key: cord-0744756-7ao8585q
authors: Weedn, Victor W.; Elizabeth Zaney, Mary; McCord, Bruce; Lurie, Ira; Baker, Andrew
title: Fentanyl‐related substance scheduling as an effective drug control strategy
date: 2021-05-05
journal: J Forensic Sci
DOI: 10.1111/1556-4029.14712
sha: 3d4402a22c967f4e56b4d72572d391645d2825b9
doc_id: 744756
cord_uid: 7ao8585q

Fentanyl is now the primary driver of the current opioid crisis. Fentanyl and its analogues are subject to the Controlled Substances Act of 1970, the Controlled Substances Analogue Enforcement Act of 1986 (Federal Analogue Act), state laws, international treaties, and the laws of foreign countries. The appearance of novel psychoactive substances led to further legislative developments in scheduling. New fentanyl analogues proliferated in a manner previously unseen since about 2016. Overdose deaths of these fentanyl analogues prompted the Drug Enforcement Administration to reactively emergency schedule each new fentanyl analogue as it appeared. The international community also acted. Finally, on February 6, 2018, a proactive temporary (emergency) class‐wide scheduling of fentanyl‐related substances was implemented based upon the fentanyl core structure to save lives. This action spurred a similar action in China. Fentanyl analogues fell dramatically in the marketplace, despite further increases in fentanyl itself. Congress temporarily extended this scheduling, but it will soon expire. Opposition to permanent class‐wide was lodged due to concerns over law enforcement overreach, inadequate Health and Human Services input, and hindrance of research. This paper reaffirms the importance of a class‐based scheduling strategy while also arguing for increased research of schedule I controlled substances.

The misuse and abuse of opiates continues to be a major crisis in America, and fentanyl is the primary driver [1] . Approximately 80% of overdose deaths involved opioids, and three quarters of these opioid overdose deaths involved illicitly manufactured fentanyls [2] .

The current crisis began two to three decades ago with an increase of prescription opioid abuse. An increase in opioid-dependent individuals and the subsequent demand for pharmaceutical opioids fueled a second wave of the opioid epidemic: a transition to heroin abuse. Illicit drug suppliers successfully exploited this demand by supplying inexpensive and higher purity heroin to the opioiddependent population. A third wave of the opioid epidemic began in 2012-2013 with the re-introduction of synthetic opioids, particularly illicitly manufactured fentanyl [3, 4] . Fentanyl and fentanyl analogues, distributed in pure powder form, in powder mixtures, and as counterfeit pills, began to supplant heroin use in certain regions of the country around 2015 [5, 6] . By 2017, fentanyl and fentanyl analogues caused over 20,000 overdose deaths in the United States, accounting for half of all opioid-related deaths and eclipsing all other overdose deaths [7] .

Despite the rise of the coronavirus pandemic, drug overdose deaths have continued to increase, following a slight decrease in 2018 [8] . In the first half of 2020, the Miami-Dade County Medical Examiner Department saw a 59% increase in the number of cases with illicitly manufactured fentanyls present compared to the first half of 2019. Fentanyl seizures were also up 59% in New York in 2020 [9] . Unfortunately, there is reason to believe that the number of overdoses may continue to escalate [10] .

Fentanyl [11] [12] [13] [14] , a schedule II substance under the CSA (21 U.S.C. § 812 Schedule II (b)(6)), has been illegally imported and has caused extensive mortality in the United States. In spite of this fact, it has a history of legitimate development and medical application. In 1953, Dr. Paul Janssen founded Janssen Pharmaceutica in Belgium [15] . Dr. Janssen recognized that the six member ring with a tertiary amine structure common to both morphine and meperidine was likely responsible for their analgesic properties. He also believed that greater lipid solubility would enhance the potency of a new drug.

Janssen produced dozens of phenoperidine derivatives in the 1950s and then fentanyl in 1959. Janssen considered fentanyl to be useful only as an intravenous analgesic because the compound was rapidly destroyed after oral administration. Fentanyl was first used as intravenous analgesic in Europe in 1963 and in the United States in 1968.

United States under the tradename Sublimaze for anesthesia [16] . Fentanyl is a narcotic opioid that has legitimate medical uses for anesthesia and analgesia, but was recognized from the outset as having a high potential for abuse. Fentanyl is a μ-opioid receptor agonist that produces euphoric effects and can serve as a direct pharmacological substitute for heroin in opioid-dependent individuals.

