William S. Jacobs, MD Chief of Addiction Medicine Medical College of Georgia Medical Director Bluff Plantation and Synthetic Thursday, April 6, 2017 9:15 am – 9:40 am Disclosure Information

William S. Jacobs, MD No disclosures

The 2006 crisis in the United States was the result of fentanyl being mixed into heroin and distributed to unsuspecting heroin users. The 2006 fentanyl crisis was fueled by a single clandestine laboratory in Toluca, Mexico, and once the laboratory was seized, the seizures of fentanyl and overdose deaths in the United States suddenly tapered off. During the current fentanyl crisis (2013-present), traffickers have not only used similar historical production and distribution techniques, but have also expanded the fentanyl market by producing wholesale quantities of counterfeit prescription medications containing various .

The current fentanyl crisis is fueled by China-sourced fentanyls and fentanyl precursor chemicals that are being sold to various individuals and organizations responsible for fentanyl processing and distribution operations; this scenario includes individuals linked to Mexican cartels and other criminal organizations that are not affiliated with Mexican cartels. The seizures of fentanyl-laced pills and clandestine pill press operations all across North America indicate that this is becoming a trend, not a series of isolated incidents. Source: Wikipedia https://ndews.umd.edu/sites/ndews. umd.edu/files/u1486/dea_emerging _threat_report_2016_quarter_4.pdf

https://www.dea.gov/docs/Counterfeit%20Prescription%20Pills.pdf

May 2015 - Chinese Customs officials seized 46 kilograms of fentanyl and 26 kilograms of acetyl fentanyl hidden in a cargo container destined for Mexico. Six customs officials became ill and one fell into a coma as a result of handling the fentanyls. The fentanyls had been transferred through five different freight forwarders before arriving

Figure 11: Synthetic Drug Factory in China. at customs.  An unrelated synthetic first made at Upjohn in the 1970s called U-47,700 was placed on Schedule I earlier this month. U-47,700 was found together with fentanyl in the blood of the musician, Prince Rogers Nelson, when he was found dead at his Minnesota home and studio. Buried within a 1978 patent, U-47,700 exemplifies the extent to which recreational drug users will scour the peer-reviewed and patent literature for research chemicals with opioid effects but which were not, at the time, illegal. https://www.forbes.com/sites/davidkroll/2016/11/30/furanyl-fentanyl-joins-u-47700-as-the-second-illicit-opioid- dea-banned-in-november/#2a258eb09ba3

 http://www.mdedge.com/emed-journal/article/130514/pain/new- opioid-epidemic-prescriptions-synthetics-and-street-drugs  May require up to 10mg for reversal follwed by naloxone infusion to prevent renarcotization DEA Temporarily Bans Synthetic Opioid U-47700 ("Pink"), Linked to Nearly 50 Deaths Posted on November 15, 2016 The U.S. Drug Enforcement Administration (DEA) has temporarily classified U-47700, nicknamed "Pink," a schedule I drug, which means it has a high potential for abuse and no approved medical use. Since last year, this dangerous synthetic opioid has been linked with at least 46 confirmed deaths—31 in New York and 10 in North Carolina. Law enforcement agencies have seized the drug in powder form and as counterfeit tablets that mimic pharmaceutical opioids. Earlier this year, law enforcement in Ohio seized 500 pills resembling a manufacturer's immediate-release tablets. However, laboratory analysis confirmed that they contained Pink. Pink belongs to a family of deadly synthetic opioids far more potent than . It is usually imported to the United States, mainly from illicit labs in China. The drug can be toxic—even in small doses. It is typically taken by itself or combined with other drugs such as heroin and fentanyl.

