a b s t r a c t

Background: Illicitly manufactured fentanyl and Fentanyl analogues (IMFs) are being increasingly suspected in overdose deaths. However, few prior outbreaks have been reported thus far of patients with laboratory- confirmed IMF toxicity after reporting intent to use only nonopioid substances. Herein we report a case series of nine patients without Opioid use disorder who presented to two urban emergency departments (EDs) with opioid toxicity after insufflating a substance they believed to be cocaine.

Case reports: Over a period of under three hours, nine patients from five discrete locations were brought to two affiliated urban academic EDs. All patients denied prior illicit opioid use. All patients endorsed insufflating co- caine shortly prior to ED presentation. Soon after exposure, all developed lightheadedness and/or respiratory de- pression. Seven patients received naloxone en route to the hospital; all had improvement in Respiratory function by arrival to the ED. None of the patients required any additional Naloxone administration in the ED. All nine pa- tients were discharged home after observation.

Blood +/- Urine samples were obtained from eight patients. All patients who provided specimens tested posi- tive for cocaine metabolites and had quantifiable IMF concentrations, as well as several detectable fentanyl deriv- atives, analogues, and synthetic opioid manufacturing intermediates.

Discussion: IMF-contamination of illicit drugs remains a Public health concern that does not appear to be re- stricted to heroin. This confirmed outbreak demonstrates that providers should elevate their level of suspicion for concomitant unintentional IMF exposure even in cases of non-opioid drug intoxication. Responsive public health apparatuses must prepare for future IMF-contamination outbreaks.

(C) 2020

1. Introduction

Illicitly-manufactured fentanyl and fentanyl analogues (IMFs) are being increasingly suspected in overdose deaths [1]. Though overall drug overdose deaths in the US decreased 4.6% between 2017 and 2018, synthetic opioid-associated deaths (excluding methadone) in- creased 10% over the same time period [2]. Fentanyl is 50-100 times more potent than morphine, and IMFs have become a common adulter- ant among illicit drug distributors and patients with Opioid use disorder . In 2018, fentanyl was found adulterating 32% of all heroin sam- ples analyzed by the Drug Enforcement Agency’s Fentanyl Signature Profiling Program [3]. In our experience, adulteration by IMFs is increas- ingly recognized among patients with OUD, but what has received less

* Corresponding author at: 455 1st Ave., Rm 123, New York 10016, USA.

E-mail address: [email protected] (P. DiSalvo).

attention is the contamination of non-opioid Illicit substances, such as cocaine, with IMFs.

To our knowledge, few prior outbreaks have been well-described of patients with laboratory-confirmed IMF toxicity after reporting intent to use only cocaine. Recently, nineteen patients were identified in Cali- fornia in 2019 with opioid toxicity after intending to insufflate cocaine; four patients had detectable fentanyl on blood and Urine analysis by LC/ MS, and three patients died [4]. In Philadelphia, PA in 2018, eighteen pa- tients without OUD were identified with opioid intoxication after intending to smoke crack cocaine. Fentanyl was identified in the urine by immunoassay and LC/MS of fifteen of the sixteen patients tested, and three patients died [5]. Similar outbreaks have been identified in New Haven in 2017 and British Columbia in 2016 [6,7].

Herein we report a case series of nine patients in New York City without OUD who presented to two urban emergency departments (EDs) with opioid toxicity, including seven requiring naloxone reversal for respiratory failure after insufflating cocaine.

https://doi.org/10.1016/j.ajem.2020.12.002

0735-6757/(C) 2020

Table 1

Blood fentanyl concentrations and naloxone doses administered before resolution of re- spiratory depression

Patient Blood [Fentanyl] Naloxone received

1 5.0 ng/mL 1 mg IN

2 4.8 ng/mL none

3 3.4 ng/mL 4 mg IN, 2 mg IN, 2 mg IV

4 3.0 ng/mL 4 mg IV

5 2.7 ng/mL 4 mg IN, 0.5 mg IV

6 2.6 ng/mL 4 mg IN, 2 mg IN, 2 mg IV

7 1.5 ng/mL 1 mg IN, 1 mg IV

8 1.1 ng/mL 2 mg IV

1. Narrative

Within a span of three hours in November 2019, nine patients from five discrete locations were brought to two affiliated academic EDs in New York City. All patients were in their third decade of life and denied prior illicit opioid use. Two patients reported prior opioid exposure in the form of prescribed analgesics only, both more than one year prior to presentation. One patient reported a remote history of deep venous thrombosis; all others denied any significant past medical history. All patients endorsed insufflating cocaine shortly prior to ED presentation. Over the seconds to minutes following insufflation, all patients devel- oped lightheadedness, and seven patients lost consciousness. In all cases of loss of consciousness, Emergency Medical Services (EMS) responded and found the patients to have respiratory depression re- quiring naloxone en route to the hospital. Doses ranged from 1 mg to 8 mg with an average dose of 4.2 mg, with variable intranasal and intra- venous administrations (Table 1). Four patients required multiple doses of naloxone for reversal of symptoms; two patients received two doses and two patients received three doses. All had improvement in respira- tory function by arrival to the ED. None of the patients required any ad- ditional naloxone administration in the ED. All nine patients reported nausea and/or emesis which resolved with Symptomatic treatment. All nine patients were discharged to home after observation periods ranging from 3 h 36 min to 8 h 13 min (average 5 h 30 min).

