The Journal of Emergency Medicine, Vol. 50, No. 3, pp. 433–436, 2016 Copyright Ó 2016 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2015.10.014
Selected Topics: Toxicology
ACETYLFENTANYL: AN EMERGING DRUG OF ABUSE Jeremy S. Rogers, DO, Seth J. Rehrer, DO, and Nathan R. Hoot, MD, PHD Department of Emergency Medicine, The University of Texas Health Science Center at Houston, Houston, Texas Reprint Address: Nathan R. Hoot, MD, PHD, Department of Emergency Medicine, The University of Texas Health Science Center at Houston, 6431 Fannin, 4th Floor, Jesse Jones Library, Houston, TX 77030
, Abstract—Background: Opioid analgesics are widely used in health care, yet have significant potential for abuse. High doses are associated with potentially fatal respiratory depression, which caused 21,314 deaths in the United States in 2011. Acetylfentanyl, a synthetic opioid agonist closely related to fentanyl, recently emerged as a drug of abuse linked to numerous deaths in North America. Case Report: A 36-year-old male developed the habit of using a propylene glycol electronic cigarette filled with acetylfentanyl to aid relaxation. He purchased the drug online in a manner that appeared legal to him, which compromised his insight about the danger of the substance. He had been using the e-cigarette with increasing frequency while on medical leave, and his wife reported finding him weakly responsive on more than one occasion. At approximately 3 AM, the family activated 911 for altered mental status. His presentation included respiratory depression, pinpoint pupils, hypoxemia, and a Glasgow Coma Scale score of 6. He responded to serial doses of intravenous naloxone with improvement in his mental status and respiratory condition. Due to the need for repeated dosing, he was placed on a naloxone infusion and recovered uneventfully in intensive care. Why Should an Emergency Physician Be Aware of This?: Complications from emerging drugs of abuse, like acetylfentanyl, frequently present first to emergency departments. Prompt recognition and treatment can help avoid morbidity and mortality. Acetylfentanyl can be managed effectively with naloxone, although higher than conventional dosing may be required to achieve therapeutic effect. Ó 2016 Elsevier Inc.
INTRODUCTION Opium and its various preparations have been used medicinally for centuries for their analgesic properties (1). The term opiates refers to alkaloid chemicals that are derived from opium, such as morphine and codeine. The term opioids refers more broadly to drugs with agonist activity at opioid receptors, including synthetic chemicals, such as methadone and fentanyl. These drugs are widely used in health care for their analgesic effects, although they are likewise known for high abuse potential due to euphoric properties. Emergency physicians are trained to recognize and manage the opioid toxidrome, which should be considered core knowledge in emergency medicine curricula (2). Intentional or unintentional opioid overdoses commonly manifest with respiratory suppression, which can be lethal. In 2011, an estimated 678,522 emergency department (ED) visits occurred in the United States due to misuse of prescription and illicit opioids (3). The yearly death rate attributed to prescription opioid overdoses rose from 4,030 in 1999 to 16,917 in 2011; for heroin, these figures increased from 1,960 to 4,397 in 1999 and 2011, respectively (4). Fortunately, opioid overdoses can be managed effectively with naloxone, a competitive antagonist of the muopioid receptor. We present the case of a young man with an opioid overdose caused by acetylfentanyl, a recently emerged opioid drug of abuse.
, Keywords—opioid analgesics; drug overdose; street drugs; naloxone
RECEIVED: 25 November 2014; FINAL SUBMISSION RECEIVED: 9 October 2015; ACCEPTED: 13 October 2015 433
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CASE REPORT A 36-year-old male presented to the ED via ambulance with altered mental status. He was last seen normal at midnight that night. At approximately 3 AM, the patient’s wife found that he could not be roused to stimulation and appeared to have difficulty breathing. She called the patient’s brother, who activated 911. On arrival, paramedics found the patient with a Glasgow Coma Scale (GCS) score of 6 and oxygen saturation of 85%. During transport he was given 2 mg of intravenous naloxone, after which he was able to converse appropriately. Upon arrival to the ED, he had an intact airway and adequate spontaneous respirations, but his mental status had declined such that he was minimally aroused by painful stimuli. He was placed immediately into a resuscitation room, where he was found to be afebrile with a pulse of 97 beats/min, blood pressure of 173/97 mm Hg, respiratory rate of 17 breaths/min, and oxygen saturation of 97% on 2 L by nasal cannula. His blood glucose was 249 mg/dL, and his pupils were constricted to pinpoint. He was given another dose of 2 mg naloxone, with rapid improvement in his mental status. The patient then described a recent habit of smoking a propylene glycol electronic cigarette to aid relaxation. He stated that he purchased what he called ‘‘synthetic opium’’ legally online, which he used to fill the e-cigarette and inhale vapors—a process known as ‘‘vaping.’’ The patient later admitted to adding the ‘‘synthetic opium’’ to alcoholic beverages as well. He had been on medical leave for the previous 3 days for the planned closure of a patent foramen ovale, which had been found after a transient ischemic attack 3 months earlier. With the free time during his medical leave, the patient had been using his e-cigarette frequently, and his wife found him difficult to rouse on more than one occasion. The patient denied recent trauma, fevers, anorexia, headaches, or any other symptoms. The history was obtained from the patient and his brother, and initially neither could identify the specific contents of the ‘‘synthetic opium.’’ The patient had no other medical history, except for the patent foramen ovale and transient ischemic attack. He took no prescription medications and denied known allergies. He smoked tobacco cigarettes daily, reported social alcohol consumption, and used an e-cigarette as noted. His physical examination showed pinpoint pupils initially, which changed to 3 mm bilaterally after naloxone administration. There was no nystagmus. His oropharynx, heart, lungs, and abdomen were normal on examination. His GCS was 15 after receiving naloxone. He had normal motor strength and sensation to light touch. Cranial nerves II to XII were intact, and no clonus was apparent. Examination of his skin showed no track
