Article

Immunoassay-based detection of fentanyl analogs in forensic toxicology

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Abstract

Purpose The abuse of fentanyl and its analogs (fentalogs) is of growing concern globally. Forensic toxicology laboratories must detect these emerging drugs in biological evidence, and immunoassay is the most widely used screening technique. In this study, the cross-reactivity of 13 fentalogs were investigated using five commercially available kits. Methods Dose–response curves were generated using six N-acyl-substituted fentalogs (4-ANPP, acetylfentanyl, butyrylfentanyl, furanylfentanyl, isobutyrylfentanyl, valerylfentanyl), one desphenethyl fentalog (norfentanyl), two piperidine-modified [(+)-cis-3-methylfentanyl, carfentanil], and four phenethyl and piperidine substituted fentalogs (alfentanil, norcarfentanil, remifentanil, sufentanil). Cross-reactivities were estimated for each assay to determine its overall effectiveness for fentalog screening in toxicological samples. Results and conclusions Several commercial assays were able to detect either N-acyl or piperidine-modified fentalogs, but none was capable of detecting both. Although this is an inherent disadvantage of the immunoassay approach, it arises from the diverse structural nature of the fentanyl analogs themselves.

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... Although these methods are accurate and sensitive, they cannot meet the increasing requirements for rapid detection (e.g., in situ and street detection) due to their time-consuming processing procedures conducted in the laboratory [21]. In recent years, studies on rapid detection methods based on immunoassays, including fluorescent immunoassay [22], homogeneous enzyme immunoassay [23], enzyme-linked immunosorbent assay [24], electrochemical immunosensor [25], and lateral flow immunochromatography [26], have also been reported. These studies have greatly enriched research on fentanyl analogs, especially for their metabonomics but challenges remain in meeting the higher requirements for sensitivity. ...
... The molecular geometric configuration of the fentanyl-related substances, referring to fentanyl (C 22 Figure 1 shows the molecular electrostatic potential (MEP) of the optimized molecular structures. It can be seen from Figure 1 that all these eight molecules have similar structures to piperidine rings, as well as the structures of phenyl group directly linked to two nitrogen atoms (in blue) by a monocyclic aromatic group. ...
Article
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Fentanyl is a potent opioid analgesic with high bioavailability. It is the leading cause of drug addiction and overdose death. To better control the abuse of fentanyl and its derivatives, it is crucial to develop rapid and sensitive detection methods. However, fentanyl-related substrates undergo similar molecular structures resulting in similar properties, which are difficult to be identified by conventional spectroscopic methods. In this work, a method for the automatic identification of 8 fentanyl-related substances with similar spectral characteristics was developed using terahertz (THz) spectroscopy coupled with density functional theory (DFT) and spectral similarity mapping (SSM). To characterize the THz fingerprints of these fentanyl-related samples more accurately, the method of baseline estimation and denoising with sparsity was performed before revealing the unique molecular dynamics of each substance by DFT. The SSM method was proposed to identify these fentanyl analogs based on weighted spectral cosine–cross similarity and fingerprint discrete Fréchet distance, generating a matching list by stepwise searching the entire spectral database. The top matched list returned the identification results of the target fentanyl analogs with accuracies of 94.48~99.33%. Results from this work provide algorithms’ increased reliability, which serves as an artificial intelligence-based tool for high-precision fentanyl analysis in real-world samples.
... Cross-reactivity data were calculated at each kit limit of detection (LOD) by comparing the lowest concentration detected of the test analog relative to the lowest concentration detected of the kit target analog (fentanyl, norfentanyl or carfentanil), as previously described (16). For example, if the detection limit of a particular kit for a test fentanyl analog (for example, 200 ng/mL) was twice that of the kit target analog, (for example, fentanyl at 100 ng/mL), the kit crossreactivity for the test analog is reported as 50%. ...
