How Can I Get a Lethal Dose of Fentanyl

Introduction

Opioid overdose deaths continue to increase in the United states, killing more than 42,000 people in 2022. The opioids detected in these cases, in increasing guild, were methadone, natural and semi-synthetic opioids (due east.thousand., oxycodone, hydrocodone), heroin and synthetic opioids (e.g., fentanyl, fentanyl-analogs). Synthetic opioids (excluding methadone) and heroin deaths specifically experienced a sharp increase from 2015 to 2022 (20 and 100%, respectively) (Seth et al., 2018). Fentanyl and its derivatives have been increasingly nowadays equally adulterants mainly in heroin, but too in other drugs such as cocaine and constructed cannabinoids (Coopman and Cordonnier, 2017; Armenian et al., 2018), due to their ease of manufacturing and readily available precursors shipped from Red china (Armenian et al., 2018). In addition to being nowadays in other drugs supply, fentanyl analogs have been also marketed every bit "research chemicals" and tin easily exist acquired over the net. Due to their high say-so and the increased utilize of heroin equally an initiating opioid of corruption (8.7% in 2005 vs. 33.3% users in 2015) (Cicero et al., 2017; O'Donnell et al., 2017), the number of opioid-related deaths have drastically increased in the recent years. Given that opioid novices have limited tolerance to opioids, a slight imprecision in dosing inherent in heroin employ and/or the presence of potent fentanyl and analogs, can be fatal.

Fentanyl, its analogs (e.g., acetyl fentanyl, 3-methylfentanyl, alphamethylfentanyl, furanyl fentanyl) and the new generation synthetic opioids (e.one thousand., AH-7921, U-47700, MT-45) accept a chemical cadre structure totally unlike from morphine, a naturally occurring opioid from Papaver somniferum and reference chemical compound of the opioids group; but all of them human action on the opioid receptor (mu-receptor) reducing the intensity of hurting and showing a high habit potential. These opioid receptor agonists also induce dose-dependent respiratory depression (Pattinson, 2008), which is the main reason for their life-threatening risk (Ujváry et al., 2017). Fentanyl is approximately 200 times more strong than morphine, and the potencies of its analogs are variable, from 7 times more potent than morphine for butyrfentanyl and furanyl fentanyl, to more than than 4,000 and 10,000 times for sufentanil and carfentanil, respectively (UNODC, 2017). The new generation opioids AH-7921 and MT-45 show similar authority to morphine (Brittain et al., 1977; EMCDDA, 2015), and U-47700 well-nigh seven.five times more potent (Cheney et al., 1985).

Synthetic opioids are widely regulated by the U.s.a. Controlled Substances Act of 1970 (CSA) in order to control their use and distribution. As new compounds arise and threaten public condom, compounds tin can exist emergency scheduled by the DEA to wearisome production and utilize of these harmful substances and aid in prosecution of drug diverters for a temporary period until the formal procedures take gone through (US Drug Enforcement Assistants, 2017). Substances are classified into schedules in the CSA based on their safety, medicinal employ and potential for abuse. A Schedule I substance is classified equally having no currently accepted medical utilize and a high abuse potential. Examples of constructed opioids in Schedule I include furanyl fentanyl, U-47700, acetyl fentanyl and iii-methyl fentanyl. Schedule 2 classified opioids have a high potential for corruption just take electric current medicinal uses like fentanyl which is used as an coldhearted and analgesic, every bit well as carfentanil, remifentanil and sufentanil (US Drug Enforcement Administration, 2017). Most recently, the DEA issued a temporary scheduling club for all fentanyl –related substances (to include all analog modifications) in Feb of 2018, which cover all substances that were non already classified into Schedule I of the CSA in an aggressive effort to regulate the manufacture and subsequent trafficking of new synthetic opioids into the United States (Drug Enforcement Administration, 2018).

The expansion of these new constructed opioids constitutes an of import challenge in forensic toxicology. First of all, most of these substances are not detected in the routine screening and confirmation methods in the laboratory. Also, due to the low doses employed of these highly potent drugs, the concentrations expected in the biological samples are in the low ng to pg/mL or ng to pg/g range, requiring extremely sensitive methods of analysis. Recently, Marchei et al. (2018) and Liu et al. (2018) reviewed the currently available screening and confirmation methods of new constructed opioids in biological and non-biological samples. As indicated by Marchei et al. (2018), gas chromatography combined with mass spectrometry (GC-MS) and more frequently liquid chromatography tandem mass spectrometry (LC-MSMS) are the most common techniques due to their sensitivity and specificity. Still, given the connected development of new derivatives, the major disadvantage of these target techniques, which utilise quadrupole mass spectrometers, is that are limited by the reference standards bachelor. High resolution mass spectrometry (time-of-flying, orbitrap) offers potential advantages to place unknown compounds without the availability of a reference standard, but this technology is not readily available in most forensic laboratories (Marchei et al., 2018).

