of spending in 2020. CONCLUSIONS: The COVID-19 pandemic exacerbated state-level disparities in buprenorphine prescribing for OUD among Medicaid patients. Legislation expanding buprenorphine-waivered providers and Medicaid expansion may have contributed to the statistically significant changes in state buprenorphine prescriptions.

First generation antipsychotic-associated serious adverse events in women: a retrospective analysis of a pharmacovigilance database.

BACKGROUND: Women have been under-represented in trials of antipsychotic medications. AIM: Our primary objective was to evaluate five adverse events (AE) associated with first-generation antipsychotics (FGAs) among women relative to men through an analysis of the FDA Adverse Event Reporting System (FAERS). METHOD: We queried 24.6 million AE reports from 2000 to 2023 involving FGAs. The study cohort consisted of chlorpromazine (n = 3317), fluphenazine (n = 1124), haloperidol (n = 16,709), loxapine (n = 3151), perphenazine (n = 816), thioridazine (n = 665), thiothixene (n = 244), and trifluoperazine (n = 360). Cases of neuroleptic malignant syndrome (NMS), tardive dyskinesia (TD), Torsades de Pointes (TdP), agranulocytosis (AG), and cerebrovascular adverse events (CVAE) were identified. Reporting odds ratios (ROR) and associated 95% confidence intervals (CI) were calculated with logistic regression for each AE among women relative to men. RESULTS: A total of 2,857 serious AEs were evaluated in the study cohort (NMS = 1810, TD = 434, TdP = 260, AG = 149, CVAE = 204). The ROR for women compared to men was 0.79 (95% CI, 0.71-0.87) for NMS, 0.83 (0.68-1.01) for TD, 1.21 (0.94-1.53) for TdP, 0.71 (0.51-0.98) for AG, and 0.91 (0.68-1.19) for CVAE. A secondary analysis revealed a higher odds in women compared to men of hospitalization associated with reports of TD (ROR = 1.95, 1.29-2.94) and death associated with reports of AG (ROR = 2.46, 1.15-5.24). A subgroup analysis of haloperidol revealed an ROR = 1.67 (1.26-2.21) for women relative to men for TdP. CONCLUSION: The subgroup analysis of haloperidol AEs revealed a significantly higher reporting odds ratio for TdP. Additionally, the secondary study findings suggest that women were more vulnerable to worse outcomes associated with certain AEs of FGAs.

Utilization of Lower-Dose Cyclobenzaprine in the Older Inpatient.

Background In older inpatients, anticholinergic medications can increase the risk of complications that may increase length of stay (LOS). Cyclobenzaprine is an anticholinergic medication associated with mental status changes, falls, and injuries in older patients. Objective The purpose of this study is to determine whether use of a lower cyclobenzaprine dose (5 mg) compared with higher dosing (10 mg) will affect LOS, 30-day readmission rates, and need for injectable psychotropic agents in inpatients 65 years of age and older. Methods This was a retrospective cohort analysis comparing outcomes in patients 65 years of age and older who received either a 5 mg or 10 mg cyclobenzaprine dose during their inpatient admission over a 2.5-year period. The primary outcome was hospital LOS, adjusted using multivariate linear regression. Secondary outcomes included 30-day readmission rate adjusted using logistic regression and use of injectable antipsychotics or benzodiazepines. A sub-analysis evaluated the impact of the institution's implementation of a geriatric prescribing context (GEM-CON) on cyclobenzaprine dose selection. Results The adjusted LOS was 32.7% longer (95% CI 25.9%-39.9%) for patients exposed to higher-dose cyclobenzaprine. Use of injectable antipsychotics or benzodiazepines was also significantly greater in the higher-dose group (P < 0.001; P = 0.025). Cyclobenzaprine dose was not significantly associated with readmission on multivariate analysis (OR = 0.93, 95% CI 0.45-1.93). After GEM-CON implementation, there was a significant increase in use of the recommended lower cyclobenzaprine dose (P < 0.001). Conclusion Use of lower cyclobenzaprine dosing in older inpatients is associated with reduced hospital LOS and need for injectable antipsychotics and benzodiazepines.

State-level variation in distribution of oxycodone and opioid-related deaths from 2000 to 2021: an ecological study of ARCOS and CDC WONDER data in the USA.