... This pilot study represents the first comparative analysis of a comprehensive set of relevant fentanyl analogs and test kits, expanding on previous reports in the literature and on information available in vendor kit inserts (13)(14)(15)(16). The reader is encouraged to consult the Supplemental Tables for individual cross-reactivity and detection limit data for each analog and each kit. ...
Article
Health-care workers, laboratorians and overdose prevention centers rely on commercial immunoassays to detect the presence of fentanyl; however, the cross-reactivity of fentanyl analogs with these kits is largely unknown. To address this, we conducted a pilot study evaluating the detection of 30 fentanyl analogs and metabolites by 19 commercially available kits (9 lateral flow assays, 7 heterogeneous immunoassays and 3 homogenous immunoassays). The analogs selected for analysis were compiled from the Drug Enforcement Administration and National Forensic Laboratory Information System reports from 2015 to 2018. In general, the immunoassays tested were able to detect their intended fentanyl analog and some closely related analogs, but more structurally diverse analogs, including 4-methoxy-butyryl fentanyl and 3-methylfentanyl, were not well detected. Carfentanil was only detected by kits specifically designed for its recognition. In general, analogs with group additions to the piperidine, or bulky rings or long alkyl chain modifications in the N-aryl or alkyl amide regions, were poorly detected compared to other types of modifications. This preliminary information is useful for screening diagnostic, forensic and unknown powder samples for the presence of fentanyl analogs and guiding future testing improvements.
... Like fentanyl, most FAs are selective for the mu-opioid Michael H. Baumann mbaumann@mail.nih.gov cross-reactivity in fentanyl immunoassays (Stogner 2014;Schackmuth and Kerrigan 2019), thus requiring additional confirmatory analysis methods such as mass spectrometry (Prekupec et al. 2017;Cooper 2023). However, even with additional confirmatory analyses, detection of FAs can be limited by analytical challenges in distinguishing between certain structural isomers (Maher et al. 2018). ...
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Rationale The potent synthetic opioid fentanyl, and its analogs, continue to drive opioid-related overdoses. Although the pharmacology of fentanyl is well characterized, there is little information about the reinforcing effects of clandestine fentanyl analogs (FAs). Objectives Here, we compared the effects of fentanyl and the FAs acetylfentanyl, butyrylfentanyl, and cyclopropylfentanyl on drug self-administration in male and female rats. These FAs feature chemical modifications at the carbonyl moiety of the fentanyl scaffold. Methods Sprague-Dawley rats fitted with intravenous jugular catheters were placed in chambers containing two nose poke holes. Active nose poke responses resulted in drug delivery (0.2 mL) over 2 s on a fixed-ratio 1 schedule, followed by a 20 s timeout. Acquisition doses were 0.01 mg/kg/inj for fentanyl and cyclopropylfentanyl, and 0.03 mg/kg/inj for acetylfentanyl and butyrylfentanyl. After 10 days of acquisition, dose-effect testing was carried out, followed by 10 days of saline extinction. Results Self-administration of fentanyl and FAs was acquired by both male and female rats, with no sex differences in acquisition rate. Fentanyl and FAs showed partial inverted-U dose-effect functions; cyclopropylfentanyl and fentanyl had similar potency, while acetylfentanyl and butyrylfentanyl were less potent. Maximal response rates were similar across drugs, with fentanyl and cyclopropylfentanyl showing maximum responding at 0.001 mg/kg/inj, acetylfentanyl at 0.01 mg/kg/inj, and butyrylfentanyl at 0.003 mg/kg/inj. No sex differences were detected for drug potency, efficacy, or rates of extinction. Conclusions Our work provides new evidence that FAs display significant abuse liability in male and female rats, which suggests the potential for compulsive use in humans.
... The problem arises from the cross-reactivity of the antibody for these other substances [23]. Although the affinity of the antibody for these substances is much lower than for fentanyl, if they are present at sufficiently high concentrations, they can cause a false positive result [24,25]. As we consider the 4th wave of the pandemic, it can be expected that drug users will need to test stimulants to see if they contain fentanyl. ...
