• Users Online: 843
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 5  |  Issue : 3  |  Page : 147-150

Fatal overdoses involving carfentanil: A case series


1 Wayne State University School of Medicine, 540 E Canfield St, Detroit, Michigan, USA
2 Department of Public Services, Oakland County Medical Examiners' Office, Oakland County, Pontiac, Michigan, USA

Date of Web Publication18-Sep-2019

Correspondence Address:
Ljubisa J Dragovic
Department of Public Services, Oakland County Medical Examiners' Office, Oakland County, 1200 N Telegraph #28, Pontiac, Michigan 48341
USA
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jfsm.jfsm_74_17

Rights and Permissions
  Abstract 


Carfentanil, an ultrapotent analog of fentanyl, has invaded the street drug market, unbeknownst to many heroin users. About 10,000 times more potent than morphine, it was initially suspected that 20 μg of the substance was lethal. In this case series, we present 17 confirmed carfentanil overdoses in Michigan, with a primary focus on the concentration levels. Through a retrospective review, each public death reported in Oakland County, Michigan, with a subsequent toxicology report was investigated for suspected carfentanil use. To characterize each fatality, the autopsy results were collected, including the postmortem findings at scene and the decedent's medical and social history. Carfentanil levels were measured through liquid chromatography and tandem mass spectrometry (LC-MS-MS) by National Medical Services (NMS) Laboratories. Our case series found postmortem carfentanil concentrations as low as 10 ng/mL, with a mean concentration of 0.387 ng/mL. Ultimately, there are implications on law enforcement, first responders, and health care providers when dealing with this emerging illicit substance, and there is an alarmingly high mortality rate associated with the abuse of carfentanil.

Keywords: Autopsy, carfentanil, death, epidemic, fentanyl, heroin, investigation, Michigan, opioid, overdose, polysubstance


How to cite this article:
Corsi NJ, Dragovic LJ. Fatal overdoses involving carfentanil: A case series. J Forensic Sci Med 2019;5:147-50

How to cite this URL:
Corsi NJ, Dragovic LJ. Fatal overdoses involving carfentanil: A case series. J Forensic Sci Med [serial online] 2019 [cited 2019 Nov 14];5:147-50. Available from: http://www.jfsmonline.com/text.asp?2019/5/3/147/267155




  Introduction Top


As fatalities have climbed, carfentanil, an ultrapotent analog of the synthetic opioid fentanyl, has elicited much concern from the medical community, including federal organizations such as the Drug Enforcement Agency (DEA).[1] Carfentanil is utilized as a general anesthetic agent for tranquilizing large animals, such as elephants, and is 10,000 times more potent than morphine.[2] Veterinarians must apply for the “Approved Carfentanil Users List” and obtain special DEA drug class approval.[3] Recently, heroin has been found to be laced with carfentanil. This drug is estimated to have a lethal dosage the size of an average grain of salt, at approximately 21 millionths of a gram.[4] Unfortunately, the exact biological and metabolic effects of the drug in humans are as yet unknown.[2],[4] It has been suggested that this opioid's high potency arises from the ease with which it crosses the blood–brain barrier and its high selectivity for mu-opioid receptors.[4],[5] This case series investigates 17 fatal intoxications involving carfentanil, considering the postmortem findings, autopsy results, and toxicological screenings.


  Background Top


As a central nervous system depressant, carfentanil's mechanism of action is through reduction of neuronal excitability.[6] Carfentanil is considered of the greatest concern among the fentanyl analogs,[7] and it is believed to cause death through respiratory arrest and pulmonary edema. From November 2016 to April 2017, 61 deaths by carfentanil were reported in eight European countries, with the majority also involving heroin.[8] Carfentanil, a schedule II drug, has concealed itself within the street drug market across North America. The current recommendations for emergency first responders treating a suspected opioid overdose include titrated naloxone doses and bag-valve-mask ventilation for respiratory therapy.[7] According to the American College of Medical Toxicology and the American Academy of Clinical Toxicology, the risk of clinically significant exposure to first responders is low, as incidental dermal absorption of fentanyl analogs such as carfentanil is unlikely to cause opioid toxicity.[9] Carfentanil has also evaded standard gas chromatography/mass spectrometry screening methods [10] in toxicological laboratories due to its potency. In 2016, 223 deaths with confirmed carfentanil concentrations were found in the state of Michigan,[11] and 17 such cases were detected only in Oakland County.


