Fatalities caused by novel opioids: a review

Figures & data

Figure 1. Structures of selected opioids.

Table 1. Publications reporting fatalities from fentanyl and other novel opioids.

Opioid(s) detected and country	Analytical method	Results	Comments	Reference*
Selected fentanyl publications
Eight fentanyl fatalities in Sweden	GC-MS-SIM	Blood (f) 0.2–17 ng/g (median 5 ng/g)	All involved other drugs including 5 with alcohol	Kronstrand et al. (1997) [17]
25 fatalities from fentanyl in Los Angeles, California (USA)	GC-MS-SIM	Blood (f) 3.1–43 ng/mL (n = 13); blood (h) 1.8–139 ng/mL (n = 23); liver 5.8–613 μg/kg (n = 22)	Abuse of transdermal patches; 15 were accidents caused by drug misuse and often with multiple drugs	Anderson et al. (2000) [31]
19 fentanyl fatalities in south western Virginia (USA)	GC-MS-SIM	Blood 2–48 ng/mL (median 18 ng/mL)	Misuse of fentanyl or abuse of fentanyl transdermal patches. Routes of administration were transdermal, transmucosal/oral, intravenous, and combinations of routes of administration. Others drugs detected	Kuhlman et al. (2003) [33]
Fentanyl patches in Belgium	LC-MS/MS	Fentanyl/(norfentanyl): blood (f) 21 ng/mL (<2 ng/mL); blood (left ventricular) 35 ng/mL (4 ng/mL); blood (s) 28 ng/mL (3 ng/mL); VH 20 ng/mL (<2 ng/mL)	10 Durogesic patches (100 μg/h) on body (elderly woman with cancer). No other drugs detected	Coopman et al. (2007) [27]
101 fentanyl deaths in Wayne county, Michigan (USA) (2005–2006)	GC-MS-SIM	Blood (f) 4–69 ng/mL (median 20 ng/mL); blood (h) 2–51 ng/mL (median 20 ng/mL)	A number had also heroin use confirmed possibly with added fentanyl; other drugs also detected; most had pulmonary edema and many also had coronary artery disease	Algren et al. (2013) [8]
81 fentanyl deaths in Montgomery county, Ohio (USA)	GC-MS	56 cases without concomitant use of heroin or cocaine: blood 1–48 ng/mL (median 9 ng/mL); 12 cases also with concomitant heroin use: blood 1–46 ng/mL (median 12 ng/mL); 7 cases also concomitant cocaine use: blood 3.3–34 ng/mL (median 6.3 ng/mL) and 6 with concomitant heroin and cocaine use: blood 3.9–60 ng/mL (median 14.5 ng/mL)	Most had additional drugs; evidence of diversion from pharmaceutical grade fentanyl and often disguised as heroin	Marinetti et al. (2014) [28]
Large series of fentanyl fatalities in Florida (USA)	GC-MS	Blood 2.5–50 ng/mL (median 9.7 ng/mL) (n = 46)	Fentanyl intoxication often involving other drugs; other cases died from other causes	Lee et al. (2016) [10]
Other fentanyl-related opioids
α-Methylfentanyl fatality in USA	GC-NPD	Blood 3.1 ng/mL; liver 78 ng/mg; bile 64 ng/mL	Despropionylfentanyl also detected presumptively as a possible metabolite	Gillespie et al. (1982) [62]
Sufentanil fatality in Missouri (USA)	GC-MS-SIM	Blood (h) 1.1 ng/mL; urine 1.3 ng/mL; VH 1.2 ng/mL	Young male anaesthetist self-injection; also with midazolam (Blood 50 ng/mL)	Ferslew et al. (1989) [88]
Three 3-methylfentanyl fatalities in Finland	LC-MS/MS	Cis-3-methyl fentanyl: blood 0.3–0.9 ng/mL (mean 0.5 ng/mL)	IV use; two with heroin, amphetamine and other drugs detected, 2 with liver disease; aged 30–41 years	Ojanpera et al. (2006) [64]
Series of 3-methylfentanyl deaths in Estonia	LC-MS/MS	Cis-3-methylfentayl: blood 0.06–3 ng/mL (median 0.9 ng/mL) Trans-3-methylfentanyl: blood 0.1–3.2 ng/mL (median 0.6 ng/mL)	100's in deaths in Estonia mainly from IV use, often with other drugs; site of blood not specified, average age 26 years	Ojanpera et al. (2008) [65]
14 fatalities from acetylfentanyl in USA	GC-MS	No details provided	Rhode Island (USA)	MMWR (2013) [112]
Nine AH-7921 fatalities in Sweden	HR-LC/MS	Blood (f) 0.08–0.99 μg/g (median 0.4 μg/g)	All cases involved other drugs and most victims had heavy lungs	Kronstrand et al. (2014) [68]
AH-7921 fatality in Delaware (USA)	GC-MS-SIM	Blood (f) 9.1 mg/L; blood (h) 3.9 mg/L; SC 120 mg	No other drugs were detected in blood	Vorce et al. (2014) [69]
Two AH-7921 fatalities in Norway	LC-MS/MS, HR-MS	Case 1: blood (f) 0.43 mg/L Case 2: blood (f) 0.33 mg/L	Case 1: 2-fluoroamphetamine, 3-methmethcathinone, codeine also detected in contributory concentrations Case 2: methoxetamine, etizolam, phenazepam, 7-aminonitrazepam, diazepam also detected in contributory concentrations	Karinen et al. (2014) [70]