Article
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Background The opioid epidemic has caused an increase in overdose deaths which can be attributed to fentanyl combined with various illicit substances. Drug checking programs have been started by many harm reduction groups to provide tools for users to determine the composition of their street drugs. Immunoassay fentanyl test strips (FTS) allow users to test drugs for fentanyl by either filling a baggie or cooker with water to dissolve the sample and test. The antibody used in FTS is very selective for fentanyl at high dilutions, a characteristic of the traditional use of urine testing. These street sample preparation methods can lead to mg/mL concentrations of several potential interferents. We tested whether these concentrated samples could cause false positive results on a FTS. Methods 20 ng/mL Rapid Response FTS were obtained from BTNX Inc. and tested against 4 different pharmaceuticals (diphenhydramine, alprazolam, gabapentin, and naloxone buprenorphine) and 3 illicit stimulants [cocaine HCl, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA)] in concentrations from 20 to 0.2 mg/mL. The FTS testing pad is divided into 2 sections: the control area and the test area. Control and test area signal intensities were quantified by ImageJ from photographs of the test strips and compared to a threshold set by fentanyl at the FTS limit of detection. Results False positive results indicating the presence of fentanyl were obtained from samples of methamphetamine, MDMA, and diphenhydramine at concentrations at or above 1 mg/mL. Diphenhydramine is a common cutting agent in heroin. The street sample preparation protocols for FTS use suggested by many online resources would produce such concentrations of these materials. Street samples need to be diluted more significantly to avoid interference from potential cutting agents and stimulants. Conclusions Fentanyl test strips are commercially available, successful at detecting fentanyl to the specified limit of detection and can be a valuable tool for harm reduction efforts. Users should be aware that when drugs and adulterants are in high concentrations, FTS can give a false positive result.
... (23) Although the a nity of the antibody for these substances is much lower than for fentanyl, if they are present at su ciently high concentrations, they can cause a false positive result. (24,25) As we consider the 4th wave of the pandemic, it can be expected that drug users will need to test stimulants to see if they contain fentanyl. ...
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Background: The opioid epidemic has caused an increase of overdose deaths which can be attributed to fentanyl combined with various illicit substances. Drug checking programs have been started by many harm reduction groups to provide tools for users to determine the composition of their street drugs. Immunoassay fentanyl test strips (FTS) allow users to test drugs for fentanyl by either filling a baggie or cooker with water to dissolve the sample and test. The antibody used in FTS is very selective for fentanyl at high dilutions, a characteristic of the traditional use of urine testing. These street sample preparation methods can lead to mg/mL concentrations of several potential interference. We tested whether these concentrated samples could cause false positive results on a FTS. Methods: 20 ng/mL Rapid Response immunoassay Fentanyl Test Strips (FTS) were obtained from BTNX Inc. and tested against 4 different pharmaceuticals (diphenhydramine, alprazolam, gabapentin, and naloxone buprenorphine) and 3 illicit stimulants (cocaine HCl, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA)) in concentrations from 20 mg/mL to 0.2 mg/mL. The FTS testing pad is divided into 2 sections: the control area and the test area. Control and test area signal intensities were quantified by ImageJ from photographs of the test strips and compared to a threshold set by fentanyl at the FTS limit of detection. Results: False positive results indicating the presence of fentanyl were obtained from samples of methamphetamine, MDMA, and diphenhydramine at concentrations at or above 1 mg/mL. Diphenhydramine is a common cutting agent in heroin. The street sample preparation protocols for FTS use suggested by many online resources would produce such concentrations of these materials. Street samples need to be diluted more significantly to avoid interference from potential cutting agents and stimulants. Conclusions: Fentanyl test strips are commercially available, successful at detecting fentanyl to the specified limit of detection and can be a valuable tool for harm reduction efforts. Users should be aware that when drug adulterants are in high concentrations, FTS can give a false positive result.
