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Clinical Nurse SpecialistA Copyright B 2017 1.0 Pharmacology and 1.5 ANCC Contact Hours Wolters Kluwer Health, Inc. All rights reserved. Pharmacology Consult Column Editor: Patricia Anne O’Malley, PhD, RN, CNS

‘‘Gray Death’’VThe Trojan Horse of the Opioid Epidemic Historical, Clinical, and Safety Evidence for the Clinical Nurse Specialist

Patricia Anne O’Malley, PhD, RN, CNS

n 2017, a new opioid configuration emerged in the South America, Europe, the Middle East, and in developed United States called ‘‘gray death.’’ This illicit opioid Africa and Asia. In the 1990s, use of fentanyl was expanded Ihas an appearance similar to dry concrete mix or a beyond surgery for the management of cancer pain and rock. Indiana, Ohio, Georgia, and Alabama have reported treatment of chronic pain. Intravenous fentanyl facilitates deaths with the use ultradangerous combinations of fenta- rapid anesthesia induction, results in less hemodynamic in- nyl, carfentanil, and U-47700, and reports are multiplying stability, has minimal cardiovascular adverse effects, and across the United States.1 This article explores the current does not increase plasma histamines such as morphine outbreak of fentanyl-related overdoses in the United States and meperidine. Metabolized via the human cytochrome and the world. The most current safety recommendations P450 (CYP3A4) isoenzyme system, onset of action and peak (known at this time) for clinicians providing care for per- plasma concentrations are a function of the dosage used and sons abusing fentanyl and fentanyl-related compounds method of delivery.3 In addition, fentanyl and fentanyl- such as ‘‘gray death’’ will be provided. related analogs have high lipid solubility. As a result, fentanyl drug can be delivered in a variety of slow release pathways THE ALLURE OF FENTANYL such as the skin, mucous membranes, or the mouth and only During the past 40 years, the United States has experienced small amounts of drug are needed because access to the 3 fentanyl epidemics. During the 1970s, fentanyl and brain is so immediate.1 fentanyl-related compounds from China were responsible for hundreds of deaths in the United States. This first epi- WORLDWIDE FENTANYL EXPERIENCE demic resulted in the implementation of the Controlled The United States is not alone in this opioid crisis. Since Substances Analog Enforcement Act of 1986. From 2005 2011, Germany, Finland, and the United Kingdom have also to 2007, nearly 1000 persons died during a second epidemic experienced outbreaks of fentanyl-related deaths. Diversion of illicit fentanyl brought into the United States from illegal from regulated supply chains and illicit production in re- laboratories in Mexico. The current fentanyl outbreak be- sponse to heroin shortages in Bulgaria and Slovakia have gan in 2013. Carfentanil has also arrived during this third fueled the European crisis. Diversion includes inappropri- wave and is responsible for nearly 400 overdose cases in ate or overprescribing of opioids, pharmacy theft, sale of 2016, with 84% of these cases occurring in the state of Ohio.2 unused fentanyl patches, as well as misuse and sale by Introduced 50 years ago, fentanyl has become the most healthcare providers. Dark sources of fentanyl are the dis- used opioid for intraoperative anesthesia in North and carded patches retrieved from hospital and nursing home waste containers. Drug is extracted from the patch and placed in liquid for injection or inhalation. The patch is also Author Affiliation: Nurse Researcher, Center of Nursing Excellence, smoked on foil, placed directly on the skin, or cut into Premier Health, Miami Valley Hospital, Dayton, Ohio. pieces to be sucked or swallowed.4 The author reports no conflicts of interest. In this rise of fentanyl use, of deep concern is evidence Correspondence: Patricia Anne O’Malley, PhD, RN, CNS, Premier Health, Miami Valley Hospital, 1 Wyoming St, Dayton, OH 45409 (pomalley@ suggesting that fentanyl has been weaponized. Rather than premierhealth.com; [email protected]). using a lethal chemical agent, it seems that the Russian military DOI: 10.1097/NUR.0000000000000326 used a combination of an aerosolized fentanyl or fentanyl