Regarding biological samples, near of these methods take been developed in blood or urine, and the target analytes are the parent compounds and rarely the metabolites (Marchei et al., 2018). In postmortem toxicology, other biological specimens such as vitreous humor, liver and brain are commonly analyzed. Unfortunately, fully validated methods for the conclusion of synthetic opioids in these specimens are lacking in the literature. This is in role due to the abiding changes in illicit synthetic opioids existence identified and laboratories beingness unable to justify the extensive time and toll associated with fully validating a method for a drug that may only exist present in cases for a brusque fourth dimension. Analytical methods in forensic toxicology are normally validated in the respective biological sample following the guidelines published by the Scientific Working Group in Forensic Toxicology (SWGTOX) (Scientific Working Group for Forensic Toxicology, 2013) to guarantee the analytical quality of the measured concentrations. The analysis of metabolites in the different biological matrices may improve the interpretation of the results, extending the detection window and indicating if it was an acute or a delayed-death evaluating the metabolite-to-parent ratios. Recent publications about the identification of new metabolites of the synthetic opioids are bachelor (Wohlfarth et al., 2022; Steuer et al., 2017; Watanabe et al., 2017; Krotulski et al., 2018a); however, its application to authentic samples is nonetheless deficient (Poklis et al., 2015; Staeheli et al., 2022; Martucci et al., 2017; Allibe et al., 2018).

Besides the analytical challenges associated with constructed opioids, due to the scarcity of available postmortem data, the interpretation of the results is extremely difficult. Conducting postmortem toxicology interpretation provides a number of very pregnant challenges to the forensic toxicologist. The range of postmortem specimens (blood, urine, vitreous humor, tissues, pilus), the lack of reference databases, the presence of other substances (due east.1000., benzodiazepines, booze), opioid tolerance, and postmortem phenomena (postmortem redistribution and drug instability) complicates the interpretation of the analytical findings. Pichini et al. (2018) and Zawilska (2017) discussed non-fatal and lethal intoxications involving the new synthetic opioids, and Drummer (2018) focused his review on fatalities due to these compounds.

The nowadays review is focused on fentanyl derivatives and new generation opioids due to the express noesis concerning these substances and their high prevalence in opioid-overdose related cases. This work complements the previously published literature reviewing the current cognition of postmortem toxicology of synthetic opioids and the chemical and pharmacological factors that may bear on drug concentrations in the unlike matrices and therefore, their interpretation in postmortem samples. These factors include key chemical properties, essential pharmacokinetics parameters, postmortem redistribution and stability data in postmortem samples. All of these data are critically compared to postmortem data of natural opioids (morphine), semi-constructed (oxycodone, hydrocodone, hydromorphone, and oxymorphone), and constructed opioids (methadone and buprenorphine). The interpretation of drug intoxication in death investigation is based on the available published literature. This review serves to facilitate the evaluation of cases where constructed opioids may exist implicated in a fatality through the review of peer reviewed published case reports and inquiry articles.

Methods

PubMed, Scopus and Google Scholar were searched for appropriate articles. Forensic case-reports and enquiry articles of natural, semi-synthetic and constructed opioids were reviewed upward to May 2018. All manufactures were manually reviewed for content and references in each manuscript were further queried. Included manufactures were limited to peer-reviewed journals indexed by the Establish for Scientific Information (ISI) and published in English. Chemic properties were retrieved from the public databases PubChem (https://pubchem.ncbi.nlm.nih.gov/) and DrugBank (https://world wide web.drugbank.ca/drugs).