OBJECTIVES: This study aims to characterise oxycodone's distribution and opioid-related overdoses in the USA by state from 2000 to 2021. DESIGN: This is an observational study. SETTING: More than 80 000 Americans died of an opioid overdose in 2021 as the USA continues to struggle with an opioid crisis. Prescription opioids play a substantial role, introducing patients to opioids and providing a supply of drugs that can be redirected to those seeking to misuse them. METHODS: The Drug Enforcement Administration annual summary reports from the Automation of Reports and Consolidated Orders System provided weights of oxycodone distributed per state by business type (pharmacies, hospitals and practitioners). Weights were converted to morphine milligram equivalents (MME) per capita and normalised for population. The Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research provided mortality data for heroin, other opioids, methadone, other synthetic narcotics and other/unspecified narcotics. RESULTS: There was a sharp 280.13% increase in total MME/person of oxycodone from 2000 to 2010, followed by a slower 54.34% decrease from 2010 to 2021. Florida (2007-2011), Delaware (2003-2020) and Tennessee (2012-2021) displayed consistent and substantial elevations in combined MME/person compared with other states. In the peak year (2010), there was a 15-fold difference between the highest and lowest states. MME/person from only pharmacies, which constituted >94% of the total, showed similar results. Hospitals in Alaska (2000-2001, 2008, 2010-2021), Colorado (2008-2021) and DC (2000-2011) distributed substantially more MME/person over many years compared with other states. Florida stood out in practitioner-distributed oxycodone, with an elevation of almost 15-fold the average state from 2006 to 2010. Opioid-related deaths increased +806% from 2000 to 2021, largely driven by heroin, other opioids and other synthetic narcotics. CONCLUSIONS: Oxycodone distribution across the USA showed marked differences between states and business types over time. Investigation of opioid policies in states of interest may provide insight for future actions to mitigate opioid misuse.

Declining but Pronounced State-Level Disparities in Prescription Opioid Distribution in the United States.

The United States (US) opioid epidemic is a persistent and pervasive public health emergency that claims the lives of over 80,000 Americans per year as of 2021. There have been sustained efforts to reverse this crisis over the past decade, including a number of measures designed to decrease the use of prescription opioids for the treatment of pain. This study analyzed the changes in federal production quotas for prescription opioids and the distribution of prescription opioids for pain and identified state-level differences between 2010 and 2019. Data (in grams) on opioid production quotas and distribution (from manufacturer to hospitals, retail pharmacies, practitioners, and teaching institutions) of 10 prescription opioids (codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, and tapentadol) for 2010 to 2019 were obtained from the US Drug Enforcement Administration. Amounts of each opioid were converted from grams to morphine milligram equivalent (MME), and the per capita distribution by state was calculated using population estimates. Total opioid production quotas increased substantially from 2010 to 2013 before decreasing by 41.5% from 2013 (87.6 MME metric tons) to 2019 (51.3). The peak year for distribution of all 10 prescription opioids was between 2010 and 2013, except for codeine (2015). The largest quantities of opioid distribution were observed in Tennessee (520.70 MME per person) and Delaware (251.45) in 2011 and 2019. There was a 52.0% overall decrease in opioid distribution per capita from 2010 to 2019, with the largest decrease in Florida (-61.6%) and the smallest in Texas (-18.6%). Southern states had the highest per capita distribution for eight of the ten opioids in 2019. The highest to lowest state ratio of total opioid distribution, corrected for population, decreased from 5.25 in 2011 to 2.78 in 2019. The mean 95th/5th ratio was relatively consistent in 2011 (4.78 ± 0.70) relative to 2019 (5.64 ± 0.98). This study found a sustained decline in the distribution of ten prescription opioids during the last five years. Distribution was non-homogeneous at the state level. Analysis of state-level differences revealed a fivefold difference in the 95th:5th percentile ratio between states, which has remained unchanged over the past decade. Production quotas did not correspond with the distribution, particularly in the 2010-2016 period. Future research, focused on identifying factors contributing to the observed regional variability in opioid distribution, could prove valuable to understanding and potentially remediating the pronounced disparities in prescription opioid-related harms in the US.

Retrospective study investigating naloxone prescribing and cost in US Medicaid and Medicare patients.

BACKGROUND: Opioid overdoses in the USA have increased to unprecedented levels. Administration of the opioid antagonist naloxone can prevent overdoses. OBJECTIVE: This study was conducted to reveal the pharmacoepidemiologic patterns in naloxone prescribing to Medicaid patients from 2018 to 2021 as well as Medicare in 2019. DESIGN: Observational pharmacoepidemiologic study SETTING: US Medicare and Medicaid naloxone claims INTERVENTION: The Medicaid State Drug Utilisation Data File was utilised to extract information on the number of prescriptions and the amount prescribed of naloxone at a national and state level. The Medicare Provider Utilisation and Payment was also utilised to analyse prescription data from 2019. OUTCOME MEASURES: States with naloxone prescription rates that were outliers of quartile analysis were noted. RESULTS: The number of generic naloxone prescriptions per 100 000 Medicaid enrollees decreased by 5.3%, whereas brand naloxone prescriptions increased by 245.1% from 2018 to 2021. There was a 33.1-fold difference in prescriptions between the highest (New Mexico=1809.5) and lowest (South Dakota=54.6) states in 2019. Medicare saw a 30.4-fold difference in prescriptions between the highest (New Mexico) and lowest states (also South Dakota) after correcting per 100 000 enrollees. CONCLUSIONS: This pronounced increase in the number of naloxone prescriptions to Medicaid patients from 2018 to 2021 indicates a national response to this widespread public health emergency. Further research into the origins of the pronounced state-level disparities is warranted.