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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. derivatives with an inhalation anesthetic to incapacitate Table 2. Changes in Drugs Used in Overdose Chechen rebels, holding 800 hostages at a Moscow theater 7 in October 2002. To save hostages who were likely to be Deaths 2010 and 2015 killed and incapacitate rebels, a ‘‘calmative’’ agent was used Drug 2010, % 2015, % in the theater described as ‘‘not lethal.’’ However, 127 of the 800 hostages died and more than 650 required hospital Natural and semisynthetic opioids 29 24 admission with what was diagnosed as ‘‘sleeping gas’’ poi- Methadone 12 6 soning. Treatment for opioid poisoning was delayed because Heroin 8 25 components of the gas were unknown by the clinicians who Synthetic opioids other than methadone 8 18 tried a variety of antidotes base on the belief that a ‘‘nerve gas’’ was used before using naloxone.5 Illicit production of fentanyl is not confined to Mexico or for all age groups, the greatest percentage increase was among China. Beginning in 1990, the first illicit fentanyl was pro- adults aged 55 to 64 years. The highest rate for overdose duced in Kansas, which resulted in the seizure of 2 illicit deaths in 2015 was for adults aged 45 to 54 years (30 deaths laboratories. From 2000 to 2005, several illicit laboratories per 100 000). The 4 states with the highest age-adjusted in the United States were also closed. Because fentanyl is drug overdose rates were West Virginia, New Hampshire, 7 more potent than heroin, demand is increasing and profit Kentucky, and Ohio. margins are expanding.6 Data suggest that opioid fatalities have increased in great Today, opioids have become the most common element part from the increasing availability of synthetic opioids in overdose deaths in the United States with 33 091 in 2015, and heroin. Fentanyl (50 times as potent as heroin) and with nearly 10 000 deaths of these deaths related to synthetic carfentanil (5000 times as potent as heroin) are increasingly opioids (fentanyl and fentanyl-related products other than laced into heroin, increasing the risk of overdose and death methadone). China and Mexico remain the primary sources even when naloxone is available. Naloxone is often ineffec- for illicit fentanyl production and distribution in the United tive or short acting depending on the amount, route, and 8 States. Vast and effective distribution is accomplished through type of opioid used. sales through the World Wide Web, dark web, and mail and via the interstate highway systemfromMexicoandCanada.6 CARFENTANILVDEATH DISGUISED AS A FEW The effects of opioid trafficking on public health are GRAINS OF POWDER dreadful. Overdose deaths are defined as deaths from un- Carfentanil (formally known as Wildnil) is a synthetic fenta- intentional or intentional overdose of a drug, receiving the nyl derivative related to fentanyl and sufentanil. Commercial wrong drug, or taking a drug in error. Natural and semisyn- production of Wildnil stopped in 2002 and available as a thetic opioids include morphine, codeine, hydrocodone, compound dosage for veterinary use. Carfentanil is used for and oxycodone. Synthetic opioids excluding methadone chemical capture and rapid of large animals in zoos and wild- include fentanyl, fentanyl analogs, and tramadol.7 life areas for examination and treatment. One hundred times Data provided in Table 1 describe the age-adjusted more potent than fentanyl and 10 000 times more potent than rates of drug overdose deaths per 100 000 non-Hispanic morphine, carfentanil is usually delivered via a dart intramus- black and white persons and Hispanic persons.7 Table 2 cularly. Personal protective gear is required when used to data describe the shift in opioid type in overdose deaths prevent accidental absorption through mucus membranes from 2010 to 2015.7 In addition, for 2015, the percentage in the eyes, nose, mouth, or through broken skin, which can of drug overdose deaths involving heroin tripled compared result in rapid onset opioid toxicity. Signs