  Subjects and Methods Top


Through a retrospective review, every public death reported to the Oakland County Medical Examiner with a subsequent toxicological result was investigated for carfentanil use. The Oakland County Medical Examiner's Office (OCMEO) investigates and determines the cause and manner of death in any violent, sudden, suspicious, or otherwise unexplained death within Oakland County. In 2017, the US census estimated approximately 1.25 million people resided within Oakland County. This study includes all cases of carfentanil-related deaths in Oakland County over a 6-month period in 2016. Private cases, for which autopsy reports were not available to the public, were excluded from this study. OCMEO maintained a standardized toxicological workup protocol for drug-related fatalities throughout the duration of the study. All autopsies were completed by a forensic pathologist.

Postmortem specimen collection was conducted for all suspected drug-related fatalities. Each decedent's blood was extracted from the matrix source of the femoral artery during autopsy. When no femoral blood was present, specimens were then collected from heart blood or hospital blood. While hospital blood is not common within these 17 reported cases, for cases where it is available, it was collected while decedents were being evaluated in the emergency department. Initially, each decedent received a basic volatile screen and a fentanyl enzyme-linked immunosorbent assay test kit (ELISA). This forensic diagnostic tool confirmed the presence of a fentanyl metabolite. Fentanyl's ELISA cutoff concentration was around 0.5 ng/mL for an analyte of 10 μl or greater. If positive, an expanded postmortem, forensic, quantitative blood test is ordered through National Medical Services (NMS) Laboratories. The specimen sample size provided for an expanded screen ranged from as low as 2 mL of hospital blood to as high as 10.2 mL for femoral blood. Carfentanil spectra were then matched through a spectral library and measured through liquid chromatography and tandem mass spectrometry (LC-MS-MS). The minimum quantification level for carfentanil in femoral blood was 0.10 ng/mL and 0.20 ng/mL for hospital blood. 6-Monoacetylmorphine's (6-MAM) minimum reporting limit was at 1.0 ng/mL for femoral blood and 1.0 ng/mL for hospital blood. The presence of naloxone was also available through NMS's expanded postmortem drug screens which were performed through liquid chromatography/time-of-flight mass spectrometry.

The retrospective sampling approach involved a standardized case review form for each carfentanil-positive death. Each case review form systemically evaluated the decedent's known fatality history collected by EMS or police, postmortem findings, autopsy results, toxicological screenings, and pathological diagnosis by a physician. The value of central interest in each case was the concentration of carfentanil. To characterize the fatality, each case review form gathered the medical and social history, postmortem findings at scene, autopsy results, and toxicological screenings. All available histories documented by the police report, medicolegal investigator, hospital record, and witness statements were reviewed. Evidence of injury and evidence of therapy for each of the decedents in the autopsy report were recorded as well as pathological findings. Demographic determinates such as place of death, age, sex, and preexisting medical conditions were also collected.


  Results Top


In these 17 cases, the mean age was 35.7 years; the youngest was 21 and the oldest was 51. Sixty-one percent of the decedents were below the age of 35 years. Fifteen decedents were Caucasian and two were African-American. Only two decedents were female, and the remaining 15 were male.

Based on the history of each case, the pathological findings, and the toxicology results, the cause of death was determined to be drug abuse in ten cases, drug intoxication in six cases, and drug overdose in the final case, per the forensic pathologist's report. Only five of the decedents had preexisting medical conditions verified on autopsy that might have contributed to their cause of death. There was arteriosclerotic heart disease in one 48-year-old male, obesity in one 29-year-old male, and emphysema of the lungs with arteriosclerotic heart disease in one 55-year-old male. One 42-year-old decedent had findings of chronic obstructive pulmonary disease and another 47-year-old male had hypertensive cardiovascular disease. The rest of the decedents were otherwise healthy individuals who had no anatomical evidence of trauma or preexisting disease.