28 MT-45 deaths in Sweden	No information given but likely to be similar to other publications reported by the Swedish laboratory	Blood 0.008–1.9 μg/g (median 0.35 μg/g)	Almost all used other drugs; two cases died from pneumonia, presumably secondary to drug toxicity and one case was an injury death, 6 cases were still under investigation	Evans-Brown et al. (2014) [75]
Five AH7921 fatalities in UK	No details	Blood 0.05–4.46 mg/L (median 0.58 mg/L)	No more details, other than additional drugs detected; two of which contributed to death.	Elliott et al. (2014) [71]
Acetylfentanyl fatality in San Diego, California (USA)	GC-MS-SIM	Blood (p) 260 ng/mL; blood (c) 250 ng/mL; VH 240 ng/mL; urine 2 600 ng/mL; liver 1 ng/mg	Young male with history of heroin abuse; likely IV use; initially detected as positive in fentanyl immunoassay	McIntyre et al. (2015) [39]
14 acetylfentanyl fatalities in Rhode Island (USA)	ELISA and GC-MS with 2 ng/mL cut-off	No blood concentration data provided	Most involved other drugs as well including cocaine, morphine/heroin, ethanol and benzodiazepines	Lozier et al. (2015) [116]
MT-45 fatality in USA	LC-MS/MS	Blood (f) 0.52 mg/L	Etizolam (0.035 mg/L), diphenhydramine 0.22 mg/L	Papsun et al. (2016) [77]
Ocfentanil death in Belgium	LC-MS/MS	Ocfentanil: blood (f) 0.015 mg/L; VH 0.012 mg/L; urine 0.006 mg/L	Young male snorting brown powder purchased over Internet. No other drugs detected in blood	Coopman et al. (2016) [66]
Butyrlfentanyl and acetyl fentanyl fatality in San Diego, California (USA)	GC-MS-SIM	Butrylfentanyl: blood (f) 0.058 mg/L; blood (c) 0.097 mg/L, liver 0.32 mg/kg; VH 0.04 mg/L; urine 0.67 mg/L; SC 170 mg Acetylfentanyl: blood (f) 0.038 mg/L; blood (c) 0.032 mg/L; liver 0.11 mg/kg; urine 0.54 mg/L; SC <70 mg	44-year old man found dead on bathroom floor: history of IV drug use; benzoylecgonine and levamisole also detected in blood	McIntyre et al. (2016) [47]
Two butyrylfentanyl fatalities in Richmond, Virginia or Tampa, Florida (USA)	LC-MS/MS	Case 1: butyrylfentanyl only detected, blood (f, h) 0.099, 0.22 mg/L; VH 0.032 mg/L, urine 0.064 mg/L; SC detected Case 2: butyrylfentanyl, blood (f,h) 0.004; 0.009 mg/L; VH 0.01 mg/L; urine 0.002 mg/L; SC detected; acetyl fentanyl, blood (f,h) 0.021, 0.095 mg/L; VH 0.068 mg/L; urine 0.008 mg/L; SC detected	Case 1: Middle-aged woman found collapsed in bathroom, but died from drug toxicity a little while later Case 2: Middle-aged woman found deceased on her bed; known to abuse oxycodone with previous suicide attempts; also alprazolam and ethanol (0.011 g/100 mL) detected	Poklis et al. (2016) [117]
U-47700 fatality in UK	LC-MS/MS, HR-MS, PAD	Blood (f) 1.46 mg/L, also N-desmethyl- and N,N-didesmethyl metabolites likely	Young male found dead at home, also snorted mirtazapine, and used cannabis, ketamine and legal highs; no disease	Elliott et al. (2016) [79]
U-47700 fatality in Belgium	LC-MS/MS	U-47700: blood 13.8 ng/mL; urine 71 ng/mL Fentanyl also detected in blood 10.9 ng/mL	Young male found dead at home inhaling fumes from a powder; sertraline 0.18 mg/L also detected	Coopman et al. (2016) [80]
Series of U-47700 and/or furanylfentanyl involved drug deaths in USA	LC-MS/MS	U-47700: blood 0.017–490 mg/L (median 0.247 mg/L) (n = 16) Furanylfentanyl: blood 0.002–76 mg/L (median 0.013 mg/L) (n = 8)	Blood, mainly femoral, some central. All bar one case involved multiple drugs including some with other opioids	Mohr et al. (2016) [56]
Acetylfentanyl fatality in West Virginia (USA)	LC-MS/MS, HR-MS	Blood (s) 235 ng/mL; liver 2 400 ng/g; urine 234 ng/mL; vitreous fluid 131 ng/mL	Young male found dead following likely IV injection; tadalafil and testosterone also detected	Cunningham et al. (2016) [89]
Acetylfentanyl, 4-methoxybutyrfentanyl and furanylfentanyl intoxications with survival in Sweden	LC-MS/MS, HR-MS	Acetylfentanyl: serum 0.6–52 ng/mL (n = 9) 4-Methoxybutyrfentanyl: serum 1.3–11 ng/mL (n = 4) Furanylfentanyl: serum 148 ng/mL (n = 1)	Other psychoactive drugs detected; many used nasal route, some oral. STRIDA project	Helander et al. (2016) [37]
Butyrfentanyl fatality in Switzerland	LC-MS/MS, HR-MS	Blood (f) 66 ng/mL; blood (h) 39 ng/mL; liver 57 ng/g; highest concentration detected in lung tissue; carboxybutyr-, hydroxy-, desbutyl- and norbutyl- metabolites detected	Young male with history of drug use found dead in bathroom of his apartment	Staeheli et al. (2016) [48]