and symptoms with 2010. Although drug overdose death rates increased include pinpoint pupils, respiratory depression, depressed mental state, lethargy, sedation, nausea, vomiting, apnea, and cardiac arrest. The lethal dose for humans is unknown. Table 1. Age Adjusted Rate of Drug Overdose Limited case studies suggest a time line of minutes for in- 7 Deaths per 100 000 tervention after face, eyes, or mouth exposure. Naltrexone hydrochloride is veterinary antidote for carfentanil exposure, Average 9,10 Increase per Percent which has an antagonistic potency twice that of naloxone. Persons 1999 2015 Year, % Increase, % The emergence of carfentanil in illicit drug production has significantly increased the number of overdoses and j Non-Hispanic 6.2 21.1 7 240 overdose-related deaths even among opioid tolerant users. white persons Carfentanil is found in many forms including powder, blot- j Non-Hispanic 7.5 12.2 2 63 ter paper, tablets, patches, and spray and can resemble black persons powdered cocaine or heroin. Routes of consumption in- j Hispanic persons 5.4 7.7 2 43 clude inhaled, injection, rectal, intranasal, transdermal,

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and transmucosal. Carfentanil and fentanyl analogs pose intervention is not routinely recommended. Intravenous significant threats to safety for first responder medical and naloxone is the preferred route administration for adults laboratory personnels.11,12 Other street names include and children. For adults without IV access, other routes in- Aunt Hazel, Emma, Batman, China Cat, Dead on Arrival, clude intramuscular (IM), subcutaneous (SQ), and intranasal. Elephant, Foo Foo Stuff, Heaven Dust, Sack, Salt, Red Off-label endotracheal installation is the least desirable route Chicken, Reindeer Dust, Skag, Sweet Dreams, The Beast, based on anecdotal evidence. Naloxone can also be given The Witch, Tiger, White Lady, White Nurse, and Zero. to adults via nebulizer (adults only) and intraosseous (IO) ‘‘Body stuffers’’ or persons who conceal these drugs vagi- when preferred access is not available. For pediatric treat- nally or rectally or ingest have an extremely high risk of ment, IO administration is considered an off-label use. death because wrapped packets often leak.12 Although naloxone can be given IM, SQ, or endotracheal (also considered off-label use), onset of action will be U-47700 delayed compared with IV administration. Supportive thera- To provide an even more powerful illicit opioid combina- pies include intravenous fluids and vasopressors if response tion, U-47700 has emerged mixed with heroin and fentanyl to fluids is poor, benzodiazepines for seizures, and surgery or fentanyl and carfentanil, creating ‘‘gray death.’’1,13 ‘‘Gray if necessary for body packers with acute poisoning, gastro- death’’ seems similar to concrete mixing powder and tex- intestinal obstruction, or perforation.12 ture ranges from chunky rocklike material to fine powder Respiration should be continuously monitored particu- and can be injected, eaten, or smoked. At this time, it is un- larly because naloxone effects range from 20 to 60 minutes known how U-47700 interacts with fentanyl, carfentanil, or and multiple doses are often needed for synthetic opioid heroin in the body.13 Some of the pills taken from Prince’s combinations. Consider chest radiography for patients with estate after the musician’s overdose death last year pulmonary signs and symptoms to rule out noncardiogenic contained U-47700.14 pulmonary edema that can occur with abuse of synthetic U-47700 is another synthetic opioid, with an abuse po- opioid combinations. Hospital admission should be con- tential similar to heroin, prescription opioids, and other sidered with pediatric ingestion, use of long-acting opioids, synthetic opioids. The drug comes in powder form and and continued respiratory depression with treatment. Body in counterfeit tablets that look like pharmaceutical opioids. packers should be admitted to the intensive care unit.12 The drug is sold as single agent and in combinations previ- Some drug combinations, particularly laced with carfentanil, ously described. Because