Pronounced State-Level Disparities in Prescription of Cannabinoids to Medicaid Patients.

Introduction: Dronabinol is approved in the USA for chemotherapy-induced nausea as well as vomiting and HIV-induced anorexia, while cannabidiol is primarily approved for childhood epileptic disorders Lennox-Gastaut and Dravet syndrome. The use pattern for these prescription cannabinoids in the USA is unknown. This study examined Medicaid claims for two FDA-approved prescription cannabinoids, dronabinol and cannabidiol, approved in 1985 and 2018, respectively, from 2016-2020 to better understand the pharmacoepidemiologic trends and distribution of these drugs in US Medicaid amidst the increasing use of non-pharmaceutical formulations of cannabis. Methods: The longitudinal study analyzed Medicaid prescription claims that were calculated by extracting the prescriptions on a state level from 2016 to 2020 for two cannabinoids, dronabinol and cannabidiol, where outcomes over each year were calculated. Outcomes were (1) the number of prescriptions for each state corrected for the number of Medicaid enrollees and (2) dronabinol and cannabidiol spending. Spending refers to the amount reimbursed by the state Medicaid program. Results: Dronabinol prescriptions per state decreased by 25.3% from 2016 to 2020, while cannabidiol prescriptions increased by 16,272.99% from 2018 to 2020. The spending on these drugs parallels that of their prescription trend with a 66.3% decrease in reimbursement for dronabinol ($5.7 million in 2020), whereas cannabidiol increased by +26,582.0% ($233.3 million in 2020). Dronabinol prescriptions, when corrected for the number of enrollees, in Connecticut were 136.4 times larger than in New Mexico, and seventeen states had zero prescriptions. Idaho's prescriptions of cannabidiol (27.8/10,000 enrollees) were significantly elevated relative to the national average and were 15.4-fold higher than Washington, DC (1.8/10K enrollees). Conclusions: The prescriptions of pharmaceutical-grade tetrahydrocannabinol decreased while those of cannabidiol increased. This study also identified pronounced state-level variation in cannabinoid prescribing to Medicaid patients. State formularies and prescription drug list variation may contribute to the drug reimbursements in Medicaid, though further research is needed to identify the health policy or pharmacoeconomic origins of these disparities.

Variation in adverse drug events of opioids in the United States.

Background: The United States (US) ranks high, nationally, in opioid consumption. The ongoing increase in the misuse and mortality amid the opioid epidemic has been contributing to its rising cost. The worsening health and economic impact of opioid use disorder in the US warrants further attention. We, therefore, assessed commonly prescribed opioids to determine the opioids that were over-represented versus under-represented for adverse drug events (ADEs) to better understand their distribution patterns using the Food and Drug Administration's Adverse Event Reporting System (FAERS) while correcting for distribution using the Drug Enforcement Administration's Automation of Reports and Consolidated Orders System (ARCOS). Comparing the ratio of the percentage of adverse drug events as reported by the FAERS relative to the percentage of distribution as reported by the ARCOS database is a novel approach to evaluate post-marketing safety surveillance and may inform healthcare policies and providers to better regulate the use of these opioids. Methods: We analyzed the adverse events for 11 prescription opioids, when correcting for distribution, and their ratios for three periods, 2006-2010, 2011-2016, and 2017-2021, in the US. The opioids include buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Oral morphine milligram equivalents (MMEs) were calculated by conversions relative to morphine. The relative ADEs of the selected opioids, opioid distributions, and ADEs relative to distribution ratios were analyzed for the 11 opioids. Results: Oxycodone, fentanyl, and morphine accounted for over half of the total number of ADEs (n = 667,969), while meperidine accounted for less than 1%. Opioid distributions were relatively constant over time, with methadone repeatedly accounting for the largest proportions. Many ADE-to-opioid distribution ratios increased over time, with meperidine (60.6), oxymorphone (11.1), tapentadol (10.3), and hydromorphone (7.9) being the most over-represented for ADEs in the most recent period. Methadone was under-represented (<0.20) in all the three periods. Conclusion: The use of the FAERS with the ARCOS provides insights into dynamic changes in ADEs of the selected opioids in the US. There is further need to monitor and address the ADEs of these drugs.