Carfentanil and furanylfentanyl in Florida (USA)	GC-MS-SIM	Case 1: blood (h) Carfentanil 1.3 ng/mL; furanylfentanyl 0.34 ng/mL; fentanyl 6 ng/mL Case 2: blood (h) Carfentanil 0.12 ng/mL	No fentanyl detected in femoral blood. Trace hydromorphone, morphine (total) and 6AM also detected in case 1. Cocaine metabolites also detected in case 2	Swanson et al. (2017) [55]
4-FBF fatality in Poland	LC-MS/MS	Case 1: blood 91 ng/mL; urine 200 ng/g; liver 902 ng/g Case 2: blood 112 ng/mL; urine 414 ng/g; liver 136 ng/g	Case 1: young male found dead Case 2: young female found dead, occasional user of novel psychoactive drugs	Rojkiewicz et al. (2016) [118]
Acetylfentanyl fatality in Japan	LC-MS/MS	Blood (h) 270 ng/mL; urine and gastric contents detected	Young male found dead by insufflation; no other drugs detected	Takase et al. (2016) [40]
Acetylfentanyl fatality in Japan	GC-MS and LC-MS/MS	Blood (f) 153 ng/mL; urine 240 ng/mL; gastric contents detected	4-Methoxy PV8 also contributed to death Blood (f) 389 ng/mL; history of methamphetamine abuse	Yonemitsu et al. (2016) [119]
Two Acetylfentanyl fatalities in Oklahoma (USA)	GC-MS-SIM	Case 1: blood (f) 192 ng/mL; blood (h) 285 ng/mL; urine 3 420 ng/mL; liver 1 100 ng/g Case 2: blood (f) 255 ng/mL; blood (h) 210 ng/mL; urine 2 720 ng/mL; VH 140 ng/mL	Case 1: young male found dead in bed; fluoxetine and methoxetamine also detected Case 2: middle aged woman found dead in bed; history of seizures and prescription drug and alcohol abuse; venlafaxine, chlordiazepoxide also detected	Fort et al. (2016) [120]
Two U-47700 fatalities in Germany	LC-MS/MS	Case 1: blood (f) 525 ng/mL; blood (h) 1 347 ng/mL; urine 1 393 ng/mL; liver 4.3 ng/mg Case 2: blood (f) 819 ng/mL; blood (h) 1 043 ng/mL; urine 1 848 ng/mL; Liver 3.1 ng/mg	Case 1: diphenidine, methoxyphenidine, ibuprofen and naloxone detected Case 2: diphenhydramine and methylphenidate detected; all in therapeutic levels	Dziadosz et al. (2017) [121]
Ocfentanil fatality in Switzerland	LC-MS/MS	Blood (f) 9.1 ng/mL (fluoride); 7.5 ng/mL (heparin); blood (h) 27.9 ng/mL; urine 480 ng/mL; nasal swab 360 ng	Young male found dead; brown powder located	Dussy et al. (2016) [67]
Severn furanylfentanyl fatalities in Sweden	LC-MS/MS	Blood 0.38 – 2.74 ng/g (median 0.9)	Five had other drugs also detected; four also had pregabalin detected	Guerrieri et al. (2017b) [57]
U-47700 death in Texas (USA)	GC-MS	U-47700: blood (f) 0.36 mg/L	Young male found dead with 3-fluorophenmetrazine (3-FPM, Blood (f) = 2.4 mg/L) also detected together with amitriptyline, diazepam, methamphetamine tr, flubromazolam and delorazepam	Ellefsen et al. (2017) [122]
40 acrylfentanyl fatalities in Sweden	LC-MS/MS	Blood 0.01– 5 ng/g (median 0.2 ng/g)	Most had other drugs also detected	Guerrieri et al. (2017) [42]
Fatalities in Germany	LC-QTOF-MS	Case 1: AH-7921, blood (f) 0.45 mg/L; blood (h) 0.48 mg/L; liver 0.53 mg/kg; urine 0.76 mg/L; VH 0.19 mg/L; hair detected Case 2: MT-45, blood (f) 0.66 mg/L; blood (h) 1.3 mg/L; liver 0.024 mg/kg; urine 0.37 mg/L; VH 0.26 mg/L	Drug-caused deaths, primarily by opioid, but other drugs also present Case 1: trace or low amounts of methadone, diphenhydramine, tetrazepam, methamphetamine, mirtazapine Case 2: trace or low amounts of lidocaine, PB-22, 5F-AKB-48	Fels et al. (2017) [72]
Two 4-fluorofentanyl deaths in Germany	LC-MS/MS	4-Flourofentanyl: blood 25–35 ng/mL; also detected in other specimens	Both suicides; young male and female with history of psychological problems and abuse of narcotics	Strehmel et al. (2017) [87]
Two furanylfentanyl deaths in Canada	No details given	Case 1: furanylfentanyl, blood 1.1 ng/mL Case 2: furanylfentanyl, blood 0.68 ng/mL (AM)	Both young women using Perocet but containing this fentanyl and alprazolam. Highlights a series of such deaths also seen in British Columbia	Milroy and Kepron (2017) [58]
o-Flourofentanyl death in Sweden	LC-MS/MS, HR-MS	o-Flourofentanyl: blood 2.4 ng/mL, urine 3.9 ng/mL	Young male who had a few days previously been admitted for an overdose found dead from likely snorting a white powder containing opioid; also alprazolam, clonazepam, diazepam metabolite and THC detected	Helland et al. (2017) [86]
25 deaths from fentanyl or fentanyl analogues (carfentanil, with butryfentanyl, flourobutryfentanyl) in UK	LC-HR-MS	Carfentanil: blood 0.09–4 ng/mL (median 0.3) (n = 22), AM 0.021–0.098 ng/mL (n = 3) Fentanyl: blood 1–3.1 ng/mL (n = 6) Butryfentanyl and 4-butryfentanyl detected with carfentanil positive cases Also alfentanil (n = 1) and despropionylfentanyl det (n = 1), furanylfentanul (n = 2)	All cases other drugs also detected, often morphine and more than one fentanyl	Hikin et al. (2017) [49]