U-47700 is produced in illicit can be absorbed through the skin or inhaled accidentally laboratories outside the United States, purity and dosage during emergency care. Onset of signs and symptoms usually are often unknown, creating a ‘‘Russian Roulette’’ scenario occur within minutes of exposure and include respiratory for any user.15 depression or arrest, drowsiness, disorientation, sedation, U-47700 has been a legal alternative to fentanyl in China pinpoint pupils, and clammy skin. Do not use hand sanitizers and a potent fentanyl derivative not unlike carfentanil.14 In for skin contact that contain alcohol (a skin penetrant), 2016, the US Drug Enforcement Administration (DEA) which may increase the absorption of fentanyl through placed U-47700 into Schedule I of the Controlled Sub- the skin. Wash hands with copious amounts of soap and stances Act, in response to reports regarding this lethal cool water. Do not disturb any substance that may be drug new street drug. The DEA action was based on reports of unless the proper protective equipment is used and nalox- 46 deaths associated with use, 31 in New York and 10 in one is readily available. Never eat, drink, or smoke in the North Carolina. From October 2015 to September 2016, presence of possible drugs.6 the DEA received 88 reports from forensic laboratories of With regard to use of gloves, while the permeation rate U-47700 detection. This DEA action will last for 24 months of fentanyl through nitrile is unknown, the National Institute and may be extended 12 months if further data is required for Occupational Safety and Health (NIOSH) recommends to permanently schedule U-47700.15 wearing nitrile gloves (minimum thickness of 5 mil), dou- bled and powder free, when handling fentanyl-related RESPONDING TO OVERDOSE AND EXPOSURE compounds because nitrile demonstrates low permeability The cornerstone of care for overdose is the reversal agent nal- to other hazardous drug compounds. Powdered gloves oxone (Narcan, Bristol-Myers Squibb, New York), 10 mg should be avoided because the powder may absorb nar- intravenous (IV) which can be repeated in 1 minute and cotic particulates and increase dermal contact and dermal then every 3 to 5 minutes until breathing without assistance absorption during removal. Gloves should be changed ev- for 15 minutes.9,11 Consider decontamination if patient pre- ery 30 to 60 minutes of use. If necessary, outer gloves can sents within 1 hour of oral ingestion with gastric lavage, be removed and inner gloves can be used to label evidence activated charcoal but only with a protected airway.Evi- if needed. Hands must be washed immediately with soap dence supporting this intervention is very weak in light of and cool water. Black gloves may be used to better visual- the risks of aspiration and lack of efficacy. As a result, this ize any powder residue and use of 2 colors for double

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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. gloving can help the clinician better visualize any holes or benefits of opioid therapy.17 Finally, a lifeboat has appeared tears for further protection.16 for clinicians trying to treat pain. The Centers for Disease Control and Prevention (CDC) 2016 recommendations for opioid prescribing may be the MOVING FORWARD most important documents for primary care clinicians for Opioid addiction or opioid use disorder is a chronic re- prescribing opioids for chronic pain outside cancer and lapsing illness requiring sustained treatment, often for years palliative care.17,18 Recommendations include to consider to achieve and sustain recovery. Limited access to addiction prescribing opioids only if benefit outweighs risk, use the specialists and programs, limited access to social support lowest effective dose, combine therapy with nonpharma- and social stigma are significant barriers to recovery. Phar- cological treatments and nonopioid drug therapy when macological resources for this battle are slim; methadone, possible, and avoid prescribing with benzodiazepines buprenorphine, and extended release naltrexone. New whenever possible and consider