Chemic and Pharmacological Properties

The chemical construction of the diverse synthetic opioids, including fentanyl and analogs, differs significally from the chemical structure of morphine and semi-synthetic opioids (e.thou., oxycodone, hydrocodone, buprenorphine). Effigy 1 summarizes the chemic structure of selected classic opioids. Fentanyl is a piperidinyl derivative with moieties on the nitrogen and the 4-position (Figure 2). The different fentanyl derivatives prove substitutions on the propionyl moiety (e.thou., acetylfentanyl, acrylfentanyl, butyrfentanyl, furanyl fentanyl), phenethyl moiety (due east.g., ohmefentanyl), Northward-phenyl band (e.g., ocfentanil, 4-methoxy-butyrylfentanyl) and/or at the 4-piperidinyl-position (e.g., carfentanil). The chemic structures of the new generation constructed opioids (AH-7921, U-47700, MT-45) are different from fentanyl. Figure three shows 20 fentanyl derivatives and 3 new generation synthetic opioids not related to fentanyl. Due to the shut chemical structure among fentanyl derivatives, some compounds, such as cyclopropyl fentanyl and crotonyl fentanyl, take exactly the same molecular formula, and therefore, the same molecular weight. As a result of this, special attending has to be paid in the evolution of the belittling methods for the decision of these compounds, and a complete chromatographic separation is required to guarantee their right identification past gas or liquid chromatography coupled to mass spectrometry (GC-MS, LC-MSMS).

Figure 1. Chemical structures of selected classic opioids.

Figure 2. Chemic structure of fentanyl.

Figure 3. Chemical structures of xx fentanyl derivatives and iii new generation opioids non related to fentanyl.

Chemically, opioids are predominantly basic drugs with pKa ranging from 7.5 to 10.9. The chemic parameter log P, the decimal logarithm of the partition coefficient Kp, is a useful indication of the lipophilicity of a chemical compound. In the instance of opioids, log P range is wide, from 0.viii (oxymorphone) to v (methadone). Morphine and related compounds bear witness the lowest log P values (0.viii–two). Fentanyl and analogs show a log P between 1.5 and 4.iii. The high lipophilicity of fentanyl and its analogs enables rapid diffusion through membranes, including the blood-encephalon barrier. Also, this lipophilicity forth with their basic characteristics brand these grouping of drugs candidates to undergo postmortem redistribution. Table 1 summarizes the molecular weight, pKa and log P of selected opioids.

Table 1. Monoisotopic molecular weight (g/mol), pKa and Log P of selected natural, semi-synthetic and constructed opioids.

Volume of distribution (Vd) and protein binding also help to predict the drugs that may exhibit postmortem redistribution. Vd is divers as the volume into which the full corporeality of the drug would have to be uniformly distributed to achieve the concentrations measured in plasma. It is expressed in 50/kg of torso weight (amount of drug in the body divided by the plasma drug concentration). Drugs highly leap to plasma proteins but not to tissue components would be expected to have a pocket-sized Vd, while those drugs which distribute into muscle, adipose tissue and other intracellular components will have a high Vd. Drugs with a Vd greater than 3 L/kg are considered to take a greater potential to undergo postmortem redistribution. Tabular array two summarizes the Vd and poly peptide binding information currently available for selected opioids.

Tabular array 2. Critical pharmacological backdrop in postmortem toxicology, volume of distributon (Vd), protein bining and potency relative to morphine, of selected natural, semi-constructed and synthetic opioids.

1 of the disquisitional bug related to fentanyl, its derivatives and the new synthetic opioids, is the low concentrations expected in the biological samples (ng to pg/mL or ng to pg/one thousand range) due to their high potency. Still, the dominance of these type of drugs varies considerably within this group, and therefore the concentrations reported show a broad range, depending on the drug. Table 2 summarizes the potencies relative to morphine for selected opioids.

Metabolism

The identification and quantification of metabolites in postmortem samples may better the estimation of the analytical results. The determination of metabolites may extend the window of detection, and besides can be employed to calculate metabolite-to-parent ratios in urine and other biological samples to differentiate acute or delayed death. In certain cases, as it happens in morphine and buprenorphine, metabolites can exist pharmacologically active. Although this type of information is limited in the case of the constructed opioids, fentanyl, sufentanil, and alfentanil'south metabolites are inactive in the opioid system (Schneider and Brune, 1986).