Pink's name comes from the pinkish hue of the powder. It has been available for purchase over the internet and is misleadingly marketed as a "research chemical." Labels that state "not for human consumption" or "for research purposes only" are likely used in an effort to avoid legal restriction. AH-7921 was originally created in the 1970s by Allen and Hanburys Ltd. in an attempt to develop an medicine, however, further production ceased due to its apparent addictive qualities. This compound has never been sold commercially or reputably as a medicine, nor as a substance with pharmaceutical, medicinal, or industrial applications, as reported by an article on AH-7921, originally published by Forensic Toxicology, and backed up by WHO However, as this source continues, at the time of publication (February 2015), this chemical was legitimately sold for research, as an “analytical reference standard.” https://www.drugtimes.org/designer- drugs/fentanyl-and-its-analogues.html Two simple modifications—the addition of one methyl group and one hydroxyl group (blue circles)— makes the molecule 6.3 times more potent than carfentanyl, 126-times more so than fentanyl, and 6,300 times more than morphine. This is just nuts. Doing the math (5), the estimated lethal dose of ohmefentanyl is 0.16 micrograms, which means that one poppy seed's worth (300 micrograms) of ohmefentanyl is enough to kill 1900 people. Another way of looking at it is even scarier: One ounce of the stuff (28 grams, 28,000,000 micrograms) would be enough to kill 175 million people—half the population of the United States (7).

 Emerging Synthetic Fentanyl Analogs  Author(s): Schueler Harold E.  Citation: Acad Forensic Pathol. 2017 Mar; 7(1):36-40.  Abstract:Hundreds of synthetic substances have been introduced into the illicit drug market over the last ten years, but none of these drugs has had as poisonous a consequence as the emergence of the synthetic fentanyl analogs. Initially, pharmaceutical grade or illicit fentanyl was mixed with heroin, allegedly to boost the potency of the heroin. Then, the amounts of fentanyl spiked gradually increased until the proportion of fentanyl was greater than the proportion of heroin. Ultimately, many overdose cases began consisting of only fentanyl. The emergence of numerous synthetic fentanyl analogs, including , butyrylfentanyl, , and β-hydroxythiofentanyl, which are manufactured in China, were made available to the illicit drug traffickers over the Internet. [continued next slide] https://doi.org/10.23907/2017.004  Abstract, continued: In July of 2016, the most potent commercially available opioid, , started appearing in illicit drug submissions and medical examiner death investigation cases in Northeast Ohio. Postmortem femoral blood carfentanil concentrations are in the picogram per milliliter (pg/mL) range, which is extremely low, and tests the limits of detection for most analytical forensic toxicology laboratories. The interpretation of these low carfentanil blood concentrations in antemortem and postmortem specimens is made difficult due to the overlap in the concentrations between these specimen types. The presence of these powerful synthetic fentanyl analogs presents a challenge to forensic toxicology laboratories preparing to analyze for these substances.

https://doi.org/10.23907/2017.004

 Street fentanyl can be taken orally, smoked, snorted, or injected  Street fentanyl has been sold as:  Pills  Blotters  Patches – cut up and sold as “chicklets”  Powder  Other forms may resemble ‘popcorn’ or ‘nerds’ candy  All have the potential to be lethal!  Fentanyl is often added to other drugs without the user’s knowledge.  Traces have been found in other drugs including cocaine, Xanax, MDMA, methamphetamine & possibly marijuana.  Fentanyl is sometimes sold as heroin, often leading to overdoses.  Organized crime groups press the powder form into fake OxyContin tablets (“greenies”).