prescribing naloxone medications on the horizon include agents to support com- where there is risk of overdose.18 pliance with therapy and reduce risks for diversion and agents to modulate reward circuits, withdrawal pathways, THE FUTURE and craving.7 Widespread adoption of the 2016 CDC guidelines could Collaboration between the National Institutes of Health help begin to bring to an end to the current epidemic of and private partners currently focus on 3 specific areas: opioid overprescribing. Additional strategies should in- development of improved overdose-reversal agents and clude correcting the gaps in insurance coverage for the preventative interventions to decrease mortality, saving treatment of chronic pain and addiction and reimburse- lives for treatment and recovery from opioid addiction with ment for nonpharmacological interventions. Essential new pharmacological and technological treatments, and to move forward is support for medication-assisted ther- the development of safe, effective, and nonaddictive inter- apies for opioid addiction such as methadone and bupre- ventions to manage chronic pain.7 norphine. Rather than assuming that this drug therapy is Initial work has begun. In 2015, the Food and Drug Ad- trading 1 addiction for another, consider that these med- ministration approved an easy-to-use intranasal naloxone ications allow patient to live and manage their disease not that provides blood levels of naloxone comparable with unlike a person with diabetes who takes insulin. Finally, parenteral administration. This new treatment option was education and training for clinicians in schools and in prac- developed through partnership of the National Institute on tice should be considered as the requirement to prescribe Drug Abuse and industry. In collaboration with private opioids.17 partners, work is in progress to develop more powerful, Finally, prescribers and patients need to acknowledge longer-acting opioid antagonists. Vaccines for prescription the elephant in the room. Only time will reveal how much opioids, heroin, and fentanyl are also on the horizon, de- constant and misleading pharmaceutical advertising has signed to induce antibody production to prevent opioids contributed to the current crisis. Pharmaceutical advertising entering the brain. Monoclonal antibodies may help pre- and education in the in the 1980s and 1990s minimized the vent overdoses and relapses. Finally, development of new risk for misuse and addiction and helped create a culture of options to manage chronic pain without opioids have promise compulsory generous opioid prescribing.19 Clinicians who and include cannabinoids, tetrahydrocannabinol, dopamine voiced fears of addiction and misuse or prescribed modest D3 antagonists, tumor necrosis factor inhibitors, brain stim- doses were perceived as practicing in an outdated, narrow- ulation technologies, and gene therapies.7 minded, nonevidence-based way. Looking back now, one can see how this marketing disguised as evidence led clini- DOSING GUIDELINES FOR OPIOID PRESCRIBING cians and patients to where we are standing now. The ‘‘perfect storm’’ leading to the present opioid crisis The 2016 CDC guidelines provide a beginning for the began in the 1980s and through the 1990s. The ‘‘mantra’’ way out of this current crisis. For the future, qualitative re- during these years was that pain was being poorly treated. search is needed to understand motivations for opioid use The result was endless education regarding treatments for and forces for relapse.4,20 Finally, perhaps clinicians and pain, adoption of pain as a vital sign, and ultimately linking patients should rethink their perceptions regarding pain. patient satisfaction surveys to physician and nursing perfor- Compassion does not mean the elimination of all pain mance score cards and, in some cases, reimbursement. and the reduction of suffering is much more complex than However, the reality was that the perfect storm lacked con- just prescribing opioids.20 crete evidence to support treatment of long-term pain for For additional safety information, check out the following diagnoses outside cancer and palliative care. Prescribers resources available on the World Wide Web.11 were caught in the storm of improving patient satisfaction CDC Health Advisory (#CDCHAN-00384): http:// rather than screening for addiction and calculating the risk- emergency.cdc.gov/han/han00384.asp