... This is despite 2 a having been polarized previously, albeit using the catalyst [Ir (COD)(PCy 3 )(py)][PF 6 ]. [54] It is proposed that 2 c did not polarize under the conditions employed here are most likely due to heroin lacking a suitable donor to ligate to the catalyst in order to become hyperpolarized and / or steric hindrance preventing successful binding; no hydride signal was detected in the 1 H NMR spectra collected (see SI). 5 was selected as the fentalogue to test given the number of other derivatives that have been encountered that have been derivatized similarly by replacing the ethyl attached to the amide for other moieties, such as methoxyacetyl, isobutyl and isovaleryl, along with many others. [24][25][26] We have also evidenced that 5 shows the most significant enhancement by SABRE of the three fentalogues synthesized herein. A solution consisting of 5 and heroin (ratio 3 : 97 w/w) were subjected to SABRE. ...
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Fentanyl was structurally designed by Paul Janssen in the early 1960s as a potent opioid analgesic (100-fold more potent than morphine). It is a full agonist at μ-opioid receptors and possesses physicochemical properties, in particular a high lipophilicity (octanol:water partition coefficient >700), which allow it to cross quickly between plasma and central nervous target sites (transfer half-life of 4.7-6.6 min). It undergoes first-pass metabolism via cytochrome P450 3A (bioavailability ~30 % after rapid swallowing), which can be circumvented by non-intravenous formulations (bioavailability 50-90 % for oral transmucosal or intranasal formulations). Non-intravenous preparations deliver fentanyl orally-transmucosally, intranasally or transdermally. Passive transdermal patches release fentanyl at a constant zero-order rate for 2-3 days, making them suitable for chronic pain management, as are iontophoretic transdermal systems. Oral transmucosal and intranasal routes provide fast delivery (time to reach maximum fentanyl plasma concentrations 20 min [range 20-180 min] and 12 min [range 12-21 min], respectively) suitable for rapid onset of analgesia in acute pain conditions with time to onset of analgesia of 5 or 2 min, respectively. Intranasal formulations partly bypass the blood-brain barrier and deliver a fraction of the dose directly to relevant brain target sites, providing ultra-fast analgesia for breakthrough pain. Thanks to the development of non-intravenous pharmaceutical formulations, fentanyl has become one of the most successful opioid analgesics, and can be regarded as an example of a successful reformulation strategy of an existing drug based on pharmacokinetic research and pharmaceutical technology. This development broadened the indications for fentanyl beyond the initial restriction to intra- or perioperative clinical uses. The clinical utility of fentanyl could be expanded further by more comprehensive mathematical characterizations of its parametric pharmacokinetic input functions as a basis for the rational selection of fentanyl formulations for individualized pain therapy.
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Fentanyl, a synthetic opiate with a (clinical) potency of 50 to 100 times that of morphine, was introduced into clinical practice in the early 1960s. Usually administered by single intravenous doses, it developed a reputation for having a short duration of action and it was assumed that this was a consequence of rapid removal from the body. However, as clinical experience increased, it was realised that administration of multiple doses or large doses during narcotic-based anaesthesia sometimes led to delayed recovery and prolonged respiratory depression, suggesting that the duration of action was limited by redistribution within the body rather than removal from the body. Recent developments in analytical techniques have allowed pharmacokinetic studies and these have confirmed this opinion; fentanyl is rightly regarded as having a redistribution-limited duration of action after single or infrequent doses (analogous to thiopentone). However, the magnitude of the pharmacokinetic constants reported for fentanyl are remarkably inconsistent even in healthy volunteers, for reasons apparently only explainable by assay differences. Hence, estimates of apparent volume of distribution (area) range from around 60L to over 300L, estimates of terminal half-life range from about 1.5 to 6 hours (15 hours in geriatric patients) and total body clearance ranges from 0.4 to over 1.5 L/min. Renal excretion accounts for up to 10% of the dose; the remainder of the clearance would appear to be predominantly hepatic, but