U-47700 fatality in San Diego, California (USA)	GC-MS-SIM	Blood (f) 0.19 mg/L; blood (c) 0.34 mg/L; VH 0.17 mg/L; urine 0.36 mg/L, SC trace	Middle-aged man found unresponsive in bed; known drug user, thought to have snorted drug; dilated left ventricle, congested lungs, some steatosis. Alprazolam, doxylamine, nordiazepam, diphenhydramine, ibuprofen, salicylic acid and THC-acid also detected	McIntyre et al. (2017) [123]
47 Acryl(oyl)fentanyl deaths in Nordic countries; numerous ED admissions	Likely to be LC-MS/MS or HR-MS	No details given of concentrations for fatalities; non-fatal mono-intoxications with serum concentrations ranging from 0.8 to 2.1 ng/mL (n = 8)	Also see EMCDDA site [124] and [43]	Ujváry et al. (2017) [44]
355 carfentanil deaths in USA	HR-LC/MS	Blood 0.1–14 ng/mL (median 38 ng/mL)	Many were acute deaths but no details were provided; four were human performance cases with blood concentrations 0.41–1.4 ng/mL; most involved other drugs including fentanyl, heroin and cocaine	Papsun et al. (2017) [54]
10 deaths from various fentanyls in Miami, Florida (USA)	LC-ion trap MS	Six cases with carfentanil, 3 cases of p-fluoroisobutryfentanyl and furanylfentanyl, and one each of acetylfentanyl, β-OH-thiofentanyl. Most had 2 or more fentanyls including fentanyl (n = 8)	No quantitative data provided; all cases had multiple drugs contributing to death	Shoff et al. (2017) [105]
Death each from carfentanil and furanylfentanyl in Tampa, Florida (USA)	Likely LC-MS/MS at a reference laboratory [125]	Case 1: carfentanil, blood (h) 1.3 ng/mL; furanylfentanyl, blood (h) 0.34 ng/mL Case 2: carfentanil 0.12 ng/mL	Case 1: young male also with traces of morphine and hydromorphone Case 2: young female with traces of cocaine	Swanson et al. (2017) [55]
Seven deaths with acetylfentanyl, plus 10 deaths with fentanyl in Tampa, Florida (USA)	Immunoassay (fentanyl) plus GC-MS-SIM	Acetylfentanyl: blood (f) 2–600 ng/mL (median 0.31 ng/mL) (n = 7) Fentanyl: blood 4–38 ng/mL (median 16) (n = 10)	All cases were mixed intoxications including these 2 drugs, heroin or other opiates/opioids and/or other drugs	Pearson et al. (2015) [97]
Nine deaths with furanylfentanyl and two with U-47700 in Tennessee (USA)	HR-MS and LC-MS/MS	Furanylfentanyl: blood (f) 2–42.9 ng/mL (median 6.5 ng/mL) U-47700: blood (f) 189 and 547 ng/mL	All cases were mixed intoxications including other opiates/opioids and/or other drugs	Papsun et al. (2017) [60]
U-47700 fatality in Wichita, Kansas (USA)	GC-MS-SIM	Blood (f) 0.4 ng/mL; blood (h) 0.26 ng/mL; urine 4.6 ng/mL; VH 0.09 ng/mL; liver 0.28 ng/mg	Young male obese drug user with enlarged heart and oedematous, congested lungs; THC Blood (h) 19 ng/mL, possible trace phencyclidine	Rohrig et al. (2017) [82]
Three acrylfentanyl fatalities (one also with furanylfentanyl) in Charleston, South Carolina (USA)	GC-MS-SIM	Acrylfentanyl: blood (p) 0.3, 0.95 and 0.32 ng/mL Furanylfentanyl: blood (p) 0.95 ng/mL (case 3)	Three male drug users, all with other drugs detected. LOQ 0.1 ng/mL	Butler et al. (2017) [46]
Numerous carfentanil deaths from various US states	LC-MS/MS	Carfentanil: blood 10–2 000 pg/mL (median 193 pg/mL) (n = 262) 13 case reports listed: blood 10–529 pg/mL (median 114 pg/mL)	Most cases involved other drugs, and in a few heart disease; LOD 5 pg/mL, LLOQ 10 pg/mL	Shanks and Behonick (2017) [125]
4-Fluoroisobutyr-fentanyl fatality in Sweden	LC-MS/MS and HR-MS	4-Fluoroisobutyrfentanyl: serum 38 ng/mL	No other drugs detected; opioid used IV Other opioids detected in other non-fatal admissions to emergency	Helander et al. (2017) [43]
41 acetylfentanyl fatalities in Pennsylvania (USA)	ELISA and GC-MS-SIM	Acetylfentanyl: blood (f,h) 0.1–2 100 ng/mL (median 11 ng/mL)	26 cases were also with fentanyl; all bar one were multiple drug toxicities; mono-intoxication: blood (f) 170 ng/mL	Dwyer et al. (2017) [38]
Furanylfentanyl fatality in San Francisco, California (USA)	ELISA and GC-MS-SIM; confirmation possibly by LC-MS/MS	Blood (p) 1.9 ng/mL; blood (h); VH <0.2 ng/mL, 2.8, SC 55 μg 4-ANPP metabolite also detected	Young man found dead following ingestion of a blue pill resembling oxycodone, found to be furanylfentanyl. No other drugs detected. Pulmonary and cerebral oedema, some coronary artery disease	Martucci et al. (2017) [59]