Like other narcotic opioids, fentanyl may cause profound and dangerous respiratory and central nervous depression, as well as miosis and constipation. Fentanyl is approximately 50-100 times more potent than morphine and 30-50 times more potent than heroin. The potency of fentanyl and of many fentanyl analogues causes extreme respiratory depression upon ingestion. It can produce immediate death in many circumstances, and in many cases, overdose victims require multiple administrations of the reversal agent naloxone following application.

The misuse and abuse of fentanyl citrate dates back to the 1980s. Fentanyl abuse was initially a result of diversion from the regulated, closed system of distribution tracked by the DEA. Abuse of transdermal patches began shortly after their introduction in the 1990s. While non-medical use of fentanyl transdermal patches often caused death when abused, the relative lack of availability of diverted transdermal patches and fentanyl substances limited the usage and attendant mortality.

Although an opioid narcotic, fentanyl is not derived from opium, but is instead chemically synthesized in the laboratory. The original Janssen method of production, patented in 1964 (U.S. Patent US3141823A), is a process that uses N-benzyl piperidone as a starting material. An alternative synthetic method, commonly referred to as the Siegfried method, was published [17, 18] and later shared on the internet. This method uses N-phenethyl-4-piperidone (NPP) and 4-anilino-N-phenethylpiperidine (4-ANPP) as key precursors and was used in clandestine laboratories to illicitly synthesize fentanyl in the early 2000s.

The U.S. federal government was not involved with drug enforcement until the 20th Century. [ [20] [21] [22] . The act begins with the acknowledgment that "Many of the drugs included within this title have a useful and legitimate medical purpose and are necessary to maintain the health and general welfare of the American people." The CSA establishes a closed system of distribution for controlled substances in the sense that the distribution is restricted and can be tracked from source to user-everyone who handles controlled substances must be registered, assigned a unique DEA number, and must maintain complete and accurate inventories and records of transactions [23] .

The CSA establishes a five-tier schedule of drugs, based upon an eight-factor analysis: 1. Its actual or relative potential for abuse.

2. Scientific evidence of its pharmacological effect, if known. 3 . The state of current scientific knowledge regarding the drug or other substance. 4 . Its history and current pattern of abuse. 5. The scope, duration, and significance of abuse. 6 . What, if any, risk there is to the public health. 7. Its psychic or physiological dependence liability. 8 . Whether the substance is an immediate precursor of a substance already controlled under this subchapter.

Schedule I drugs have no accepted medical use as determined by the U.S. FDA, a high potential for abuse, and cannot be safely prescribed, but other scheduled drugs may be prescribed by an appropriate medical provider and dispensed by a pharmacist. Changes to the drug scheduling can be initiated by the DEA, the FDA, or by petition and executed by the DEA in consultation with the FDA.

Immediate precursors to an already scheduled drug can also be placed on the same schedule or higher schedule. The DEA implements and enforces the CSA.

The CSA ( § 802(14)) defines "controlled substance" as, "a drug or other substance, or immediate precursor, included in schedule I, II, III, IV, or V of part B of this subchapter. The term does not include distilled spirits, wine, malt beverages, or tobacco, as those terms are defined or used in subtitle E of the Internal Revenue Code of 1986."

It seems apparent that when the CSA was originally promulgated, the drafters had individual drugs in mind, rather than entire classes of drugs, but did include language for derivatives of schedules I, II, and III. Specifically, § 812(c)(a) listed an initial 42 substances as schedule I and stated, "Unless specifically excepted or unless listed in another schedule, any of the following opiates, including their isomers, esters, ethers, salts, and salts of isomers, esters, and ethers, whenever the existence of such isomers, esters, ethers, and salts is possible within the specific chemical designation." Congress has since modified the schedules to include classes and groups of substances, anabolic steroids, and synthetic cannabinoids, respectively.

Fentanyl is a schedule II substance because it has a high potential for abuse, has a currently accepted medical use in treatment in the United States, and abuse of the drug or other substances may lead to severe psychological or physical dependence. The 

Section "d" of the CSA acknowledges the additional ability to schedule drugs based upon international treaties, conventions, and protocols. In fact, the CSA was promulgated in large part to fulfill treaty obligations. Currently, three major international drug control treaties are in force [24] [25] [26] [27] . The U.S. Secretary of State is to notify the U.S. Attorney General of international scheduling efforts for federal scheduling consideration.