The manner of death reported by the forensic pathologist was undetermined in 16 of the cases. the one exception was suicide by overdose. As reported by next of kin, the case of suicide had a history of self-harm ideation and depression. The decedent had overdosed in a wooded area adjacent to a rehabilitation facility within a church. Nine cases were found dead either in their own home or in an acquaintance's dwelling. Four were pronounced dead on arrival/en route to the hospital; three expired in the emergency room.

[Table 1] offers the toxicological results. Postmortem toxicology results were interpreted in the context of all available medical evidence. In the 17 decedents' toxicological profiles, 15 had blood samples taken from the femoral matrix source, 1 from heart blood, and 1 from hospital blood. As quantified by NMS laboratories, every case presented with a complex panel of drugs. There was not a single case with only carfentanil in the bloodstream. The largest detected carfentanil concentration was 1.2 ng/mL and the smallest was <0.10 ng/mL. [Figure 1] details the case-specific concentrations of carfentanil. The greatest concentration of 6-MAM, detected at 31 ng/mL, was found in conjunction with the largest concentration of carfentanil. The least medicinally diverse case tested positive for carfentanil, naloxone, 11-hydroxy-delta-9 tetrahydrocannabinol (THC), delta-9-carboxy THC, and delta-9 THC. Carfentanil was found to be coupled with antidepressants in seven cases, including bupropion, alprazolam, and O-desmethylvenlafaxine. The greatest mixture of illicit substances included U-47700, furanylfentanyl, diazepam, nordiazepam, free-morphine, free-oxycodone, and diphenhydramine. U-47700 is an emerging nonfentanyl-based synthetic opioid that has about 7.5 times the potency of morphine.[12] This decedent was noted to be on prescribed dicyclomine as well as prednisone. According to the medicolegal investigator report, the decedent had a fresh needle mark on his left antecubital fossa and was holding a syringe in his right hand at the time he was found by EMS. First responders had issued a naloxone kit and “administered one full dose,” per investigators. U-47700 was found in conjunction with carfentanil in three instances, which all were derived from femoral blood sources.
Table 1: Toxicological screenings

Click here to view
Figure 1: Bar graph with case-specific carfentanil-positive test results

Click here to view


[Table 2] depicts the autopsy results of cases in which fresh needle tracks were localized within the right antecubital fossa or inner aspect of the right wrist. Four cases presented with biventricular hypertrophy and three demonstrated left ventricle myocardium hypertrophy. On internal examination of the respiratory tract, the lumen of the larynx and trachea possessed abundant frothy fluid in 12 cases. All cases exhibited remarkable pulmonary congestion, ranging from moderate to severe pulmonary edema.
Table 2: Autopsy results

Click here to view


[Table 3] offers a numerical breakdown of the postmortem findings at scene. The six cases of illicit drug paraphernalia included heroin powder, a syringe cap and lighter, sponge with chore boy, glass pipe, and one instance of brown powder, which led to an inconclusive heroin field test. Of the 11 chronic substance users, 7 either actively abused heroin or had used within the past 6 months prior to their death, per family members and friends.
Table 3: Postmortem findings

Click here to view



  Discussion Top


As the opioid epidemic continues to evolve, there are growing data on postmortem carfentanil concentrations and confirmed overdose deaths.[10] In the Midwest region, it was reported by Shanks and Behonick that there were 262 identified postmortem blood specimens with carfentanil [13] detected by LC-MS-MS. Swanson et al. provided two case reports of carfentanil overdose, which included a heart blood carfentanil concentration of 1.3 ng/mL and another with a heart blood concentration of 0.12 ng/mL from NMS laboratories. In our findings, there was not a single concentration above 1.3 ng/mL. Our study found postmortem concentrations as low as 0.10 ng/mL, thus reaffirming this fentanyl analog's excessive toxicity. While the lethal dose of carfentanil in humans is unknown, it was previously suggested by Prekupec et al. that the relative potency from animal models estimates 20 μg of carfentanil could induce death.[4]