*Publications arranged in order of publication year; f: femoral; h: heart; s: subclavian; c: central; p:peripheral; VH: vitreous humour; SC: stomach contents; LC-MS/MS: tandem mass spectrometry with liquid chromatography; GC-NPD: gas chromatography with nitrogen phosphorous detection; GC-MS-SIM: selected ion monitoring mass spectrometry with gas chromatography; HR-MS: high-resolution mass spectrometry; PAD: photodiode array detection; STRIDA: Swedish project involving Karolinska Institute and Laboratory and Swedish Poisons Information Centre; AM: antemortem; 4-Methoxy PV8: 1-(4-methoxyphenyl)-2-(pyrrolidine-1-yl)hepatan-1-one; 4-ANPP: 4-anilino-N-phenethylpiperidine; ELISA: enzyme linked immunosorbent assay; LC-QTOF-MS: liquid chromatography-quadruple time-of-flight mass spectrometry.

Table 2. Analysis details for published methods targeting two or more fentanyls.

Type of Analysis	Specimen(s)	Extraction technique and conditions	Chromatography	Analysis technique and conditions	Reference*
Quantitative analysis of fentanyl, alfentanil, sufentanil and metabolites	Urine (no hydrolysis)	SPE using Extrelut® NT1; elution with n-heptane/isoamyl alcohol (98.5:1.5)	GC using pentafluorobenzamide derivatives on a DB-35 capillary column	MS-SIM; LOD from 0.002 5 ng/mL; deuterated IS	Van Nimmen et al. (2004) [98]
Quantitative analysis of 13 fentanyls: alfentanil, carfentanil, fentanyl, lofentanil, ohmefentanyl, 3-methylfentanyl, α-methylfentanyl, sufentanil and some metabolites	Urine (no hydrolysis)	SPE Oasis HLB C18 columns; eluted with MeOH	LC using a Xterra MS C18 column (2.1 mm × 150 mm, 3.5 μm); ammonium acetate buffer in 95:5 MeOH/ACN gradient	Micromass Quattro Ultima triple quadrupole MS; LOD 0.003 – 0.027 ng/mL; deuterated IS	Wang et al. (2006) [104]
Quantitative analysis of 9 fentanyls: alfentanil, fentanyl, p-fluorofentanyl, cis-3-methylfentanyl, trans-3-methylfentanyl, α-methylfentanyl, norfentanyl, remifentanil, sufentanil and other opioids	Blood, urine (β-glucuronidase hydrolysis) (PM)	LLE extraction using butyl acetate	LC using Gemini C18 column (100 mm × 2.0 mm, particle size 3 μm); using an acetonitrile–ammonium acetate gradient at pH 3.2	MS/MS Sciex 3200 QTrap, MRM; LOQ 0.01–0.2 ng/mL; deuterated IS	Gergov et al. (2009) [102]
Quantitative analysis of 6 fentanyls: alfentanil, fentanyl, 3-methylfentanyl, remifentanil, norfentanyl, sufentanil	Plasma and urine	LLE from K2CO3 basified specimen using n-hexane:ethylacetate (7:3)	LC XTerra MS C18 (2.1 mm × 150 mm, 3.5 μm); moving phase 0.15% formic acid in ACN gradient	MS/MS with MRM (Waters Quattro) LLOQ from 0.1 ng/mL; deuterated IS	Cooreman et al. (2010) [100]
Quantitative analysis of 10 fentanyls: alfentanil, carfentanil, fentanyl, lofentanil, 3-methylfentanyl, α-methylfentanyl, sufentanil, and some metabolites	Urine (no hydrolysis)	SPE Oasis HLB 30 μm columns; eluting with 1% formic acid in ACN, plus on-line extraction	LC Symbiosis system using a 3.0 mm × 50 mm XTerra MS C18 column with 2.5 μm; 1% formic acid ACN gradient	Sciex 5500 Qtrap, ESI, RM; LOQ 0.01 – 0.05 ng/mL; deuterated IS	Shaner et al. (2014) [103]
Quantitative analysis of 5 fentanyls: alfentanil, fentanyl, norfentanyl, remifentanil, sufentanil and other opioids	Serum/blood and PM tissues	SPE with Bakerbond C18; eluted with DCM/isopropanol/ammonium hydroxide (40:10:2)	LC using Zorbax Eclipse Plus C18 (2.1 mm × 150 mm, 1.8 μm); eluted with DCM/2-propanol/ammonium hydroxide (40:10:2)	MS (Agilent 6490 TQ) ESI MRM; LLOQ 0.1 ng/mL or higher; deuterated IS	Eckart et al. (2015) [99]
Quantitative analysis of furanylfentanyl, U-47700 and U-50488	Blood	SPE using CleanScreen® DAU columns; elution with® DCM/MeOH/ammonium hydroxide (78:20:2)	LC using Zorbax Eclipse plus C18 (4.6 mm × 200 mm, 3.5 μm); mobile phase 0.1% formic acid in MeOH	MS/MS MRM (Agilent TQ); LOD 0.5 ng/mL, LOQ 1 ng/mL; deuterated IS	Mohr et al. (2016) [56]
Quantitative analysis of 6 fentanyls: acetylfentanyl, carfentanil, 3-methylfentanyl, 2-furanylfentanyl, norfentanyl; fentanyl	Blood, vitreous humour	SPE using mixed mode CleanScreen® ZSDAU020 cartridges; then eluted with DCM:isopropanol:ammonium hydroxide (78:20:2)	LC Kinetex F5 column (50 mm × 2.1 mm I.D., particle size 1.7 μm); 0.1% formic acid and ACN gradient	Thermo ESI MRM LC-MS/MS LOQ from 0.1 ng/mL acetylfentanyl, carfentanil; deuterated IS	Sofalvi et al. (2017) [101]
Qualitative analysis for 15 fentanyls (alfentanil, 3-methylfentanyl, acetylfentanyl, β-hydroxyfentanyl, Butyrfentanyl, carfentanil, desproprionylfentanyl, fentanyl, norfentanyl, furanylfentanyl, p-fluorobutyrfentanil, p-fluoroisobutyrfentanyl, sulfentanil, U-47700, W-18 and 30 other opioids/analgesics)	Blood, urine, liver and brain homogenates	SPE CleanScreen® mixed mode from basified specimen; washed, then eluted with DCM:isopropanol:ammonium hydroxide (78:20:2)	uHPLC (Thermo Acclaim RSLC 120 C18 – 2.1 mm × 100 mm, 120 A); mobile phase 2 mmol/L ammonium formate, 0.1% formic acid, ACN gradient	Ion Trap-MS (Bruker AmaZon Speed) ESI full scan with MS^2 and MS^3 for selected compounds; LOD 0.1-0.5 ng/mL; deuterated IS	Shoff et al. (2017) [105]