The Single Convention on Narcotic Drugs of 1961 [28, 29] was promulgated to consolidate, replace, and update nine predecessor treaties. Earlier treaties that dealt with opium, coca, and derivatives such as morphine, heroin, and cocaine; the Single Convention also included new synthetic opioids and cannabis. Moreover, the Single Convention established a mechanism to schedule drugs apart from including specific drugs in treaties, thus allowing a more responsive and uniform listing. Scheduling responsibility was given to the 

There are two types of drug analogues. A chemical analogue has a similar structure to that of another compound, while a functional analogue is a compound with a very different structure yet has similar physical, biochemical, or pharmacological properties [34] . A chemical derivative is a modification of a drug's chemical structure.

Positional isomers are molecules composed of the same atomic elements (compounds with the same molecular formula but variations in the position of structural elements), and stereoisomers are two chemicals with the same structural elements but with differences in orientation (similar to your left and right hands). The definitions of the CSA ( § 802 (14)) define "isomer" as "the optical isomer, except as used in schedule I(c) and schedule II(a) (4) . As used in schedule I(c), the term "isomer" means any optical, positional, or geometric isomer.

In schedule II(a)(4), the term "isomer" means any optical or geometric isomer."

The CSA ( § 802) gives a legal definition for "controlled substance analogue" as "a substance-(i) the chemical structure of which is substantially similar to the chemical structure of a controlled substance in schedule I or II; (ii) which has a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in schedule I or II; or (iii) with respect to a particular person, which such person represents or intends to have a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in schedule I or II. …".

Not long after the development of fentanyl, other prescription fentanyl analogues became available, such as carfentanil, sufentanil, and thiafentanil. As part of the FDA drug approval process, they were scheduled and made available for medical use. Other fentanyl analogues have no currently recognized medical use. Collectively they are called fentanyl-related substances (FRS). Kemp Chester noted that the U.S. Department of Homeland Security has estimated that there are about 3,024 potential fentanyl derivatives that might be synthesized [35] .

A chemical analogue is technically a different chemical than the controlled substance that it resembles; hence, regulations specific to that substance may not apply to its analogues. Thus, a non-pharmaceutical manufacturer can design and legally produce a chemical analogue of a controlled substance, despite a similar structure and pharmacologic function. This is done precisely to evade traditional chemical-specific regulations. The term "designer drug" was coined in 1984 and popularly applied to such chemical analogues, but the preferred technical term is a "novel psychoactive substance" (NPS) [36, 37] .

Beginning in 1979, deaths began to occur in Orange County, California from "China White," that was eventually determined to be alpha-methylfentanyl, a simple chemical analogue of fentanyl and twice as potent as fentanyl [38, 39] . Because the analogue was not the CSA to, among other things, create a mechanism for temporary control of a substance as schedule I "to avoid an imminent hazard to public safety" (21 U.S.C. § 811 (h)). Thus, the Attorney General was given the emergency authority to ban an uncontrolled substance with no accepted medical use that was being abused and was a risk to public health while formal scheduling procedures were conducted. This temporary scheduling was considered an interim measure while further information on the eight-factor analysis was gathered by the FDA for permanent scheduling. Originally, this temporary scheduling lasted for one year with a possible extension of up to six months, but these times were doubled in 2012 allowing for a maximum period of three years.

Temporary scheduling of synthetic drugs has been and continues to be a key tool in combating new synthetic drugs as they emerge and interdicting these substances at ports of entry [40] . When NPSs appear and medical examiner and coroner offices report overdose deaths, this information can then be used as the finding of the "imminent hazard to public safety" for the emergency declaration. The 

Meanwhile, in response to the highly publicized development of Parkinson's disease caused by an impurity during the intentional synthesis of a non-fentanyl morphine analogue [43] , the U.S. Congress passed the Controlled Substances Analogue Act of 1986 (The Federal Analogue Act, P.L. 99-570), which amended the CSA (21 U.S.C. § 813) to prohibit innovative drugs that are not yet listed as controlled substances [44, 45] . The Federal Analogue Act provides that if a jury finds that a drug that is "substantially similar" to a controlled substance listed in schedule I or II, a "controlled substance analogue," is to be treated as a schedule I substance, if intended for human consumption. Exempted from treatment under the analogue provision is substances subject to an Investigational New Drug Approval. Since such analogues are not developed for medicinal purposes, they are not controlled, but instead outlawed as schedule I substances.

