Fentanyl has very euphoric properties, and is a favorite of drug abusers. Medical personnel abuse fentanyl in the parenteral form, but most street use comes from substituting fentanyl for heroin by drug dealers or from the illicit extraction of fentanyl from used or new transdermal patches. Recently, a close relative to medical fentanyl, acetyl fentanyl, has surfaced as a drug of abuse that has potentially fatal consequences. Little can be found in the medical literature about acetyl fentanyl, and your hospital laboratory will not find it. It might be identified on the rare occasion when a sophisticated reference laboratory is contacted.
Notes from the Field: Acetyl Fentanyl Overdose Fatalities-Rhode Island, March-May 2013
The Morbidity and Mortality Weekly Report provided probably the first reference to acetyl fentanyl overdose when they reported a number of unusual toxicology-related deaths earlier this year in Rhode Island. Ten overdose deaths from suspected illicit drug use were initially identified by the Rhode Island State Health Laboratories as fentanyl with an enzyme-linked immunosorbent assay (ELISA) for fentanyl. Medical-grade fentanyl was not identified, however, when the analysis was attempted to be confirmed by gas chromatography-mass spectrometry (GC-MS), the gold standard for laboratory identification. Instead, the spectrum analysis was consistent with a fentanyl analog, acetyl fentanyl.
This substance is not available as a prescription medication, and it had not been previously documented as a cause of overdose from street use. As with other types of fentanyl, acetyl fentanyl is more potent than heroin, and in this case was considered to be about five times more powerful.
Fourteen deaths were confirmed because of acetyl fentanyl in Rhode Island; the subjects' ages ranged from 19 to 57 years, and all were male. Most deaths occurred in a small town in northern Rhode Island. The assessment was that the drug was injected intravenously as street heroin, but the exact route of administration was undetermined in some individuals. Additional substances were found, including cocaine, ethanol, and benzodiazepines, as is common with other fatal overdoses.
A few scattered deaths from acetyl fentanyl were confirmed in other states after this report. The CDC recommended that laboratories use an ELISA test to screen specimens for fentanyl in suspicious cases because of these findings. The CDC recommends confirmation testing by GC-MS if the ELISA test for fentanyl is positive. If no fentanyl is detected by GC-MS, the fentanyl analog, acetyl fentanyl, should be suspected, and subsequent testing to confirm its presence could be considered.
This short report re-emphasizes the fact that naloxone is an opioid antagonist that can readily reverse opioid-induced respiratory depression, including that caused by fentanyl. It is emphasized that larger doses of naloxone may be required to achieve reversal because of the increased potency of fentanyl acetyl and other forms of fentanyl.
Comment: A narcotic overdose is relatively straightforward when it is an isolated event, but it is likely that many deaths from acetyl fentanyl go unrecognized or unconfirmed. Many medical examiners might detect fentanyl derivatives, but a hospital-based toxicology lab will not identify fentanyl or any analog. If cocaine, benzodiazepines, or other drugs of abuse are found in the screen and the investigation did not test for fentanyl, most cases are written off as death caused by substances that were readily found. Extensive testing on individuals who die in the field from multiple drug overdoses is not that common, and even medical examiners may fail to recognize acetyl fentanyl.
I know of no hospital where the fentanyl ELISA test is used; our hospital lab does not have it available. ED cases certainly go unrecognized unless someone has a burning interesting in pursuing an opioid-negative case that responded to naloxone. Usually that course is simply not pursued. The presence of even large amounts of fentanyl or acetyl fentanyl does not register as positive on any opioid screening test in a general hospital screen for opioids.
Naloxone would readily reverse all opioids, and it's often part of the resuscitation cocktail when the cause of the lethargy, coma, or OD is unknown. A standard dose for naloxone is 0.4 mg. Some titrate lower doses, such as 0.1 mg aliquots to revive the subject yet not produce severe opioid withdrawal. Given the high potency of fentanyl, 2-5 mg may be required, but do not give it initially when fentanyl is the main culprit. An out-of-hospital fentanyl- or acetyl fentanyl-related death would simply appear to be a heroin problem, yet the opioid screen, readily positive with heroin and its morphine metabolite, would be negative unless it were mixed with heroin. Under those circumstances most would readily attribute the overdose to too much heroin and not pursue other substances. One might consider that fentanyl is involved when your suspected heroin overdose does not respond to standard doses of naloxone but is revived with megadoses.
Fentanyl patches are another likely source of fentanyl in the field, and even patches discarded after a three-day use contain a significant amount of residual fentanyl embedded in the discarded patch. It's not uncommon for patients to sell their fentanyl patch after a three-day use or for savvy medical personnel to abscond with used patches. Most hospitals have specific procedures where fentanyl patches are meticulously destroyed, but this is often an outpatient medication where the patch is simply thrown in a garbage can after three days.