marks or bruising. Laboratory evaluation showed a basic metabolic profile that was normal except for mild hyperglycemia and creatinine increased to 1.7 mg/dL from his baseline of 0.8 mg/dL. His creatinine kinase (CK) was elevated at 11,715 U/L. Venous blood gas analysis showed a pH of 7.12 and pCO2 of 89 mm Hg. Other studies, including a complete blood count, liver function tests, urinalysis, and chest x-ray study were unremarkable. Computed tomography of the head was considered but not obtained, because the working diagnosis of an opioid toxidrome seemed clear based on his reported history and normal mental status after naloxone. Similarly, urine screening for drugs of abuse was considered but not obtained, because this was felt unlikely to alter management for the patient (5). During his ED course, the patient’s mental status began to decline again, so a third dose of 2 mg of naloxone was administered. He was aggressively hydrated with intravenous crystalloid due his elevated CK. Continuous waveform capnography was used to monitor his respiratory status, and a continuous infusion of naloxone was started at 1.5 mg/h. With these interventions, his mental status remained adequate, and results of arterial blood gas sampling improved to a pH of 7.32, pCO2 of 55 mm Hg, and pO2 of 84 mm Hg. He was admitted to the medical intensive care unit (ICU) in improved condition for further management of an opioid toxidrome, complicated by acute hypercarbic respiratory insufficiency and rhabdomyolysis with acute kidney injury. Upon request, the patient navigated to the website where he purchased the ‘‘synthetic opium,’’ which showed chemical abbreviations and structures. Using this information, providers from the ICU and the regional Poison Control Center identified the substance as acetylfentanyl, an analogue of fentanyl with similar clinical effects. DISCUSSION Acetylfentanyl is a synthetic analogue of fentanyl that is similar to heroin in color, consistency, and pharmacologic activity (Figure 1). It acts in the human body by agonism at the mu-opioid receptor, where its activity is 15.7 times more potent than morphine and 3 times less potent than fentanyl (6,7). It was discovered in the late 1960s, about the same time that fentanyl was discovered. It remains unused in health care and, aside from rare use during the 1980s, did not establish a significant presence on the streets for decades. In 2013, the drug re-emerged after 3 kg and 12,400 pills were seized during a drug bust in Canada (8). In early 2013, fourteen deaths in Rhode Island and 50 deaths in Pennsylvania were linked to acetylfentanyl, prompting the Centers for
Abuse of Acetylfentanyl
Figure 1. Chemical structures of acetylfentanyl (left) and fentanyl (right). The two compounds are differentiated by the presence of one additional methyl group in the structure of fentanyl. Image provided courtesy of the Drug Enforcement Administration, Office of Diversion Control (6).
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Most urine drug screens use an enzyme-mediated immunoassay (EIA) to test for opiates, not opioids (15,16). Therefore, morphine and its derivatives will be detected, but synthetic opioids like fentanyl and acetylfentanyl will not. The semi-synthetic opioids, in particular hydrocodone and oxycodone, may cross-react with EIA, given adequate concentrations. Synthetic opioids may be detected using an enzyme-linked immunosorbent assay (ELISA), but distinguishing between fentanyl and acetylfentanyl requires gas chromatography and mass spectroscopy (GC-MS). CDC recommends that public health officials collaborate with laboratories to first screen for fentanyl variants using an ELISA for fentanyl, then confirm the presence of acetylfentanyl using GC-MS (9). WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?
Disease Control and Prevention (CDC) to issue a report warning of its re-emergence (9,10). Like other street drugs that have emerged in the past decade, acetylfentanyl exists within a legal gray area (11). In the United States, it is currently not scheduled per the Controlled Substances Act, while in Canada it is listed as a Schedule 1 drug under the Controlled Drugs and Substances Act (12,13). However, when acetylfentanyl is intended for human consumption, it can be viewed as a controlled substance analogue and therefore becomes illicit (6). Distributors may circumvent prohibition, however, by marking the drug as ‘‘not for human consumption,’’ much like the synthetic cathinones were previously marketed as ‘‘bath salts’’ to avoid illegal status. The patient described here purchased acetylfentanyl from a website that did not market the drug for human consumption, and its apparent legality may have limited his insight regarding its potential for harm. The street names for acetylfentanyl include ‘‘China white’’ and ‘‘synthetic heroin.’’ The drug may be packaged into pills or mixed with heroin to allow distributors to increase revenue. The clinical effects of acetylfentanyl are similar to those of other mu-opioid receptor agonists, including analgesia, euphoria, miosis, and potentially fatal respiratory depression. It may be reasonably expected to cause further somnolence and respiratory depression when combined with alcohol or sedative-hypnotics, such as benzodiazepines. Due to its action at the muopioid receptor, it is believed that naloxone may reverse respiratory depression caused by acetylfentanyl. Our experience with this patient was consistent with this claim. However, it has also been suggested that the dose of naloxone may need to exceed 2 mg in order to be effective against fentanyl-like compounds (14).