Specifically:

A controlled substance analogue shall, to the extent intended for human consumption, be treated, for the purposes of any Federal law as a controlled substance in schedule I. The reading of these two cases suggests that the statute must be tested on a case-by-case basis to determine whether substantial similarity can be determined or not. Moreover, these cases clearly illustrate the difficulty in trying to prosecute cases under the Federal Analogue Act. Although fentanyl analogues for the most part share a common chemical structural backbone, whether their structure is substantially similar, under the analogue law, is often debated by subject matter experts in a court of law. Studies to determine whether each of these analogues has a similar or greater stimulant, depressant, or hallucinogenic effect on the central nervous system rarely exist, nor are they required, creating the need for experts to provide and justify their opinions in court.

The first synthetic cannabinoids ("spice" and "K2") were reported in 2008 and 2009, but an expanding array of other synthetic cannabinoids followed. Synthetic cathinones ("bath salts") began to appear as well. The Office of National Drug Policy (ONDCP) recognized these compounds as the new synthetic drug threat, but did not include any fentanyl analogues [46] . Prior to 2010, synthetic can- A constantly evolving list of fentanyl analogues began to appear, such as acetyl fentanyl, furanyl fentanyl, and cyclopropyl fentanyl, as well as other novel synthetic opioids, such as U-47700 [49] [50] [51] .

For a period of time, novel drugs would appear at a rate of approximately one every two weeks. As new unscheduled fentanyl analogues appeared on the market, deaths would follow [52, 53] .

Standard toxicology testing such as gas chromatography mass spectrometry (GC-MS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) targets certain known drugs and will miss novel substances. Detection and identification of novel compounds are aided by non-targeted testing with newer instrumentation (high-resolution time-of-flight mass spectrometry (HR-TOF-MS) that is unavailable in many laboratories. Thus, particularly early on, these fentanyl analogues were underreported [54] . (Table 1 ) [58] . 

The DEA issued a press release November 9, 2017, indicating that they intended to take immediate action to emergency schedule all fentanyl analogues based upon core structure of the chemical derivative so that it would no longer be necessary to wait to see if the analogue would cause deaths [65] . Prior to this announcement, the DEA had consulted with the Department of Health and Human Services (HHS), which responded that they had no objection, although they did not produce an eight-factor analysis as a class [66] . This proactive proposal was formally announced in the Federal Register on December 29, 2017 [67] .

A question arose as to whether the CSA permitted class scheduling because it spoke in the singular terms "controlled substance" and "ana- Despite this class scheduling effort, the DEA continues to individually schedule FRS during the period of temporary class control.

Core structure scheduling has been adopted by several states and by

China, forbidding the manufacture of fentanyl analogues. In 2018, the appearance of new fentanyl analogues died away. Thus, this scheduling effort has been highly effective.

The 2018 amendments to the U.S. Sentencing Commission guidelines define "fentanyl analogue" as "any substance (including any salt, isomer, or salt of isomer thereof), whether a controlled substance or not, that has a chemical structure that is similar to fentanyl (N-phenyl-N-[1-(2-phenylethyl)-4-piperidyl] propanamide)"

[70]. The Sentencing Commission declares that because the CSA defines "analogue," the sentencing guidelines definition may exclude scheduled substances for fentanyl analogues. Gerbasi notes that this "clarification is particularly important given the DEA's temporary scheduling of fentanyl related substances" [71] .

The DEA's temporary class-wide scheduling was a catalyst to international counterparts elsewhere. On April 1, 2019, China announced the class-wide control of fentanyl-related substances, effective May 1, 2019 [72] . Temporary core structure scheduling coupled with the Chinese scheduling action directly resulted in a substantial drop in Chinese-origin FRS encountered in the United States by 2019 [73] . The downturn in FRS is reflected in the NFLIS ( Figure 6 ) and medical examiner data (Tables 2 and 3 ). Thus, the federal government has attempted to move from reactive individual substance scheduling to some type of proactive class scheduling [74] .