Real Xanax Fake Xanax Fentanyl and a Novel Synthetic Opioid U-47700 Masquerading as Street “Norco” in Central California: A Case Report Alexander Olson, MS, Andres Anaya, MD, Alicia Kurtz, MD, Rawnica Ruegner, MD, Roy R. Gerona, PhD DOI: http://dx.doi.org/10.1016/j.annemergmed.2016.06.014 | In 2013 and 2014, more than 700 deaths were attributed to fentanyl and fentanyl analogues in the United States. Of recent concern is the cluster of unintentional fentanyl overdoses because of tablets thought to be “Norco” purchased on the street in Northern California. U-47700 (trans-3,4-dichloro-N- [2-(dimethyl-amino)cyclohexyl]-N-methylbenz-amide) is a nonfentanyl-based synthetic opioid with 7.5 times the binding affinity of morphine to μ-opioid. We report a case of fentanyl and U-47700 intoxication from what was thought to be illicitly purchased Norco. [continued next slide] A 41-year-old woman presented to the emergency department (ED) for altered mental status shortly after ingesting 3 beige Norco pills bearing a Watson imprint. She had pinpoint pupils and respiratory depression, which reversed after 0.4 mg naloxone administration intravenously. She had complete recovery and was discharged from the ED after a 4-hour observation period. Serum testing with liquid chromatography–quadrupole time-of-flight mass spectrometry (LC 1260 QTOF/MS 6550; Agilent, Santa Clara, CA) confirmed the presence of the medications the patient reported receiving, and additionally fentanyl (15.2 ng/mL) and U-47700 (7.6 ng/mL). In this case report, street Norco purchased in Central California resulted in altered mental status requiring naloxone reversal because of fentanyl and the novel synthetic opioid U-47700. [continued next slide] Because these compounds are not detected by routine urine drug testing and physical examination findings are similar to those of a traditional opioid toxidrome, emergency providers should use the patient’s history and other circumstantial details to aid in diagnosis. In cases with suspicion of opioid or opioid analogue cause, we recommend that emergency providers contact their local poison control center, medical toxicologist, or public health department to aid in the investigation.  Fentanyl is a powerful and dangerous drug – carfentanil is about 100 times more toxic than fentanyl.  Carfentanil was never intended for use in humans.  Its most common use is to tranquilize very large animals in veterinary practice.  It is known as the “elephant tranquilizer.” Carfentanil blotter tabs June 27, 2016, members of the RCMP go through a decontamination procedure in Vancouver after intercepting a package containing approximately one kilogram of the powerful opioid carfentanil imported

As little as 10 mg carfentanil would be needed to sedate – or even kill – an elephant A deadly dose of carfentanil may be as small as 20 micrograms (0.02 mg)

A single snowflake weighs about 30 micrograms One million doses of fentanyl would fit in a shoebox.

One million doses of carfentanil would fit in a golf ball. 1982: Invented by three chemists at the University of Alberta in Edmonton. It’s one of W-18 is one of 32 compounds, W- 1 to W-32, with W-18 being the most toxic. A US patent is granted in 1984  August 2015: Calgary police seize 110 Fentanyl pills from a home in southern Alberta. Health Canada confirms three pills contain W-18.  January 2016: Sweden makes the chemical substance illegal.  March 2016: A Florida man is sentenced for smuggling fentanyl into the states. Federal prosecutors confirm that DEA agents also found around 2.5 pounds of W-18 powder in the man’s possession. Investigators testify the drugs came from China via an inmate named Daniel Ceron serving time in a Montreal prison. Six months earlier in July of 2015, Ceron arrested in Panama and accused of running a drug operation in the United States while locked up in prison.  April 2016: The Alberta Law Enforcement Response Team (ALERT) confirms a seizure of 4 kilograms of an unknown substance during a fentanyl investigation in Edmonton in December 2015, is confirmed by Health Canada to be W-18.  May 2016: RCMP seize counterfeit oxycodone and percocet tablets during a drug bust in West Kelowna. Testing confirms the tablets contain W-18.  June 1st, 2016: Government of Canada announces W-18 has been added to Schedule 1 of the Controlled Drugs and Substances Act, making production, possession, importation, exportation or trafficking of W-18 illegal.  June 7th, 2016: Delta Police confirm that drugs seized in a bust on a suspected drug lab in Burnaby tests positive for W-18. Drug investigators suspect the W-18 was being manufactured to appear like heroin or oxycodone before being sold at the street level. They warn recreational drug users to “know your source”. http://news.ubc.ca/2017/02/27/w-18-new-fentanyl-analogue-confirmed-in-surrey-and-victoria-street-drugs/ Adolphe Joseph, 34, is serving a 10-year prison sentence for smuggling fentanyl – an opiate 50 to 100 times more powerful than morphine. But he has not been charged for the nearly three pounds of a synthetic opiate more than 10,000 times as powerful as morphine investigators found in his South Florida home last Fall. Nor will he be, say prosecutors.