*In order of publication starting 2000; A: angstrom; ACN: acetonitrile; DCM: dichloromethane; DAU: drugs of abuse; ESI: electrospray ionization; IS: internal standard; LC: liquid chromatography; LLE: liquid–liquid extraction; LOD: limit of detection; LOQ: limit of quantitation; LLOQ: lower limit of quantitation; GC: gas chromatographic; MeOH: methanol; MRM: multiple reaction mode; MS: mass spectrometry; PM: postmortem; SPE: solid phase extract.

Kronstrand R, Druid H, Holmgren P, et al. A cluster of fentanyl-related deaths among drug addicts in Sweden. Forensic Sci Int. 1997;88:185–193.

 PubMed Web of Science ®Google Scholar

Anderson DT, Muto JJ. Duragesic® transdermal patch: postmortem tissue distribution of fentanyl in 25 cases. J Anal Toxicol. 2000;24:627–634.

 PubMed Web of Science ®Google Scholar

Kuhlman JJ Jr., McCaulley R, Valouch TJ, et al. Fentanyl use, misuse, and abuse: a summary of 23 postmortem cases. J Anal Toxicol. 2003;27:499–504.

 PubMed Web of Science ®Google Scholar

Coopman V, Cordonnier J, Pien K, et al. LC-MS/MS analysis of fentanyl and norfentanyl in a fatality due to application of multiple Durogesic transdermal therapeutic systems. Forensic Sci Int. 2007;169:223–227.

 PubMed Web of Science ®Google Scholar

Algren DA, Monteilh CP, Punja M, et al. Fentanyl-associated fatalities among illicit drug users in Wayne County, Michigan (July 2005–May 2006). J Med Toxicol. 2013;9:106–115.

 PubMedGoogle Scholar

Marinetti LJ, Ehlers BJ. A series of forensic toxicology and drug seizure cases involving illicit fentanyl alone and in combination with heroin, cocaine or heroin and cocaine. J Anal Toxicol. 2014;38:592–598.

 PubMed Web of Science ®Google Scholar

Lee D, Chronister CW, Broussard WA, et al. Illicit fentanyl-related fatalities in Florida: toxicological findings. J Anal Toxicol. 2016;40:588–594.

 PubMed Web of Science ®Google Scholar

Gillespie TJ, Gandolfi AJ, Davis TP, et al. Identification and quantification of alpha-methylfentanyl in post mortem specimens. J Anal Toxicol. 1982;6:139–142.

 PubMed Web of Science ®Google Scholar

Ferslew KE, Hagardorn AN, McCormick WF. Postmortem determination of the biological distribution of sufentanil and midazolam after an acute intoxication. J Forensic Sci. 1989;34:249–257.

 Web of Science ®Google Scholar

Ojanpera I, Gergov M, Rasanen I, et al. Blood levels of 3-methylfentanyl in 3 fatal poisoning cases. Am J Forensic Med Pathol. 2006;27:328–331.

 PubMed Web of Science ®Google Scholar

Ojanpera I, Gergov M, Liiv M, et al. An epidemic of fatal 3-methylfentanyl poisoning in Estonia. Int J Legal Med. 2008;122:395–400.

 PubMed Web of Science ®Google Scholar

Centers for Disease Control and Prevention. Acetyl fentanyl overdose fatalities–Rhode Island, March-May 2013. MMWR Morb Mortal Wkly Rep. 2013;62:703–704.

 PubMed Web of Science ®Google Scholar

Kronstrand R, Thelander G, Lindstedt D, et al. Fatal intoxications associated with the designer opioid AH-7921. J Anal Toxicol. 2014;38:599–604.

 PubMed Web of Science ®Google Scholar

Vorce SP, Knittel JL, Holler JM, et al. A fatality involving AH-7921. J Anal Toxicol. 2014;38:226–230.

 PubMed Web of Science ®Google Scholar

Karinen R, Tuv SS, Rogde S, et al. Lethal poisonings with AH-7921 in combination with other substances. Forensic Sci Int. 2014;244:e21–e24.

 PubMed Web of Science ®Google Scholar

Evans-Brown E, Cunningham A, Gallegos A, et al. MT-45 risk assessment. Lisbon: EMCDDA; 2014.

 Google Scholar

Elliott S, Bodenschaft C, Beran D. AH-7921: critical review report. Geneva: World Health Organization; 2014. p. 22.

 Google Scholar

McIntyre IM, Trochta A, Gary RD, et al. An acute acetyl fentanyl fatality: a case report with postmortem concentrations. J Anal Toxicol. 2015;39:490–494.