With the most detrimental effects relative to other commonly abused drugs, it is evident that carfentanil played a significant role in each death presented. However, it is challenging to pin down the extent that other drugs contributed to the death. Mu-opioid receptor agonists, such as carfentanil, induce adverse side effects such as respiratory depression and apnea.[14],[15] This mechanism of fatality was reflected within the autopsy findings of pulmonary edema in all cases. Noncardiogenic pulmonary edema is a terminal finding associated with multiple opioid intoxications. In particular, the effects of noncardiogenic pulmonary edema from opioid overdose include hypoxemia, respiratory acidosis, and decreased lung volumes and lung compliance.[16] Our results also considered the clinical findings of overdose victims, using lung mass as a diagnostic criterion for acute pulmonary distress.

For first responders reversing the effects of carfentanil intoxication, naloxone acts a mu-opioid receptor antagonist. Due to the predicted potency of carfentanil, Leen and Juurlink. reported that the initial naloxone dose administered by first responders should be greater than the maximum empiric dose (0.4 mg intravenous/intramuscular or 2 mg IN) recommended by the American Heart Association.[17] In addition, Birmingham et al.'s 2-year review examining emergency department overdoses of mixed opioids and heroin showed that the amount of naloxone needed per patient to titrate into consciousness has increased.[18] In review of our toxicological results, naloxone was detected and used to reverse respiratory depression from carfentanil in six instances. In one case, a decedent was found unconscious and given two doses of 0.4 mg naloxone with no vital response en route to the emergency department.

In addition, the methods presented in this study could perhaps provide a template for medical examiner offices to monitor carfentanil-related deaths through standardized toxicological screening. Shoff et al. conducted a study testing a comprehensive and sensitive screening method, through UHPLC-Ion Trap-MS n, to identify carfentanil.[19] They found 134 cases of carfentanil within 375 instances of illicit fentanyl analog use. However, this study only provided carfentanil detection results, without quantification values. Our study's mandate of requesting an expanded drug screen reduces toxicological discrepancies between cases. As the drug market constantly evolves, toxicologists and law enforcement continue to battle the ongoing “revolving door” of synthetic opioids. The expanded blood screen, through LC-MS-MS, can lead to greater accuracy in identifying unique designer drug overdoses. Our methods reaffirm the argument that GC-MS's detection limit for carfentanil is insufficient,[10] even though it is commonly used by medical examiner offices.

Certain limitations of this study merit attention. Of central concern, the small sample size of 17 fatalities prevents the results from reaching any significant conclusion regarding the trends in carfentanil deaths. Perhaps, further studies can instigate collaboration between medical examiner offices to establish testing protocol and quantify the trends in deaths from this opioid. In future research that builds on findings such as these, it may be possible to measure the impact of carfentanil on an epidemiological basis.


  Conclusion Top


This case series investigates the qualitative and postmortem quantitative characteristics of 17 carfentanil-related deaths. There is an alarmingly high mortality rate associated with the abuse of carfentanil and its increasing prevalence has implications. Even though each case here presented with unique polysubstance abuse, it is apparent that carfentanil contributed to their final death. This is attributable to carfentanil's extreme potency with respect to other commonly abused opioids.

Acknowledgment

The authors wish to acknowledge the following individuals and organizations whose efforts contributed to the success of this project: Diana Schell, Oakland County Medical Examiner Forensic Pathologists, NMS Laboratories, and Michigan State University Department of Epidemiology's T-32 Lab.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
United States Drug Enforcement Agency. DEA Releases 2016 Drug Threat Assessment: Fentanyl-Related Overdose Deaths Rising at an Alarming Rate. DEA Public Affairs; December, 2016. Available from; https://www.dea.gov/divisions/hq/2016/hq120616.shtml. [Last accessed on 2017 Jul 27].  Back to cited text no. 1
    
2.
Van Bever WF, Niemegeers CJ, Schellekens KH, Janssen PA. N-4-substituted 1-(2-arylethyl)-4-piperidinyl-N-phenylpropanamides, a novel series of extremely potent analgesics with unusually high safety margin. Arzneimittelforschung 1976;26:1548-51.  Back to cited text no. 2
    