Although the utility of metabolite determination in biological samples is known, its awarding to authentic specimens is still scarce in the case of synthetic opioids due to the limited data available about their metabolism (Poklis et al., 2015; Staeheli et al., 2022; Martucci et al., 2017; Allibe et al., 2018). Recent publications almost the identification of new metabolites of the synthetic opioids in vivo and in vitro are available (Wohlfarth et al., 2022; Steuer et al., 2017; Watanabe et al., 2017; Krotulski et al., 2018a). While in vitro studies utilizing human being liver hepatocytes or microsomes can identify multiple primary and secondary metabolites for a particular fentanyl derivative, actual man specimens typically show lower number and/or a different metabolite prevalence profile, so studies investigating the presence of the in vitro metabolites in authentic homo samples are highly encouraged. Table three summarizes contempo publications nigh the identification of new metabolites of synthetic opioids in vitro and in vivo.

Table three. In vitro and in vivo metabolism of synthetic opioids.

Fentanyl-derivatives metabolism studies showed similarities and differences from fentanyl metabolism pathways and rates. These unlike metabolic pathways observed for sure derivatives, demonstrate the need to perform private metabolism studies for each new compound. In the example of fentanyl, only less than 8% of fentanyl is excreted unchanged. Approximately 85% of the dose is excreted inside 72 h in feces and urine, the majority as metabolites mainly equally norfentanyl generated by N-dealkylation at the piperidine nitrogen (McClain and Hug, 1980). Minor fentanyl metabolites are despropionylfentanyl, likewise known as 4-ANPP, which is formed past carboxamide hydrolysis, and hydroxyfentanyl and hydroxynorfentanyl metabolites, both hydroxylated at the propionyl moiety (Goromaru et al., 1984; Mahlke et al., 2014).

Several synthetic opioids follow a similar metabolic pathway to fentanyl. Alfentanil undergoes piperidine Due north-dealkylation to noralfentanil (Meuldermans et al., 1988). Major alpha-methylfentanyl metabolites in rats were norfentanyl and hydroxypropionyl norfentanyl metabolites, exactly as fentanyl (Sato et al., 2010). Meyer et al. (2012) investigated the metabolism in rats of isofentanyl and 3-methyl fentanyl. After the assistants of suspected recreational doses, the parent drugs could non be detected in urine and their common nor-metabolite was the predominant compound.

Patton et al. (2014) detected high concentrations of acetylfentanyl and acetyl norfentanyl (>16,500 ng/mL, 180 min mail-dose) in urine samples from rats treated with a toxic dose of acetylfentanyl (3 mg/kg); all the same, Melent'ev et al. (2015), showed that the principal pathway of the biotransformation of acetylfentanyl was hydroxylation by the phenylethyl moiety rather than N-dealkylation in authentic man samples. Melent'ev et al. (2015) and Watanabe et al. (2017) recommended as target analytes in human urine hydroxy-methoxy at phenylethyl moiety and monohydroxylated metabolites, although the reported hydroxylation position in both publications was different. In both publications, the parent compound acetylfentanyl was highly arable in urine samples, indicating that the parent drug is a suitable target.

Acrylfentanyl underwent N-dealkylation at the piperidine nitrogen producing the major nor-metabolite (Watanabe et al., 2017). The parent compound was besides detected at high concentrations in urine samples. N-Dealkylation and monohydroxylation of the piperidine ring were the dominant metabolic pathways for carfentanil in vitro (Feasel et al., 2022). In that study, the authors observed a slow parent depletion in the hepatocytes. For 4-fluoroisobutyrylfentanyl the master metabolites identified in urine were the nor-metabolite, and monohydroxy metabolites at the piperidine ring or at the ethyl linker, equally well every bit the parent compound. In terms of specificity, Watanabe et al., recommended as target compounds in urine the monohydroxy metabolites and the hydroxymethoxy metabolite (Watanabe et al., 2017).

In the case of butyrfentanyl, hydroxylation of the butanamide side chain followed by subsequent oxidation to the carboxylic acid represented the major metabolic step (Steuer et al., 2017). Although the norbutyrfentanyl was not among the most abundant metabolites in man samples in that report, the authors suggested its inclusion every bit a recommended target analyte because it showed a high intensity in the in vitro experiment. In authentic postmortem blood and urine samples, butyrfentanyl was still detected at 66 and 1,000 ng/mL, respectively.

Furanylfentanyl contains a furan group that affects its metabolic contour. This structure seemed to favor the amide hydrolysis, which is the main metabolite in vitro and in vivo (Watanabe et al., 2017). In terms of specificity of the target metabolites, Watanabe et al. (2017) recommended the dihydrodiol-metabolite and Goggin et al. (2017) recommended the same metabolite, besides as the sulfate of the metabolite that results from the amide hydrolysis. As it happened with butyrfentanyl (Steuer et al., 2017), the hepatocyte experiment also suggested loftier prevalence for the nor-metabolite, which was non significantly present in the accurate urine samples, illustrating the need to analyze homo specimens. Furanylfentanyl parent compound was detected in authentic urine samples. For ocfentanyl, the predominant metabolite detected in claret, along with the parent drug, was the O-desmethylated metabolite (Allibe et al., 2018).