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CDC Health Update (#CDCHAN-00395): http:// 11. United States Department of Justice, Drug Enforcement Admin- emergency.cdc.gov/han/han00395.asp istration. Carfentanil: a Dangerous New Factor in the Opioid Crisis. Drug Enforcement Administration Web site. https://www. DEA fentanyl warning video: https://www.dea.gov/ dea.gov/divisions/hq/2016/hq092216_attach.pdf. Accessed video_clips/Fentanyl%20Roll%20Call%20Video.mp4 September 1, 2017. 12. Lexicomp Online, Opioids (Lexi-Tox), Lexi-Drugs Online. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2016. http:// www.wolterskluwercdi.com/lexicomp-online/. Accessed July 15, References 2017. 1. Mammoser G. ‘Grey death’ is the latest dangerous street drug. 13. Murphy M. Emerging trend bulletin: potent new opioid/opiate Healthline Web site. http://www.healthline.com/health-news/ compound known as ‘‘Grey Death’’. Gulf Coast HIDTA inves- gray-death-latest-dangerous-street-drug. Accessed July 17, 2017. tigative Support NetworkMassachusetts Technical Assistance 2. Casale JF, Mallette JR, Guest EM. Analysis of illicit carfentanil: emer- Partnership for Prevention Web site. http://masstapp.edc.org/sites/ Y gence of the death dragon. Forensic Chem. 2017;2017:74 80. masstapp.edc.org/files/Grey-Death-GCHIDTA-0517.pdf. Accessed Y 3. Stanley TH. The fentanyl story. JPain. 2014;15(12):1215 1226. July 17, 2017. 4. Mounteney J, Giraudon I, Denissov G, Griffiths P. Fentanyls: 14. Watt L. China bans more synthetic opioids blamed for US drug are we missing the signs? Highly potent and on the rise in Europe. Y deaths. The Seattle Times Web site. http://www.seattletimes. Int J Drug Policy. 2015;26(7):626 631. com/nation-world/china-bans-more-deadly-synthetic-opioids- 5. Wax PM, Becker CE, Curry SC. Unexpected ‘‘gas’’ casualties in including-u-47700/. Accessed July 20, 2017. Moscow: a medical toxicology perspective. Ann Emerg Med. 15. Drug Enforcement Administration.. DEA schedules deadly syn- 2003;41(5):700Y705. thetic drug U-47700. Drug Enforcement Administration. Web 6. US Department of Justice, Drug Enforcement Administration. site. https://www.dea.gov/divisions/hq/2016/hq111016.shtml. Fentanyl: A Briefing Guide for First Responders. Drug Enforce- Accessed July 20, 2017. ment Administration Web site. https://www.dea.gov/druginfo/ Fentanyl_BriefingGuideforFirstResponders_June2017.pdf. Accessed 16. National Institute for Occupational Safety and Health. Fentanyl: July 18, 2017. preventing occupational exposure to emergency responders. 7.HedegaardH,WarnerM,MininoM.Drugoverdosedeathsinthe Centers for Disease Control and Prevention Web site. https:// www.cdc.gov/niosh/topics/fentanyl/risk.html. Accessed July 19, United States, 1999Y2015. NCHS Data Brief, no. 273.National Center for Health Statistics: Hyattsville, MD; 2017. 2017. 8. Volkow ND, Collins FS. The role of science addressing the opioid 17. Olsen Y. The CDC guideline on opioid prescribing: rising to the Y crisis. N Engl J Med. 2017;377:391Y394. Available at http://www. challenge. JAMA. 2016;315(15):1577 1579. nejm.org/doi/full/10.1056/NEJMsr1706626#t=article. Accessed 18. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescrib- July 6, 2017. ing Opioids for Chronic PainVUnited States, 2016. MMWR 9. Lust L, Barthold C, Malesker M, Wichman T. Human health hazards Recomm Rep. 2016;65(1):1Y49. of veterinary medications: information for emergency depart- 19. Kolodny A, Courtwright DT, Hwant CS, et al. The prescription ments. J Emerg Med.2011;40(2):198Y207. opioid and heroin crisis: a public health approach to an epidemic 10. George AV, Lu JJ, Pisano MV, et al. CarfentanilVan ultra potent of addiction. Annu Rev Public Health. 2015;36:559Y574. opioid. Am J Emerg Med.2010;28(4):530Y532. 20. Lee T. Zero pain is not the goal. JAMA. 2016;315(15):1575Y1577.

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