 PubMed Web of Science ®Google Scholar

Lozier MJ, Boyd M, Stanley C, et al. Acetyl fentanyl, a novel fentanyl analog, causes 14 overdose deaths in Rhode Island, March-May 2013. J Med Toxicol. 2015;11:208–217.

 PubMed Web of Science ®Google Scholar

Papsun D, Krywanczyk A, Vose JC, et al. Analysis of MT-45, a novel synthetic opioid, in human whole blood by LC-MS-MS and its identification in a drug-related death. J Anal Toxicol. 2016;40:313–317.

 Web of Science ®Google Scholar

Coopman V, Cordonnier J, De Leeuw M, et al. Ocfentanil overdose fatality in the recreational drug scene. Forensic Sci Int. 2016;266:469–473.

 Web of Science ®Google Scholar

McIntyre IM, Trochta A, Gary RD, et al. An acute butyr-fentanyl fatality: a case report with postmortem concentrations. J Anal Toxicol. 2016;40:162–166.

 PubMed Web of Science ®Google Scholar

Poklis J, Poklis A, Wolf C, et al. Two fatal intoxications involving butyryl fentanyl. J Anal Toxicol. 2016;40:703–708.

 Web of Science ®Google Scholar

Elliott SP, Brandt SD, Smith C. The first reported fatality associated with the synthetic opioid 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) and implications for forensic analysis. Drug Test Anal. 2016;8:875–879.

 PubMedGoogle Scholar

Coopman V, Blanckaert P, Van Parys G, et al. A case of acute intoxication due to combined use of fentanyl and 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700). Forensic Sci Int. 2016;266:68–72.

 PubMed Web of Science ®Google Scholar

Mohr AL, Friscia M, Papsun D, et al. Analysis of novel synthetic opioids U-47700, U-50488 and furanyl fentanyl by LC-MS/MS in postmortem casework. J Anal Toxicol. 2016;40:709–717.

 PubMed Web of Science ®Google Scholar

Cunningham SM, Haikal NA, Kraner JC. Fatal intoxication with acetyl fentanyl. J Forensic Sci. 2016;61 Suppl 1:S276–S280.

 PubMed Web of Science ®Google Scholar

Helander A, Backberg M, Beck O. Intoxications involving the fentanyl analogs acetylfentanyl, 4-methoxybutyrfentanyl and furanylfentanyl: results from the Swedish STRIDA project. Clin Toxicol (Phila). 2016;54:324–332.

 PubMed Web of Science ®Google Scholar

Staeheli SN, Baumgartner MR, Gauthier S, et al. Time-dependent postmortem redistribution of butyrfentanyl and its metabolites in blood and alternative matrices in a case of butyrfentanyl intoxication. Forensic Sci Int. 2016;266:170–177.

 Web of Science ®Google Scholar

Swanson DM, Hair LS, Strauch Rivers SR, et al. Fatalities involving carfentanil and furanyl fentanyl: two case reports. J Anal Toxicol. 2017;41:498–502.

 PubMed Web of Science ®Google Scholar

Rojkiewicz M, Majchrzak M, Celinski R, et al. Identification and physicochemical characterization of 4-fluorobutyrfentanyl (1-((4-fluorophenyl)(1-phenethylpiperidin-4-yl)amino)butan-1-one, 4-FBF) in seized materials and post-mortem biological samples. Drug Test Anal. 2017;9:405–414.

 Web of Science ®Google Scholar

Takase I, Koizumi T, Fujimoto I, et al. An autopsy case of acetyl fentanyl intoxication caused by insufflation of ‘designer drugs’. Leg Med (Tokyo). 2016;21:38–44.

 Web of Science ®Google Scholar

Yonemitsu K, Sasao A, Mishima S, et al. A fatal poisoning case by intravenous injection of “bath salts” containing acetyl fentanyl and 4-methoxy PV8. Forensic Sci Int. 2016;267:e6–e9.

 PubMed Web of Science ®Google Scholar

Fort C, Curtis B, Nichols C, et al. Acetyl fentanyl toxicity: two case reports. J Anal Toxicol. 2016;40:754–757.

 PubMed Web of Science ®Google Scholar

Dziadosz M, Klintschar M, Teske J. Postmortem concentration distribution in fatal cases involving the synthetic opioid U-47700. Int J Legal Med. 2017;131:1555–1556.

 PubMed Web of Science ®Google Scholar

Dussy FE, Hangartner S, Hamberg C, et al. An acute ocfentanil fatality: a case report with postmortem concentrations. J Anal Toxicol. 2016;40:761–766.

 Web of Science ®Google Scholar

Guerrieri D, Rapp E, Roman M, et al. Postmortem and toxicological findings in a series of Furanylfentanyl-related deaths. J Anal Toxicol. 2017;41:242–249.

 PubMed Web of Science ®Google Scholar

Ellefsen KN, Taylor EA, Simmons P, et al. Multiple drug-toxicity involving novel psychoactive substances, 3-Fluorophenmetrazine and U-47700. J Anal Toxicol. 2017;41:765–770.

 Web of Science ®Google Scholar

Guerrieri D, Rapp E, Roman M, et al. Acrylfentanyl: another new psychoactive drug with fatal consequences. Forensic Sci Int. 2017;277:e21–e29.

 Web of Science ®Google Scholar

Fels H, Krueger J, Sachs H, et al. Two fatalities associated with synthetic opioids: AH-7921 and MT-45. Forensic Sci Int. 2017;277:e30–e35.

 Web of Science ®Google Scholar

Strehmel N, Vejmelka E, Kastner K, et al. NPS-findings in forensic toxicology – three case reports. Toxichem Krimtech. 2017;84:199–204.