Blood samples were obtained from eight patients, and urine samples from six of these eight. One patient declined laboratory testing. Samples were analyzed with liquid chromatography or gas chromatography and mass spectrometry. All patients who provided specimens tested posi- tive for cocaine metabolites and had quantifiable serum fentanyl conc- entrations ranging from 1.1 ng/mL to 5.0 ng/mL (average 3.0 ng/mL). (Table 1) Other compounds detected were norfentanyl, n-methyl norfen- tanyl, 4-anilino-n-phenethylpiperidine (4-ANPP), beta-hydroxyfentanyl, acetylfentanyl, levamisole, lidocaine, benzoylecgonine, ethylbenzoyl- ecgonine, gabapentin, pregabalin, ondansetron, methylenedioxyamphe tamine, methylenedioxymethamphetamine, ethanol, cannabinoids, nico- tine, and cotinine. (Table 2) Original drug product samples were not avail- able for analysis from any patient.

law enforcement, poison control center staff, and the New York City Department of Health were alerted to a possible new adulteration/con- tamination of the local cocaine supply. To our knowledge, no further cases of fentanyl-contaminated cocaine intoxications have been identified since this outbreak in the catchment area of our poison control center.

1. Discussion

New challenges continue to present themselves in the fight against the opioid epidemic in the United States. IMF-contamination of illicit drugs is emerging as a public health concern that does not appear to be restricted to only heroin. In April of 2016, our municipal department of health issued the first of several Health Alert Network (HAN) advi- sories warning of the likelihood of fentanyl contaminating cocaine based on the presence of fentanyl found in overdoses cases not involv- ing heroin and based on analysis of police drug seizures. However there have been no reported laboratory-confirmed outbreaks in living patients without OUD in our area until this series.

The geographic and temporal proximity of our patients’ presenta- tions, combined with the overlap in fentanyl precursors and analogues found on laboratory testing, strongly suggests a common source. Inter- pretation of this data, however, is subject to a number of limitations, in- cluding variations in time between exposure and lab collection limiting interpatient comparability.

Table 2

Additional exogenous compounds detected.

4-ANPP = 4-anilino-N-phenethylpiperidine, D = positive qualitative detection, MDA = Methylene-dioxy-amphetamine, MDMA = Methylenedioxy methamphetamine NA = no urine available for analysis.

Therapeutic blood fentanyl concentrations have been reported in prior literature to range between 0.3 ng/mL to as high as 11 ng/mL for single intravenous doses [8,9]. While higher serum concentrations tend to be associated with fentanyl toxicity, there is significant overlap between therapeutic ranges and concentrations reported in cases of suspected toxicity [10,11]. Thus, the serum fentanyl concentration is of unclear clinical utility in suspected overdose. Instead, the clinical con- text and patient factors must be considered. Serum fentanyl concentra- tions ranged from 1.1 to 5 ng/mL in our patients, consistent with previously reported data. At such concentrations we would not have ex- pected our patients to have needed the high doses of naloxone that were documented by EMS for reversal of respiratory depression; this may reflect an element of the limitations of prehospital care and docu- mentation rather than resistance to naloxone.

Other compounds identified in our patients are commonly identified in patients who have used cocaine. Levamisole has been known to be an adulterant of cocaine since 2003, as well as lidocaine, first reported decades earlier [12,13]. The presence of methylenedioxymetham- phetamine (MDMA), ethanol, cannabinoids, nicotine, and cotinine in several patients reflects the high rate of coincident substance use disor- ders among our patients. Of the IMFs, norfentanyl, n-methyl norfen- tanyl, 4-ANPP, and beta-hydroxyfentanyl are all fentanyl metabolites; 4-ANPP is also an opioid manufacturing precursor, and beta- hydroxyfentanyl is also an active analogue. Acetylfentantyl is an active analogue.

Several characteristics of the IMFs make them appealing to the drug trafficking organizations. They can be readily pressed into counterfeit prescription opioid tablets and their potency makes the smuggling of relatively smaller masses of product economically viable. Mixtures of fentanyl into other drugs of abuse appears to be uncommon at the wholesale level, however, suggesting that contamination or adultera- tion takes place within the United States, and motives at the level of the retailers are speculative [3].

Several factors limit the identification of additional cases. Many hos- pitals do not routinely screen specifically for Fentanyl exposure and commonly used immunoassays for opioids do not detect IMFs. Local or regional syndromic surveillance systems, developed after the terror- ist attacks of September 11th, 2001 to track patterns emerging in emer- gency department visits, have been employed to monitor drug overdose cases, but may not have the granularity necessary to detect cases of in- toxication with contaminated nonopioids among the far more common opioid cases [14]. Prior experience with other toxicologic outbreaks in our area has demonstrated significant degrees of nonoverlap between cases identified with syndromic surveillance and those voluntarily re- ported to the poison control center [15]. Further problematizing identi- fication is the question of intent. The intentional simultaneous use of opioids and cocaine (“speedballing”) has been well described and can often be ascertained by history, but there is significant variability in clin- ical presentation.

The increasing prevalence of IMF toxicity demands that the respon- sible provider be knowledgeable about the treatment of opioid toxicity, elevate their level of suspicion for concomitant IMF exposure even in cases of non-opioid drug intoxication, and maintain commitment to vol- untary reporting to regional Poison control centers. Responsive public health apparatuses need to prepare for future IMF-contamination out- breaks and continue efforts to educate nonopioid users about risks of contamination.

Declaration of Competing Interest

None.

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