Though U-47700 has not been specifically criminalized in the US, prosecutors can still file charges under the Controlled Substance Analogue Act if the compound is “substantially similar” to a controlled substance. Still, even if the prosecutor has a strong case, these arguments can be difficult to make to a jury. “It’s very difficult to get jurors to understand the complex science behind that,” said Hall. When Broward prosecutor Anita White was charging Joseph, she found that W-18 was too chemically different from any other controlled substance to make a case at all. Ottawa Sun March 4, 2017

 DEA Schedules Deadly Synthetic Drug U-47700  46 confirmed deaths linked to dangerous opioid in ’15 and ’16 spark emergency action  NOV 10 (WASHINGTON) – Responding to the imminent threat to public health and safety, the U.S. Drug Enforcement Administration (DEA) has placed U-47700 into Schedule I of the Controlled Substances Act, effective on November 14th. Emergency scheduling of dangerous drugs such as U-47700 on a temporary basis is one of the most significant tools DEA can utilize to address the problems associated with deadly new street drugs.  DEA received reports of at least 46 confirmed fatalities associated with U-47700 31 of those fatalities occurred in New York and 10 in North Carolina. From October 2015 to September 2016, DEA received 88 reports from State and local forensic laboratories of U-47700 submissions.  This scheduling action will last for 24 months, with a possible 12-month extension if DEA needs more data to determine whether it should be permanently scheduled. [continued next slide]  U-47700 is a novel synthetic opioid, and its abuse parallels that of heroin, prescription opioids, and other novel opioids. Law enforcement agencies report seizures of the drug in powder form and counterfeit tablets that mimic pharmaceutical opioids. Abuse of the drug often happens unknowingly to the user, and is encountered as a single substance as well as in combination with other drugs such as heroin and fentanyls. Some bags are marked with stamped logos, imitating a heroin sale. In addition, the drug can be pressed into pill format and marketed as a wide variety of prescription opioids. Because substances like U-47700 are often manufactured in illicit labs overseas, the identity, purity, and quantity are unknown, creating a “Russian Roulette” scenario for any user. [continued next slide]  DEA's Final Order is available for public viewing today in the Federal Register and outlines the purpose of the action and details the threats it poses to public health and safety. On Monday, November 14th, the Final Order will be published in the Federal Register and will take effect. Also included in Monday's Federal Register notice will be DEA's 3-factor analysis of the drug as required by the Controlled Substances Act, including DEA’s analysis of U-47700, which includes the drug’s chemical structure; history and current pattern of abuse; scope, duration and significance of abuse; and risk to the public health. Also included in DEA's evaluation are detailed charts of opioid receptors binding and functional results of U-47700, and all other supporting documentation.  The Final Order for public viewing in the Federal Register can be found here.  In October 2015, China banned more than 100 synthetic chemicals, including some fentanyl products. But Baer says there's an ongoing battle between legislation and clandestine labs; each time one substance is banned, a new one pops up to replace it.  DEA spokesman Russ Baer confirmed that China made the announcement Wednesday night, after six months of talks between the Chinese and US governments. That included a January visit by acting DEA Administrator Chuck Rosenberg -- the first DEA administrator to go to China in more than a decade -- to to discuss the issue.  The ban will stop carfentanil, furanyl fentanyl, acrylfentanyl and valeryl fentanyl from being legally manufactured and sold in China, effective March 1.  Proposal: Add Fentanyl Analogs to the New York Controlled Substances Schedule

 According to the CDC, overdose deaths from synthetic opioids like fentanyl have increased by 135 percent in New York State in just one year. New York City has seen 300 fatal overdoses in the last 6 months, while 220 of the 464 fatal overdoses on Long Island in 2016 were caused by fentanyl.  To get the synthetic opioid fentanyl off our streets, Governor Cuomo proposes adding the eight fentanyl analogs, variations of the substance, into the New York controlled substances schedule, which would subject them to criminal drug penalties. [continued next slide]  To enable New York State to act nimbly in response to future threats like fentanyl, Governor Cuomo will also advance legislation to create emergency Executive authority to add new substances to our controlled substance schedule. Executive authority, based on the recommendation of experts and the Commissioner of Health, will help law enforcement fight threats like fentanyl as they emerge. The Commissioner will consider a number of factors, including risk to public health, in making recommendations to add new substances to the controlled substances schedule.  The 60th Session of the Commission on Narcotic Drugs has scheduled two precursors of fentanyl under international control, 4-anilino-N-phenethylpiperidine (ANPP) and N-phenethyl-4- piperidone (NPP) listed in Table I of the 1988 Convention. Also scheduled is , a potentially deadly fentanyl analogue.  Vienna, 16 March 2017