In the case of the new synthetic opioids not structurally related to fentanyl, different metabolic pathways has been reported. For AH-7921, the preferred metabolic sites were the amine function and the cyclohexyl ring. The two most dominant metabolites after hepatocyte incubation (likewise identified in a urine case specimen) were desmethyl and di-desmethyl AH-7921. Together with the glucuronidated metabolites, they were recommended as suitable analytical targets for documenting AH-7921 intake (Wohlfarth et al., 2022). In the case of MT-45, Montesano et al reported hydroxy-MT-45-glucuronide and di-hydroxy-MT-45-glucuronide every bit the about arable metabolites in rat urine, while the parent drug was found at concentrations <10 ng/mL after 300 min (Montesano et al., 2017). Although similar in chemic construction, U-47700 and U-49900 showed specific metabolites. N-Desmethyl-U-47700 was identified as the major metabolite in human urine specimens, and N,N-Didesethyl-N-desmethyl-U-49900 was identified equally the virtually abundant metabolite nowadays. Unlike U-47700 specimens, U-49900 was detected in low affluence in urine samples (Krotulski et al., 2018a).

Equally indicated by Watanabe et al. (2017), the target metabolites should more often than not be abundant, specific of the parent drug, and prevalent in most, if non all, case samples. Given the strong structural similarities among emerging designer fentanyls, many of them are coincidentally biotransformed to the exact aforementioned metabolite. This fact can make identification of the specific parent drug in a instance hard. The ability to place minor metabolites that are unique and specific to the parent drug is therefore of considerable importance. 4-ANPP tin be formed past fentanyl and other different fentanyl analogs metabolism, and it is as well a precursor contaminant plant in seized illicit fentanyl and analogs, then its presence is not particularly diagnostic. Other common metabolites are: acetylnorfentanyl from acetyl-alpha-methylfentanyl or acetylfentanyl (Watanabe et al., 2017); norfentanyl from fentanyl, beta-hydroxythiofentanyl and alpha-methyl-fentanyl (Sato et al., 2010); norcarfentanil from carfentanil, sufentanil and remifentanil (Feasel et al., 2022). three,4-dichloro-N-(two-aminocyclohexyl)-N-methyl-benzamide is a common metabolite of U-47700 and U-49900, but it is not a major metabolite in urine for either compound (Krotulski et al., 2018a).

Another of import attribute of the metabolism is the identification of the enzymes involved. Pharmacokinetic interactions may be produced due to the presence of other substances metabolized past the same enzymes, ultimately affecting the drug blood concentrations. Fentanyl, sufentanyl and alfentanil are mainly metabolized by CYP 3A4 (Feierman and Lasker, 1996; Guitton et al., 1997). Steuer et al., identified CYP 3A4 and CYP 2D6 every bit the isoforms involved in the metabolism of butyrfentanyl (Steuer et al., 2017). Meyer et al., reported that CYP 3A4, CYP 3A5 and CYP 2C19 are involved in the metabolism of 3-methylfentanyl and isofentanyl and, in the case of isofentanyl, additionally CYP2D6 (Meyer et al., 2012). Remifentanil is the simply family member of this class establish to be ~95% metabolized in the blood and tissues by non-CYP enzymes, probably due to an easily accessible ester group assuasive rapid hydrolysis by circulating blood esterases (Bürkle et al., 1996).

Concentrations in Postmortem Specimens and Other Findings

The concentrations determined in postmortem specimens varied considerably depending on the type of constructed opioid detected. Derivatives with potencies relative to morphine of more than 170, showed concentrations in femoral blood in the low ng/mL or pg/mL range, while those derivatives with potencies similar to morphine showed concentrations of hundreds, and fifty-fifty thousands, of ng/mL. An exception happens with furanyl fentanyl, which is seven times more potent than morphine (Higashikawa and Suzuki, 2008), but the reported femoral concentrations were less than 50 ng/mL. Typical morphine postmortem concentrations in blood in fatalities are from 200 to ii,300 ng/mL, for methadone 400 to one,800 ng/mL, for buprenorphine 1.i–29 ng/mL and norbuprenorphine (active metabolite) 0.2–13 ng/mL (Baselt, 2017), and for oxymorphone 23–554 ng/mL (Crum et al., 2013). The potency of the unlike drugs affects their lethal levels, merely other important issues, such as the presence of other CNS depressant drugs, and developed opioids tolerance, have to be taken into account in the estimation of the concentrations. The derivative with the highest number of published cases was acrylfetanyl, and with the lowest MT-45. Table 4 summarizes the concentrations of the parent drugs plant in case reports and articles where overdose due to a specific opioid was the cause of death.