Acetylfentanyl is a potent agonist of the mu-opioid receptor and emerging drug of abuse, which has been implicated in a rash of recent deaths. Its effects on the human body are identical to the opioid toxidrome, which emergency physicians are trained to suspect in cases of undifferentiated altered mental status. However, conventional drug screens will not detect acetylfentanyl, and high doses of naloxone—beyond those often administered—may be required to reverse the respiratory depression and eliminate the need for mechanical ventilation. Furthermore, the drug exists within a legal gray area in the United States, which can exacerbate the problem by facilitating availability while limiting patients’ knowledge about the dangers associated with its consumption. Acetylfentanyl has spread rapidly from the northeast to the southern states, so CDC recommends reporting deaths associated with its use to help track evolution of this new drug. REFERENCES 1. Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE. Goldfrank’s Toxicologic Emergencies. 9th ed. New York: McGraw-Hill; 2011. 2. Counselman FL, Borenstein MA, Chisholm CD, et al. The 2013 model of the clinical practice of emergency medicine. Acad Emerg Med 2014;21:574–98. 3. The DAWN report: highlights of the 2011 Drug Abuse Warning Network (DAWN) findings on drug-related emergency department visits [Internet]. Rockville, MD: Substance Abuse and Mental Health Services Administration; c2012. Available at: http://www. samhsa.gov/data/2k13/DAWN127/sr127-DAWN-highlights.htm. Accessed September 27, 2014. 4. Watchdog update—overdose deaths from opioids, heroin on the rise [Internet]. Milwaukee, WI: Journal Sentinel; c2014. Available at: http://www.jsonline.com/watchdog/watchdogreports/overdosedeaths-from-opioids-heroin-on-the-rise-b99302962z1-265452991. html. Accessed September 28, 2014. 5. Eisen JS, Sivilotti ML, Boyd KU, Barton DG, Fortier CJ, Collier CP. Screening urine for drugs of abuse in the emergency department: do
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6.
7. 8.
9. 10.
test results affect physicians’ patient care decisions? CJEM 2004;6: 104–11. Acetylfentanyl (N-(1-phenethylpiperidin-4-yl)-N-phenylacetamide) [Internet]. Springfield, VA: Drug Enforcement Administration, Office of Diversion Control; c2013. Available from: http:// www.deadiversion.usdoj.gov/drug_chem_info/acetylfentanyl.pdf. Accessed October 5, 2015. Skulska A, Ka1a M, Parczewski A. Fentanyl and its analogues in clinical and forensic toxicology. Przegl Lek 2005;62:581–4. Extremely potent painkiller hits Montreal black market [Internet]. Toronto: CBC News; c2013. Available from: http://www.cbc.ca/ news/canada/montreal/extremely-potent-painkiller-hits-montreal-bl ack-market-1.1340808. Accessed September 28, 2014. Centers for Disease Control and Prevention. Acetyl fentanyl overdose fatalities—Rhode Island, March-May 2013. MMWR Morb Mortal Wkly Rep 2013;62:703–4. Department of Drug and Alcohol Programs warns about acetyl fentanyl [Internet]. Pennsylvania Department of Drug and Alcohol
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11. 12. 13. 14. 15. 16.
Programs c2013. Available at: http://www.portal.state.pa.us/portal/ server.pt/document/1345188/department_of_drug_and_alcohol_pro grams_warns_about_acetyl_fentanyl. Accessed September 28, 2014. Stogner JM. The potential threat of acetyl fentanyl: legal issues, contaminated heroin, and acetyl fentanyl ‘‘disguised’’ as other opioids. Ann Emerg Med 2014;64:637–9. Controlled Substances Act, Title 21 U.S.C. (October 27, 1970). Controlled Drugs and Substances Act, S.C. 1996, c. 19 (June 20, 1996). Schumann H, Erickson T, Thompson TM, Zautcke JL, Denton JS. Fentanyl epidemic in Chicago, Illinois and surrounding Cook County. Clin Toxicol (Phila) 2008;46:501–6. Ruangyuttikarn W, Law MY, Rollins DE, Moody DE. Detection of fentanyl and its analogs by enzyme-linked immunosorbent assay. J Anal Toxicol 1990;14:160–4. Keary CJ, Wang Y, Moran JR, Zayas LV, Stern TA. Toxicologic testing for opiates: understanding false-positive and false-negative test results. Prim Care Companion CNS Disord 2012;14.