 Google Scholar

Milroy CM, Kepron C. Two deaths associated with Furanylfentanyl toxicity. Forensic Sci Int. 2017; IAFS special issue:88.

 Web of Science ®Google Scholar

Helland A, Brede WR, Michelsen LS, et al. Two hospitalizations and one death after exposure to ortho-fluorofentanyl. J Anal Toxicol. 2017;41:708–709.

 Web of Science ®Google Scholar

Hikin L, Smith PR, Hudson S, et al. Multiple fatalities in the North of England associated with synthetic fentanyl analogue exposure; detection and quantitation in a case series from early 2017. Forensic Sci Int. 2018;282:179–183.

 PubMed Web of Science ®Google Scholar

McIntyre IM, Gary RD, Joseph S, et al. A fatality related to the synthetic opioid U-47700: postmortem concentration distribution. J Anal Toxicol. 2017;41:158–160.

 Web of Science ®Google Scholar

Acryloylfentanyl. EMCDDA – Europol joint report on a new psychoactive substance. Lisbon: EMCDDA; 2017.

 Google Scholar

Helander A, Backberg M, Signell P, et al. Intoxications involving acrylfentanyl and other novel designer fentanyls — results from the Swedish STRIDA project. Clin Toxicol (Phila). 2017;55:589–599.

 PubMed Web of Science ®Google Scholar

Ujvary I, Jorge R, Christie R, et al. Acrylfentanyl, a recently emerged new psychoactive substance: a comprehensive review. Forensic Toxicol. 2017;35:232–243.

 Web of Science ®Google Scholar

Papsun D, Isenschmid D, Logan BK. Observed carfentanil concentrations in 355 blood specimens from forensic investigations. J Anal Toxicol. 2017;41:777–778.

 Web of Science ®Google Scholar

Shoff EN, Zaney ME, Kahl JH, et al. Qualitative identification of fentanyl analogs and other opioids in postmortem cases by UHPLC-Ion Trap-MSn. J Anal Toxicol. 2017;41:484–492.

 PubMed Web of Science ®Google Scholar

Shanks KG, Behonick GS. Detection of Carfentanil by LC-MS-MS and reports of associated fatalities in the USA. J Anal Toxicol. 2017;41:466–472.

 Web of Science ®Google Scholar

Pearson J, Poklis J, Poklis A, et al. Postmortem toxicology findings of acetyl fentanyl, fentanyl, and morphine in heroin fatalities in Tampa, Florida. Acad Forensic Pathol. 2015;5:676–689.

 Google Scholar

Papsun D, Hawes A, Mohr AL, et al. Case series of novel illicit opioid-related deaths. Acad Forensic Pathol. 2017;7:477–486.

 Google Scholar

Rohrig TP, Miller SA, Baird TR. U-47700: a not so new opioid. J Anal Toxicol. 2017;42:e12–e14.

 Web of Science ®Google Scholar

Butler DC, Shanks K, Behonick GS, et al. Three cases of fatal Acrylfentanyl Toxicity in the United States and a review of literature. J Anal Toxicol. 2018;42:e6–e11.

 PubMed Web of Science ®Google Scholar

Dwyer JB, Janssen J, Luckasevic TM, et al. Report of increasing overdose deaths that include acetyl fentanyl in multiple counties of the southwestern region of Pennsylvania in 2015–2016. J Forensic Sci. 2017;63:195–200.

 Web of Science ®Google Scholar

Martucci HFM, Ingle EA, Hunter MD, et al. Distribution of furanyl fentanyl and 4-ANPP in an accidental acute death: a case report. Forensic Sci Int. 2018;283:e13–e17.

 Web of Science ®Google Scholar

Van Nimmen NF, Poels KL, Veulemans HA. Highly sensitive gas chromatographic-mass spectrometric screening method for the determination of picogram levels of fentanyl, sufentanil and alfentanil and their major metabolites in urine of opioid exposed workers. J Chromatogr B Analyt Technol Biomed Life Sci. 2004;804:375–387.

 PubMed Web of Science ®Google Scholar

Wang L, Bernert JT. Analysis of 13 fentanils, including sufentanil and carfentanil, in human urine by liquid chromatography-atmospheric-pressure ionization-tandem mass spectrometry. J Anal Toxicol. 2006;30:335–341.

 Web of Science ®Google Scholar

Gergov M, Nokua P, Vuori E, et al. Simultaneous screening and quantification of 25 opioid drugs in post-mortem blood and urine by liquid chromatography-tandem mass spectrometry. Forensic Sci Int. 2009;186:36–43.

 PubMed Web of Science ®Google Scholar

Cooreman S, Deprez C, Martens F, et al. A comprehensive LC-MS-based quantitative analysis of fentanyl-like drugs in plasma and urine. J Sep Sci. 2010;33:2654–2662.

 Web of Science ®Google Scholar

Shaner RL, Kaplan P, Hamelin EI, et al. Comparison of two automated solid phase extractions for the detection of ten fentanyl analogs and metabolites in human urine using liquid chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2014;962:52–58.

 Web of Science ®Google Scholar

Eckart K, Rohrich J, Breitmeier D, et al. Development of a new multi-analyte assay for the simultaneous detection of opioids in serum and other body fluids using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2015;1001:1–8.

 PubMed Web of Science ®Google Scholar

Sofalvi S, Schueler HE, Lavins ES, et al. An LC-MS-MS method for the analysis of carfentanil, 3-Methylfentanyl, 2-Furanyl Fentanyl, acetyl fentanyl, fentanyl and norfentanyl in postmortem and impaired-driving cases. J Anal Toxicol. 2017;41:473–483.

 PubMed Web of Science ®Google Scholar