Fentanyl abuse is increasing. The Pennsylvania Department of Drug and Alcohol Programs noted that 50 known overdose deaths secondary to fentanyl or acetyl fentanyl occurred this year alone. The source of the deadly opioid is rarely known, but it is likely used as a substitute for heroin when that substance is not readily available. The overdose likely would be incorrectly attributed to fentanyl if the more sophisticated screen is positive for fentanyl and a GC-MS confirmatory test is not done. Clinically, that's what is reported, so cases of fentanyl analogs may go undetected. Usually they are uncovered when there is a significant increase in drug-related deaths and a medical examiner gets curious.
Fentanyl Epidemic in Chicago, Illinois, and Surrounding Cook County
Schumann H, Erickson T, et al
This article, though not about acetyl fentanyl, is one of the few reports outlining epidemic fentanyl poisoning. The events in the article describe ED visits from opioid toxicity surrounding illicit fentanyl fatalities in 2005. Immunoassay drug screens were not readily available to identify fentanyl, so many more cases could have gone undetected. Again noted is that fentanyl overdose because of its potency may require large doses of naloxone for reversal. John H. Stroger Hospital of Cook County (formerly Cook County Hospital) treated six opioid overdoses within a single eight-hour shift, an unusually high number of opioid overdoses even for that area.
The patients later reported that they had received free heroin from a new drug dealer attempting to attract new customers. The substance was found to be fentanyl, not heroin. The authors described 26 ED visits related to fentanyl overdose. Two patients arrived in cardiac arrest and subsequently died.
The naloxone required for reversal of these patients ranged from 0.4 to an amazingly high 12 mg. A urine test in each case was negative for opioids, but did reveal other substances, commonly cocaine. The medical examiner of Cook County later identified 342 illicit fentanyl-related fatalities occurring during the study period. Exactly how fentanyl got onto the street was not determined.
The standard dose of 0.4 mg of the opioid antagonist naloxone effectively reversed fentanyl toxicity in only 15 percent of cases. It was not uncommon to require up to 6 mg to produce reversal. The requirement for very high doses of naloxone is a tipoff that fentanyl is the offending substance. The reporting hospital and the surrounding hospitals ran low on naloxone, and some hospitals actually had none available because of the high doses required.
The routine urine drug screen used in a standard hospital laboratory does not detect fentanyl. Patients do not test positive for opioids even if there were enough fentanyl to be fatal. Many overdoses are polydrug overdoses, so it is difficult to select out the exact cause of death in many cases where numerous drugs are found. Fentanyl was likely used to bolster the effects of street heroin if fentanyl and opioids are found in a subject's toxicology testing.
Comment: Patients exhibiting opioid toxicity — respiratory depression, bradycardia, hypothermia, pinpoint pupils, and coma — can be suffering from an overdose of any heroin derivative or synthetic opioid. It is not particularly important to the emergency physician to determine which drug is the culprit, but it is important to know if there is an outbreak of non-heroin-induced opioid overdoses in your area. One way to suggest that fentanyl is the cause is the lack of response to high doses of naloxone, generally defined as greater than 2-3 mg, yet a response to higher doses and the presence of a negative opioid screen. Opioid drug tests readily identify a morphine-related drug, including morphine, codeine, hydrocodone (Vicodin), and hydromorphone (Dilaudid). The standard hospital immunoassay opioid test will not detect oxycodone (Percocet, Oxycontin) because it is a substance not directly related chemically to morphine. Likewise, the opioids methadone, meperidine (Demerol), propoxyphene (Darvon), tramadol, and fentanyl would escape detection by the laboratory in most hospitals.
One should not stop after the first 1-2 mg of unsuccessful naloxone administration if the overdose is thought to be caused primarily by an opioid. I doubt it would require more than 8 to 10 mg in the vast majority of patients who arrived alive, but 10-12 mg of naloxone may be recommended if the suspicion is high and the clinical scenario is consistent. That's certainly too much naloxone for the initial routine injection for a symptomatic heroin overdose, but suffice it to say that it's warranted if standard doses are not effective.
Of course, supporting respiration is the main intervention required to keep the patient alive from opioid overdose. Occasionally bradycardia and hypotension intervene, but those who are alive upon hospital admission will likely be saved by intubation and mechanical ventilation alone. The downside of giving everyone large doses naloxone is that opioid withdrawal can be precipitated, which usually makes the patient miserable and causes him to want to leave prematurely. If one is experiencing a pattern of overdose that requires high doses of naloxone to reverse a seemingly straightforward heroin overdose, it may be time to send out some specimens to a local reference laboratory looking for fentanyl and these days, acetyl fentanyl.
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