Table 4. Postmortem concentrations in different biological samples for constructed opioids (median, range, number of cases).

In several cases, multiple constructed opioids were detected. Acetylfentanyl and fentanyl were often found together (Pearson et al., 2015; Poklis et al., 2015; Dwyer et al., 2018). Other combinations were butyryl fentanyl and acetyl fentanyl (McIntyre et al., 2022b; Poklis et al., 2022), or U-47700 (Mohr et al., 2022); furanyl fentanyl and acetyl fentanyl (Papsun et al., 2017), acryl fentanyl (Butler et al., 2017), butyryl fentanyl (Mohr et al., 2022), fentanyl (Guerrieri et al., 2017a), or carfentanil (Shanks and Behonick, 2017); carfentanil and fentanyl (Shanks and Behonick, 2017); and tetrahydrofuran fentanyl and U-49900 (Krotulski et al., 2018b). The femoral concentrations reported in those combination cases were oftentimes below the range of the concentrations summarized in Table iv. Acetylfentanyl median and concentration range in multiple constructed opioids cases were 9.4, 0.4–240 ng/mL (northward = 15); acrylfentanyl 0.iii ng/mL (n = 1); butyrfentanyl 14.nine, 0.3–58 ng/mL (n = 4); carfentanil 0.08, 0.05–0.1 ng/mL (due north = 2); fentanyl 8.ii, 1.1–38 ng/mL (n = 14); furanyl fentanyl 1.7, 0.6–6.i ng/mL (n = four) and U-47700 17 ng/mL (n = i).

In all of the reports mentioned in Table iv and higher up, constructed opioids were commonly detected with other drugs, particularly other CNS depressants, such as benzodiazepines, ethanol and other opioids. This combination may produce a pharmacodynamic interactions and increase the risk of respiratory depression. This possible interaction between opioids, alcohol and benzodiazepines has been previously described for other opioids, such as buprenorphine (Häkkinen et al., 2012; Seldén et al., 2012), methadone (Jones et al., 2012; Pilgrim et al., 2013; Nielsen et al., 2015), oxycodone (Ogle et al., 2012), and heroin (Thaulow et al., 2014). Among the reviewed cases positive for constructed opioids other than fentanyl, 44 reported equally cause of death intoxication due to multiple drugs and 77 intoxication mainly due to one specific opioid. The way of death was predominantly accidental (northward = 99), and suicides were reported in vii cases.

Postmortem Redistribution and Stability

Postmortem changes in drug concentrations can happen via postmortem redistribution (PMR) from tissues of a college to a lower concentration. Physicochemical and pharmacological backdrop of the analytes, such as pKa, log P, volume of distribution (Vd) and poly peptide bounden, may signal drugs that experience this postmortem phenomenon. Lipophilic basic drugs with a Vd > 3 L/kg, such equally fentanyl, may undergo PMR. Fentanyl has been reported to undergo extensive PMR (Luckenbill et al., 2008; Olson et al., 2010; Palamalai et al., 2013; Brockbals et al., 2018). In the case of the constructed opioids, limited data is currently bachelor about PMR, and as well as information almost pKa, log P and Vd (Tables 2, 3). Staeheli et al. (2016) reported postmortem concentration changes of butyrfentanyl and metabolites, suggesting these compounds were prone to PMR. PMR reports about other synthetic opioids are not currently available.

Based on currently published instance reports and articles, the cardiac blood-to-femoral claret and liver-to-femoral blood ratios were calculated to predict candidates of PMR. Results are summarized in Table 5. Due to the deficient amount of data available (one–iv cases per analyte), no conclusions could be drawn. Synthetic opioids showed median cardiac-to-femoral ratios around 1, and a trend to accumulate in the liver. Regarding the distribution to vitreous humor, it may exist slow showing higher concentrations in blood. Other factors, such as time of expiry and sample collection, or rapid vs. delayed deaths, has not been taken into account in this assay due to the limited information available.