Examination of methadone involved overdoses during the COVID-19 pandemic.

BACKGROUND: The US opioid overdose epidemic continues to escalate. The restrictions on methadone availability including take-home dosing were loosened during the COVID-19 pandemic although there have been concerns about the high street value of diverted methadone. This report examined how fatal overdoses involving methadone have changed over the past two-decades including during the pandemic. METHODS: The CDC's Wide-ranging Online Data for Epidemiologic Research (WONDER) was used to find the unintentional methadone related overdose death rate from 1999 to 2020. Unintentional methadone deaths were defined using the ICD X40-44 codes with only data for methadone (T40.3). Data from the DEA's Automation of Reports and Consolidated Orders System (ARCOS) on methadone overall use, opioid treatment programs use, and pain management use was gathered for all states for 2020 and corrected for population. RESULTS: There have been dynamic changes over the past two-decades in methadone overdoses. Overdoses increased from 1999 (0.9/million) to 2007 (15.9) and declined until 2019 (6.5). Overdoses in 2020 (9.6) were 48.1% higher than in 2019 (t(50) = 3.05, p < .005). The state level correlations between overall methadone use (r(49) = +0.75, p < .001), and opioid treatment program use (r(49) = +0.77, p < .001) with overdoses were positive, strong, and statistically significant. However, methadone use for pain treatment was not associated with methadone overdoses (r(49) = -0.08). CONCLUSIONS: Overdoses involving methadone significantly increased by 48.1% in 2020 relative to 2019. Policy changes that were implemented following the COVID-19 pandemic involving methadone take-homes may warrant further study before they are made permanent.

An Analysis of Oxycodone and Hydrocodone Distribution Trends in Delaware, Maryland, and Virginia Between 2006 and 2014.

Objective Opioid medications are widely recognized for their use in analgesia and their addictive properties that have led to the opioid epidemic. Areas with historically high prescribing patterns have been shown to suffer more from the crisis. There is also regional variability in these trends. This study is a county level analysis of oxycodone and hydrocodone use in Delaware, Maryland, and Virginia between 2006 and 2014. Materials and methods A retrospective analysis of oxycodone and hydrocodone distributed as collected by the Drug Enforcement Administration's (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) using publicly available population estimates for all state counties. Purchasing data collected from ARCOS was used to compare distribution trends during this period. This study was limited in that ARCOS report quantity of drug distribution rather than average dose of script written.  Results There was a 57.59% increase in the weight of oxycodone and hydrocodone prescribed between 2006 and 2014. Oxycodone prescriptions increased by 75.50% and hydrocodone by 11.05%. Oxycodone increased across all three states between 2006 and 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% of hydrocodone purchased. Practitioners and mid-level providers, including Nurse Practitioners and Physician Assistants, did not significantly contribute to this increase. Conclusion In 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 and 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. Increased monitoring at regional health centers and improving substance abuse treatment infrastructure at the county level may be a more efficient strategy in combating the opioid epidemic. Future research is needed to understand the socioeconomic trends that may influence prescribing trends of opioid medications.

Reductions and pronounced regional differences in morphine distribution in the United States.

OBJECTIVES: The purpose of this longitudinal study was to describe the temporal pattern of morphine distribution nationally and between states. METHODS: Drug weight was obtained from Report 5 of the US Drug Enforcement Administration's Automation of Reports and Consolidated Orders System (ARCOS) to characterize patterns in the distribution of morphine from 2012 to 2021. Morphine distribution amounts were separated by state and business type and corrected for population. States outside a 95% confidence interval relative to the national average were considered statistically significant. KEY FINDINGS: In 2012, there was a 4.6-fold difference in morphine distribution between the highest-prescribing state, Tennessee (180.2 mg/person), and the lowest-prescribing state, Texas (39.4 mg/person). By the end of 2021, national distribution of morphine had decreased by 59.9% when compared to the peak year 2012. In 2021, Tennessee (51.1 mg/person) remained the highest-prescribing state with a 3.0-fold difference relative to Texas (17.2 mg/person). The average hospital decrease (-73.9%) from 2012 to 2021 was larger than that of pharmacies (-58.2%). CONCLUSIONS: The national 59.9% decline in morphine in the last decade may be attributable to prioritization of the US opioid crisis as a public concern. Further research is necessary to understand the persistent regional difference between states.