 The AP identified 12 Chinese businesses that said they would export the chemical — a synthetic opioid known as carfentanil — to the United States, Canada, the United Kingdom, France, Germany, Belgium and Australia for as little as $2,750 a kilogram (2.2 pounds), no questions asked.  Oct. 08, 2016 ACS Chem Neurosci. 2015 Sep 16;6(9):1570-7. doi: 10.1021/acschemneuro.5b00137. Epub 2015 Jul 21. Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction. Váradi A1, Palmer TC1, Haselton N1, Afonin D1, Subrath JJ1, Le Rouzic V1, Hunkele A1, Pasternak GW1, Marrone GF1, Borics A2, Majumdar S1. Author information Abstract We report a novel approach to synthesize carfentanil amide analogues utilizing the isocyanide-based four-component Ugi multicomponent reaction. A small library of bis-amide analogues of carfentanil was created using N-alkylpiperidones, aniline, propionic acid, and various aliphatic isocyanides. Our lead compound showed high affinity for mu (MOR) and delta opioid receptors (DOR) with no appreciable affinity for kappa (KOR) receptors in radioligand binding assays. The compound was found to be a mixed MOR agonist/partial DOR agonist in [(35)S]GTPγS functional assays, and it showed moderate analgesic potency in vivo. [continued next slide] ACS Chem Neurosci. 2015 Sep 16;6(9):1570-7. doi: 10.1021/acschemneuro.5b00137. Epub 2015 Jul 21. Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction. Váradi A1, Palmer TC1, Haselton N1, Afonin D1, Subrath JJ1, Le Rouzic V1, Hunkele A1, Pasternak GW1, Marrone GF1, Borics A2, Majumdar S1. Author information Abstract, continued The compound showed no visible signs of physical dependence or constipation in mice. In addition, it produced less respiratory depression than morphine. Most mixed MOR/DOR opioids reported in the literature are peptides and thereby systemically inactive. Our approach utilizing a multicomponent reaction has the promise to deliver potent and efficacious small-molecule with potential clinical utility.

KEYWORDS: Ugi reaction; carfentanil; mu-delta; multicomponent reactions; opioid analgesics Drug Alcohol Depend. 2017 Feb 1;171:107-116. doi: 10.1016/j.drugalcdep.2016.11.033. Epub 2016 Dec 16. A review: Fentanyl and non-pharmaceutical fentanyls. Suzuki J1, El-Haddad S2. Abstract BACKGROUND: Fentanyl and non-pharmaceutical fentanyls (NPFs) have been responsible for numerous outbreaks of overdoses all over the United States since the 1970s. However, there has been a growing concern in recent years that NPFs are contributing to an alarming rise in the number of opioid-related overdoses. METHODS: The authors conducted a narrative review of the published and grey literature on fentanyl and NPFs in PubMed, Google Scholar, and Google using the following search terms: "fentanyl", "non-pharmaceutical fentanyl", "fentanyl analogs", "fentanyl laced heroin" and "fentanyl overdose". References from relevant publications and grey literature were also reviewed to identify additional citations for inclusion. [continued next slide] RESULTS: The article reviews the emergence and misuse of fentanyl and NPFs, their clinical pharmacology, and the clinical management and prevention of fentanyl-related overdoses. CONCLUSIONS: Fentanyl and NPFs may be contributing to the recent rise in overdose deaths in the United States. There is an urgent need to educate clinicians, researchers, and patients about this public health threat. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved. KEYWORDS: Fentanyl; Non-pharmaceutical fentanyl; Opioid use disorder; Overdose PMID: 28068563 DOI: 10.1016/j.drugalcdep.2016.11.033