Table 5. Postmortem concentration ratios in unlike biological samples for synthetic opioids (median, range, number of cases).

PMR is still a controversial issue for archetype opioids. Hargrove and Molina (2014) showed insignificant redistribution of morphine from primal sites within 24 h after death in bodies kept at iv°C, while Staeheli et al. (2017) observed a significant increase of morphine concentration, although these changes were not relevant for forensic interpretation. Morphine-derivatives, such u.s. hydrocodone (Saitman et al., 2015), codeine (Frost et al., 2022), and oxycodone (Brockbals et al., 2018), are unlikely to undergo substantial PMR changes. More lipophilic opioids with higher Vd, similar methadone (Jantos and Skopp, 2013; Holm and Linnet, 2015; Brockbals et al., 2018), may undergo PMR.

Several studies have been conducted to evaluate stability of fentanyl and some of its derivatives in fortified biological samples, such as claret, plasma and urine. Eleven fentanils (fentanyl, norfentanyl, carfentanil, norcarfentanil, sufentanil, norsufentanil, lofentanil, 3-methylfentanyl, alfa-methylfentanyl, ohmefentanyl, and remifentanil acid metabolite), were stable in urine samples stored at −20°C or below for at least 2 months. However, remifentanil in urine samples decreased by approximately ninety% within 1 week at room temperature and by more than l% in samples stored for 1 week at 4°C. Considering of the instability of that analyte, the authors recommended to analyze the chief metabolite, remifentanil acrid (Wang and Bernert, 2006). Fentanyl and its metabolites norfentanyl, despropionylfentanyl and hydroxynorfentanyl were stable in urine after 3 freeze-thaw cycles, and subsequently storage at −20°C for 2 months (Mahlke et al., 2014).

Fentanyl, norfentanyl, acetyl fentanyl and acetyl norfentanyl spiked into whole blood were stable after iii freeze-thaw cycles and at room temperature for 72 h (Poklis et al., 2015). No loss of fentanyl concentration could be observed afterward 3 months of storage at 4–8°C and −20°C in claret samples at 5 and 10 ng/mL (Andresen et al., 2012). However, some other study showed fentanyl and its metabolites norfentanyl, despropionylfentanyl and hydroxynorfentanyl lose up to 51.6% afterward 3 freeze-thaw cycles, and fentanyl and despropionylfentanyl up to 34.8% afterwards storage at −20°C for 2 months (Mahlke et al., 2014). Furanylfentanyl showed no significant degradation in blood samples at 5 and 10 ng/mL 48 h room temp and at 4°C 7 days (Guerrieri et al., 2017a) and up to 30 days (Mohr et al., 2022).

Regarding the new constructed opioids not related to fentanyl, U-47700 was stable in blood refrigerated for up to 30 days (Mohr et al., 2022). AH-7921 was institute to be stable for at to the lowest degree 21 days in blood and plasma at room temperature (Soh and Elliot, 2014). In the instance of MT-45, a loss of 50% was observed after 12 months of storage (Papsun et al., 2022). Further studies are necessary to evaluate the stability of the unlike synthetic opioids and metabolites, and in additional biological samples of forensic interest, such as vitreous humor and tissues.

Conclusion

We performed a disquisitional review of the currently available literature to aid in the toxicological interpretation of constructed opioids postmortem cases. Synthetic opioids constitute a heterogenous group of compounds related or not to fentanyl, more often than not basic and lipophilic, with a broad range of potencies related to morphine, from 1 to ten,000. Research has been conducted in the investigation of metabolic pathways and identification of target metabolites of fentanyl derivatives and not-structurally related constructed opioids, showing similarities and differences from fentanyl depending on the compound. Postmortem concentrations seemed to correlate with their potency, although the presence of other CNS depressants, such every bit ethanol and benzodiazepines has to exist taken into account. Further enquiry is guaranteed to investigate postmortem redistribution phenomena of this course of compounds, and stability bug in postmortem samples.

Author Contributions

MC and GC contributed conception and pattern of the review. MC, RC, and JP searched, organized, reviewed and analyzed the case reports and enquiry articles. MC wrote the first draft of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

Conflict of Interest Argument

The authors declare that the research was conducted in the absence of any commercial or fiscal relationships that could be construed as a potential conflict of interest.

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