Pronounced declines in dispensed licit fentanyl, but not fentanyl derivatives
Introduction
The opioid crisis continues to impact healthcare in the United States (US) despite legislation enacted by both the federal and state government, greater scrutiny placed on pharmaceutical companies, and limitations restricting opioid prescribers. Fentanyl, a synthetic μ-receptor agonist, is an important analgesic administered in several formulations including injectable and transdermal patches.1 Fentanyl and its derivatives alfentanil, sufentanil, and remifentanil are most often utilized as intraoperative analgesics and in the management of chronic pain, particularly related to cancer and chemotherapies.1,2 The potency of fentanyl, the diversity of administrative routes, and the low-cost of its production have resulted in it becoming a frequently misused substance.2,3
Since the early 2000s, the opioid crisis has been evolving. The steep increase in drug-related mortality has been linked to two major factors—the over-prescription of opioids and the illegal manufacturing of fentanyl and fentanyl analogues.4, 5, 6, 7, 8, 9 These factors led to an increase in opioid dependence and increased the diversion and misuse of prescribed opioids in the street markets. The extent of this crisis gained national attention when roughly 11 million people were estimated to have misused prescription opioids in 2016.10 The preponderance (84%) of commercially insured patients were prescribed transdermal fentanyl in a fashion that was inconsistent with the package insert.11 One of every thousand (0.1%) persons aged 12 or older misused prescription fentanyl products in the past year in 2019.12
The initial focus of combating this growing epidemic was directed at regulating prescription fentanyl, specifically related to the apparent over-prescribing of opioids. Some of these measures included state legislation limiting the amount of opioids prescribed, utilization of drug monitoring programs, and new prescribing guidelines.10,13,14 Despite some success, fentanyl-related deaths have continued to increase with a larger proportion attributed to illicit fentanyl.
Fentanyl distribution throughout the country has changed according to reports using similar methods to this study and others describing associations between overdose deaths and underlying causative substances.5,7,14, 15, 16, 17, 18 A 3.5-fold regional difference in prescription fentanyl per state was identified between Oregon (1,718 μg/person) and Alaska (418.2 μg/person). An 18% reduction in licit fentanyl distribution was identified in 2016; however, less is known about more recent use or trends over the last decade.14 Between 2011 and 2017, states in the Northeastern US experienced an increase in fentanyl-related overdoses and increased seizures of diverted substances.5,7,16 New England states reported that 60–90% of overdose deaths were attributed to fentanyl (i.e. prescribed and illicit).5,7 In contrast, states west of the Mississippi River reached a plateau in fentanyl deaths during that same period.16 States like Ohio, West Virginia, and Wisconsin reported that only 30–55% of deaths were associated with fentanyl.5,7 Despite these apparent trends, the distribution of fentanyl across the US was very variable.16
The objective of this paper was to explore the trends in prescription fentanyl and select fentanyl derivatives distribution throughout the US over the last decade (2010–2019). It also examines prescriber practices for fentanyl formulations in Medicare during the same period. Identification of regional differences in pharmacoepidemiological patterns could be valuable in identifying variability in fentanyl use which could form the basis for corrective efforts to minimize population level harms.
Section snippets
Procedures
Distribution of fentanyl base and select fentanyl derivatives in the US were obtained from the Drug Enforcement Administration's (DEA) Automated Reports and Consolidated Ordering System (ARCOS) from 2010 to 2019. As a result of the 1970 Controlled Substance Act, this program mandates that the federal government track the distribution of controlled substances in grams by pharmacies, hospitals, providers, and treatment programs. The hospital business activity includes inpatient procedures (e.g.,
Results
From 2010 to 2019, the amount of fentanyl distributed declined from 1,689.9 μg/person to 583.9 μg/person, which was a −65.5% overall decrease across the US (Fig. 1). Further examination was completed by business activity looking at distribution to both hospitals and retail pharmacies. Hospitals showed a −63.4% decrease which was similar (−64.5%) among pharmacies (S Fig. 1).
The heat map shows that all states had a reduced utilization of prescription fentanyl with the greatest overall decrease in
Discussion
Fentanyl base experienced a pronounced and consistent year-over-year decline in distribution throughout the US over the last decade (2010–2019) according to the DEA's ARCOS. This 65.5% decrease is congruent with and extends upon past research which found that the US reduction in fentanyl was significantly greater than that of hydrocodone, morphine, or oxycodone.16 This decline was likely the result of efforts directed at one aspect of the opioid crisis. The over-prescribing of opioids including
Limitations
While this manuscript employed three complementary databases, no study is without limitations. While ARCOS is comprehensive and Medicaid and Medicare cover important segments of the population, other data sources can also target private insurance fentanyl prescriptions.11 A concern with ARCOS is reporting by drug weight instead of more standard units like prescriptions as Medicaid does. However, there was an excellent concordance (r = 0.985) between ARCOS and a state prescription drug
Conclusions
Despite the progress, the opioid crisis continues to amass an escalating death count.39 The majority of these deaths are attributed to the illegal drug trades. Persons with substance abuse disorder want to avoid fentanyl, but the illegal industry utilizes fentanyl in so many ways that it is hidden even to the most seasoned user.43 Most of the successful efforts to mitigate the crisis have targeted the legal production of fentanyl. Although we are cautiously optimistic that gradual reductions
Author statement
Raymond A. Stemrich & Jordan V. Weber: Conceptualization, Investigation, Writing - Original Draft, Writing - Review & Editing.
Kenneth L. McCall: Resources, Writing - Review & Editing.
Brian J. Piper: Conceptualization, Investigation, Resources, Writing - Review & Editing.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Software used in this research was provided by the National Institute of Environmental Health Sciences (T32ES007060-31A1).
Declaration of competing interest
BJP is part of an osteoarthritis research team supported by Pfizer and Eli Lilly. He receives research support from the Health Research Services Administration (D34HP31025). The other authors have no conflicts of interest to declare.
Acknowledgement
Thanks to Iris Johnston for technical assistance.
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