Congress could modify the Federal Analogue Act to drop the functional similarity requirement, such that a drug need only be chemically similar. Such would still beg the question of how to determine "substantial similarity." Such structural similarity could be quantitatively determined using a computational medicinal scoring metric, such as the Tanimoto coefficient (Tc), and a threshold set in legislation [75] [76] [77] [78] . This approach would be similar to Canada's control of fentanyl derivatives. Instead of looking to the overall chemical similarity, scheduling could focus on chemical similarity to the structural portion or portions of the molecule responsible for the pharmacological effect of the molecule. This is the so-called pharmacophore moiety. The pharmacophore and its derivatives could be chemically defined, or computational methods could score the similarity to the parent drug [79] . In 2014, Ohio enacted legislation applying the "Pharmacophore Rule" to synthetic cathinones, cannabinoids, and opioids. The pharmacophore for fentanyl-related agents is a five-, six-, or seven-membered ring containing a nitrogen, with a polar group and an aryl or aryl substitution attached to the ring for binding to the μ-opioid receptor.

Alternatively, the Federal Analogue Act could emphasize functional similarity based upon biomedical studies. However, studies of pharmacologic effects on human beings cannot always be ethically conducted. Unlike a drug trafficker, the safety of a substance must first be investigated prior to feeding to humans. Congress should require any substance intended for human consumption, first be approved by the FDA for safety. Nonetheless, in vitro binding studies and functional assays of cell cultures or animals might be conducted [80] [81] [82] [83] . These policies may also consider the neurobiology of drug use and dependence.

The fentanyl core structure scheduling was set to expire as of positive impact on the application process [86] .

Several letters were written against the proposed permanency of FRS class scheduling, including from the Human Rights Watch coalition [87] , the College of Problems of Drug Dependence (CPDD), the Friends of NIDA, and the American Psychological Association [88] .

They argued that class-wide scheduling provides for overly broad DEA powers, perpetuates a failed "war on drugs," and will result in harsher penalties. They claimed that such scheduling precludes input from HHS. The Human Rights Watch letter pointed to Congressman Charlie Dent (R-PA)'s 2015 introduction of a bill to schedule more than 300 synthetic fentanyl analogues as schedule I, but was ultimately reduced to 22 substances "after scientists could reach agreement that this small subset met schedule I's criteria." Critics also argued that class-wide scheduling will limit biomedical research, may adversely affect public health, and could dissuade young investigators from potentially promising research pathways.

A second hearing entitled "Fentanyl Analogues: Perspectives [94] .

Congress tasked the Government Accountability Office (GAO), but not National Institute on Drug Abuse (NIDA) or FDA, to report on the effectiveness and ramifications of the temporary class control of FRS;

this report was not publicly available as this article was written.

It is significant that during the temporary scheduling and during the Congressional deliberations that the pharmaceutical industry did not express concern that the scheduling prevented the development of new medicines. As noted by registered researchers, no pharmaceutical companies are currently conducting studies on FRS per the registration requirement discussed below. The majority of researchers are registered in detection method development and are DEA contractors studying the pharmacological effects of FRS to inform policy decision and drug strategies.

The most specific criticism of class-wide fentanyl scheduling is that it will inhibit research on FRS. Research on fentanyl analogues is useful to understand their physiologic and pharmacologic effects, but moreover in attempts to find treatments. Such research may allow Research on schedule I substances is not precluded-as is sometimes falsely believed. The CSA does contain language that authorizes pre-clinical and clinical research-including schedule I substances.

Schedule I substance research is conducted on a substance-bysubstance basis under schedule I research registration, which has been seen as burdensome and inhibitory [95, 96] . Thus, claims that class scheduling will hinder research may have some merit, but this must be balanced against the number of deaths. Recent efforts have been made to facilitate such research [97, 98] . Dr. Sandra Comer in her testimony at the second hearing made specific suggestions for further relief [99] .

Critics of the extension of fentanyl core structure scheduling have suggested that scheduling as schedule II, rather than schedule I, would allow clinical research but still permit significant control. This is not plausible, for a substance to be placed under schedule II, it must have an approved medical use. Moreover, lesser control would certainly eventuate in more overdose deaths. Even under a classwide scheduling regime, individual substances may be removed or moved to a different schedule upon the recommendation from HHS or upon approval for medical use by U.S. FDA.

The temporary reauthorization act did seem to recognize that the legislation might contain language to facilitate research on FRS when they tasked GAO to: 

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