3.
Lust EB, Barthold C, Malesker MA, Wichman TO. Human health hazards of veterinary medications: Information for emergency departments. J Emerg Med 2011;40:198-207.  Back to cited text no. 3
    
4.
Prekupec MP, Mansky PA, Baumann MH. Misuse of novel synthetic opioids: A Deadly new trend. J Addict Med 2017;11:256-65.  Back to cited text no. 4
    
5.
Feasel MG, Wohlfarth A, Nilles JM, Pang S, Kristovich RL, Huestis MA, et al. Metabolism of carfentanil, an ultra-potent opioid, in human liver microsomes and human hepatocytes by high-resolution mass spectrometry. AAPS J 2016;18:1489-99.  Back to cited text no. 5
    
6.
National Center for Biotechnology Information. Pubchem Compound Database. CID=62156. National Center for Biotechnology Information; 2017. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/carfentanil#section=Top. [Last accessed on 2017 Jul 29].  Back to cited text no. 6
    
7.
Cole JB, Nelson LS. Controversies and carfentanil: We have much to learn about the present state of opioid poisoning. Am J Emerg Med 2017;35:1743-5.  Back to cited text no. 7
    
8.
Frisoni P, Bacchio E, Bilel S, Talarico A, Gaudio RM, Barbieri M, et al. Novel synthetic opioids: The pathologist's point of view. Brain Sci 2018;8. pii: E170.  Back to cited text no. 8
    
9.
Moss MJ, Warrick BJ, Nelson LS, McKay CA, Dubé PA, Gosselin S, et al. ACMT and AACT position statement: Preventing occupational fentanyl and fentanyl analog exposure to emergency responders. Clin Toxicol (Phila) 2018;56:297-300.  Back to cited text no. 9
    
10.
Swanson DM, Hair LS, Strauch Rivers SR, Smyth BC, Brogan SC, Ventoso AD, et al. Fatalities involving carfentanil and furanyl fentanyl: Two case reports. J Anal Toxicol 2017;41:498-502.  Back to cited text no. 10
    
11.
Papsun D, Isenschmid D, Logan BK. Observed carfentanil concentrations in 355 blood specimens from forensic investigations. J Anal Toxicol 2017;41:777-8.  Back to cited text no. 11
    
12.
Rambaran KA, Fleming SW, An J, Burkhart S, Furmaga J, Kleinschmidt KC, et al. U-47700: A clinical review of the literature. J Emerg Med 2017;53:509-19.  Back to cited text no. 12
    
13.
Shanks KG, Behonick GS. Detection of carfentanil by LC-MS-MS and reports of associated fatalities in the USA. J Anal Toxicol 2017;41:466-72.  Back to cited text no. 13
    
14.
Ling GS, Spiegel K, Nishimura SL, Pasternak GW. Dissociation of morphine's analgesic and respiratory depressant actions. Eur J Pharmacol 1983;86:487-8.  Back to cited text no. 14
    
15.
Shook JE, Watkins WD, Camporesi EM. Differential roles of opioid receptors in respiration, respiratory disease, and opiate-induced respiratory depression. Am Rev Respir Dis 1990;142:895-909.  Back to cited text no. 15
    
16.
Radke JB, Owen KP, Sutter ME, Ford JB, Albertson TE. The effects of opioids on the lung. Clin Rev Allergy Immunol 2014;46:54-64.  Back to cited text no. 16
    
17.
Leen JL, Juurlink DN. Carfentanil: A narrative review of its pharmacology and public health concerns. Can J Anaesth 2019;66:414-21.  Back to cited text no. 17
    
18.
Birmingham LE, Nielson JA. An increase in per-patient naloxone requirements in an opioid epidemic. Am J Emerg Med 2017;35:1958-9.  Back to cited text no. 18
    
19.
Shoff EN, Zaney ME, Kahl JH, Hime GW, Boland DM. Qualitative identification of fentanyl analogs and other opioids in postmortem cases by UHPLC-ion Trap-MSn. J Anal Toxicol 2017;41:484-92.  Back to cited text no. 19
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Background
Subjects and Methods
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed477    
    Printed27    
    Emailed0    
    PDF Downloaded86    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]