key: cord-0308500-xqxvfvun authors: Dowd, M. E.; Tang, E. J.; Yan, K. T.; McCall, K. L.; Piper, B. J. title: Reductions and pronounced regional differences in morphine distribution in the United States date: 2022-05-16 journal: nan DOI: 10.1101/2022.05.16.22275134 sha: 7355d3c9081b2ac0b0df2edeb1120f0de7cf5ed2 doc_id: 308500 cord_uid: xqxvfvun Background: Morphine is one of the oldest, most commonly prescribed, and widely used opioids in the United States (US). The potent analgesic properties of morphine have also been associated with the increase in misuse, addiction and opioid-related deaths in the US since the 1990s. Despite federal regulations, population-adjusted prescription opioid distribution varies markedly between states. The objective of this study was to describe the temporal pattern of morphine distribution nationally and between states. Methods: Drug weight and population data were obtained from Report 5 of the US Drug Enforcement Administrations Automation of Reports and Consolidated Orders System (ARCOS) to characterize patterns in the distribution of morphine from 2012 to 2020. 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. Results: Pharmacies and hospitals distributed 24,200 kilograms of morphine in 2012. Tennessee (180.2 mg/person) was 4.7-fold higher than Texas (39.4 mg/person). National distribution decreased 56.4% to 10,723 kilograms in 2020. Tennessee (56.4 mg/person) was 3.8-fold higher than the District of Columbia (15.0 mg/person). The decline in Illinois (-40.9%) was significantly less than the national average (-56.8%) while that of Oregon (-71.1%) and Arizona (-70.4%) were significantly higher. Hospital decrease (-72.7%) from 2012-2020 was larger than that of pharmacies (-56.12%). Conclusions: The national 56% decline in the distribution of morphine in the last decade may be attributable to prioritization of the opioid crisis as a public concern, including subsequent growth of opioid misuse and treatment programs and decreased production quotas for opioids, including morphine. This decline also coincides with the national shortage of parenteral opioids resulting in greater prescriptions of alternative opioids such as nalbuphine and buprenorphine. Further research is necessary to understand the persistent four-fold regional difference between states. Morphine, a potent analgesic commonly prescribed for around-the-clock management of moderate to severe pain, is one of the most commonly abused opioids in the US (1) and, by weight, is the number two prescription opioid worldwide (2) . The wide variety of formulations and strengths enables broad use for acute and chronic pain not only for adults but also for a wide variety of pediatric (age > 2) indications (3) . In contrast, many opioids are only US FDA approved for adults. It is commonly prescribed for many conditions that cause acute and/or chronic pain, most notably in the palliative/end-of-life and postoperative care setting, as well as in the emergency department and cath lab (1) . Adverse effects include increased risk of infections, including COVID-19 and COVID-19-related complications, increased risk of falls and fractures among elderly patients, neonatal opioid withdrawal syndrome, and death (1, 4) . The varied routes of administration (oral, intravenous, epidural, intrathecal, sublingual, nasal) create greater opportunity for misuse. Treating opioid misuse is estimated to cost $78.5 billion each year, comparable to medical costs for asthma and diabetes (5) . Opioid prescriptions increased by 64% between 2004-2011 but, after peaking in 2012, have since declined (6) . Despite an overall national decrease in morphine prescriptions, there was marked variation between states concerning the percent change in population-adjusted opioid distribution since the peak of prescription opioid distribution, including morphine usage, in 2011 (7). Substantial regional disparities have been identified for other opioids and may warrant additional attention including for improvements in opioid stewardship . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 16, 2022. ; https://doi.org/10.1101/2022.05.16.22275134 doi: medRxiv preprint 5 (7, 8, 9, 10, 11). Therefore, our objectives in this study were to: 1) describe national patterns in morphine distribution from 2010-2020 and 2) compare these at a state level. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) All data was collected through the Automation of Reports and Consolidated Orders System (ARCOS). ARCOS is an automated, comprehensive drug reporting system that allows the US Drug Enforcement Administration (DEA) to monitor the flow of controlled substances from the point of manufacture through commercial distribution channels to point of sale or distribution at the dispensing/retail level-hospitals, retail pharmacies, practitioners, mid-level practitioners, and teaching institutions (12). ARCOS tracks controlled substances transactions and monitors the distribution of controlled substances by weight (grams). The total grams per year per state and dispenser/retailer was accessed through the publicly available ARCOS Report 5. ARCOS showed very high correspondence with state Prescription Drug Monitoring Programs and has been widely used in prior pharmacoepidemiology investigations (7, 8, 9, 10, 11). This study was approved by the Institutional Review Boards of Geisinger and the University of New England. The programs GraphPad Prism, Microsoft Excel, and JMP were used to graph and analyze the data. As the weight (g) distributed directly to practitioners, mid-level practitioners, and teaching institutions was negligible, the state-level analysis was only completed on pharmacies and hospitals. We totaled pharmacy and hospital weights of morphine for each year per state and divided them by the population of the state for a population-adjusted calculation for 2012, which was the peak year of total morphine distributed, and 2020. Population information for 2012 and 2020 was obtained from the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 16, 2022. ; https://doi.org/10.1101/2022.05.16.22275134 doi: medRxiv preprint 7 US Census Bureau. Then, the percent change between 2012 and 2020 was calculated for each state using their respective population adjusted weights. The same procedure was repeated for percent changes for hospitals alone and pharmacies alone. States with a percent change outside a 95% confidence interval (mean + 1.96 * Standard Deviation) were considered statistically significant (p < .05). . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 16, 2022. ; https://doi.org/10.1101/2022.05.16.22275134 doi: medRxiv preprint The peak year for total morphine distribution between 2010 and 2020 was 2012 (24.2 metric tons). This decreased by -55.6% in 2020 (10.7 metric tons, Figure 1 ). Pharmacies accounted for the preponderance of morphine prescribed by any business type in 2012 (87.3%) which increased even further in 2020 (92.0%). Hospitals peak for morphine (2010) was earlier than pharmacies (2012). . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The overall reduction in morphine distribution nationally coincides with more aggressive and comprehensive policies and initiatives prioritizing the opioid crisis as a healthcare issue, including the US Department of Health and Human Services' $1 billion fund allocated to states to be used for addiction prevention, treatment, and recovery services, data collection, pain management, overdose reversing drugs such as naloxone, and research (13). Usage of these funds has largely lied within individual state legislation (13). The US DEA decreased quotas after the passage of the SUPPORT Act, which called on the DEA to quantify diversion of prescription opioids and "make appropriate quota reductions" (14). In 2012, the DEA quota for morphine production (for sale) was 48,200 kilograms; this was decreased by 42.4% to 27,784 kilograms in 2020 (15, 16) . Interestingly, this reduction in the overall production quotas of opioids is concurrent with the rise in the production of marijuana (14,17). Indeed, another factor contributing to the decline in morphine prescriptions may be the nationwide shortage of parenteral opioids . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 16, 2022 It did not escape notice that despite pronounced declines in morphine distribution during the past decade, state level variation was both considerable and consistent over time. For comparison, the state-level variation in 2016 for the MME total of eight opioids used for pain was 3.6 fold between Tennessee (932 MME/person) and Washington D.C. (256 MME/person) (7). The difference for individual opioids was 4.3 fold for fentanyl to hospitals, 6.2 for fentanyl to pharmacies (9), but 18-fold for meperidine (8) and almost 20-fold different for buprenorphine (11). We do not believe that there are four-fold biological nociceptive differences between the residents of Tennessee relative to those in an adjacent state (e.g., Kentucky) that receive much less morphine. Future research should continue to explore the provider (22) or patient attitudes (23), insurance company (24) or pharmacy policies (25) that would account for this sizable variation. This might aid in the identification of practices that are incongruent with evidence-based medicine and warrant improved efforts to balance the benefits of morphine (e.g. for acute pain, chronic cancer pain, and palliative care) with the appreciable risks for this Schedule II substance. A strength of this study was that it consolidated both hospital and pharmacy morphine distributions. This controls for potential inconsistencies in defining "hospital" vs. "pharmacy" prescribed opioids, as postoperative morphine prescriptions that are written in a hospital but filled in an outside pharmacy are considered "pharmacydistributed" by ARCOS. The ARCOS data is comprehensive and includes public (Veteran's Affairs) and private health care facilities. A potential limitation of this study is that the drug distribution amounts are listed in weight (grams) rather than number of prescriptions. However, ARCOS showed a very high correlation (r = 0.985) for . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 16, 2022 oxycodone with a state prescription drug monitoring program (12). Also notable was that during the COVID-19 pandemic, prohibitions against sending controlling substances across state lines were relaxed (26) . As the state level differences in 2019 (4.7 fold) and 2020 (3.8 fold) were similar, we believe any impact of telemedicine for this opioid was modest. Finally, this data was limited to the US. The United Nation's International Narcotic Control Board has reported that there are tremendous disparities between countries in prescription opioid use in North America, Western Europe, Australia, relative to all other countries (2) . In conclusion, this study was conducted to observe the national and state-bystate changes in morphine prescriptions by pharmacies and hospitals in the US from 2012, the peak year for opioid distribution, to 2020. Since 2012, morphine prescriptions have decreased in every state, although states with higher morphine distribution in 2012 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 16, 2022. ; https://doi.org/10.1101/2022.05.16.22275134 doi: medRxiv preprint 1 3 were observed to have more pronounced decreases in morphine distribution over the 7year period. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 16, 2022. ; https://doi.org/10.1101/2022.05.16.22275134 doi: medRxiv preprint National Library of Medicine Web site Global, regional, and national consumption of controlled opioids: a cross-sectional study of 214 countries and non-metropolitan territories IBM Watson Health COVID-19 risk and outcomes in patients with substance use disorders: Analyses from electronic health records in the United States National Institute on Drug Declines and regional variation in opioid distribution by U.S. hospitals. Pain 2021-in press International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity DEA proposes to reduce the amount of five opioids manufactured in 2020, marijuana quota for research increases by almost a third Controlled substances: final adjusted aggregate production quotas for 2012 Prescription opioid distribution after the legalization of recreational marijuana in Colorado What parenteral opioids to use in face of shortages of morphine, hydromorphone, and fentanyl Effect of a "pill mill" law on opioid prescribing and utilization: The case of Texas CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity States with prescription drug monitoring mandates saw a reduction in opioids prescribed to Medicaid enrollees Covid-19: DEA confirms public health emergency exception for telemedicine prescribing of controlled substances. 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The copyright holder for this preprint this version posted May 16, 2022. ; https://doi.org/10.1101/2022.05.16.22275134 doi: medRxiv preprint