with contributions from other tissues. Continued clinical developments of narcotic-based anaesthetic techniques have resulted in high doses of narcotic being used, with oxygen, as the sole anaesthetic agents. At present these techniques are usually based on fentanyl, and the technique is frequently called ’stressfree anaesthesia’ because of the effects in obtunding the ’stress response’ caused by surgery (elevation of plasma concentrations of cortisol, glucose, ADH, etc. in the intra- and postoperative period) and the lack of deleterious effects on the cardiovascular system. With the hypothesis that increased potency is associated with increased specific opiate effects and decreased nonspecific cardiovascular depressant effects, chemical congeners of fentanyl were developed. Alfentanil has about one-third the (clinical) potency of fentanyl, while sufentanil has about 5 to 10 times the (clinical) potency of fentanyl. Lofentanil and carfentanil have about 20 to 30 times the potency of fentanyl and have yet to find clinical roles. Alfentanil is characterised by a rather small apparent volume of distribution for a base (Varea = 40-70L), short terminal half-life (100 minutes), intermediate total body clearance (0.3–0.5 L/min) and negligible renal clearance. Sufentanil would appear to have pharmacokinetic properties intermediate to those of alfentanil and fentanyl. At physiological pH, approximately 15 to 20% of fentanyl is unbound in plasma compared with 5 to 10% of alfentanil, sufentanil and lofentanil. Except for alfentanil, there is a marked plasma binding dependence on pH. Also except for alfentanil, there is a predominance of ionised drug species and a high octanol: water partition coefficient in the physiological pH range. These factors act to influence the tissue binding of the agents and reflect back on other important factors such as uptake by blood cells. Whole blood: plasma concentration ratios of 0.97, 0.63, 0.74 and 0.71 have been reported for fentanyl, alfentanil, sufentanil and lofentanil, respectively. The range of opiate duration of action has been extended by the appearance of these newer compounds, where alfentanil may be regarded as having an ultrashort duration of action, fentanyl and sufentanil as short acting, while lofentanil has a long duration of action. Knowledge of the pharmacokinetic properties of these agents has provided more information than could be obtained from clinical studies alone, and has added a basis on which to rationalise and enhance their usefulness.
Article
Fentanyl was determined using gas chromatography (GC) and alkali flame ionisation detection (AFID), in the plasma of patients who had received a high single dose (up to 60 microgram/kg body weight). The relative standard deviation is 6% for 11 ng/ml while the calculated detection limit is 3.3 ng of fentanyl per 1 ml of plasma. The concentration of fentanyl in patients ranged from 40 to 3 ng/ml of plasma. The concentration of fentanyl in patients ranged from 40 to 3 ng/ml of plasma in the first hour after administration. In the plasma of patients treated with fentanyl two metabolites could be detected and identified using GC-AFID and GC-MS.
Article
Fentanyl is a potent synthetic narcotic analgesic administered in the form of a transdermal patch for the management of chronic pain. A 78-year-old woman with a history of cancer was found dead in bed. She was lying on her back. The external examination revealed 10 Durogesic transdermal therapeutic systems (100 microg/h fentanyl) on the body. Liquid-liquid extraction and liquid chromatography tandem mass spectrometry with electrospray source in positive ionization mode was applied for the quantitation of fentanyl and its major metabolite norfentanyl in the post-mortem samples. Fentanyl-d5 and norfentanyl-d5 were used as internal standards. Multiple reaction monitoring was used for specific detection. Calibration was performed by addition of standard solutions to drug-free matrix (blood, urine and liver) prior to extraction. The method showed good linearity for fentanyl and norfentanyl over a concentration range of 5-150 microg/L in reconstituted extracts with coefficients of determination equal or greater than 0.998. Percent mean within-day precision and accuracy of 0.9-1.0% and 99.4-101.1% for fentanyl and 2.0-4.5% and 93.1-101.0% for norfentanyl were obtained. Mean extraction recoveries varied between 95.5% and 100.3% for fentanyl and 39.2-57.4% for norfentanyl. The following fentanyl (norfentanyl) concentration in the post-mortem samples were measured; 28.6 microg/L (3.0 microg/L) in right and 28.2 microg/L (3.5 microg/L) in left subclavian blood, 21.3 microg/L (<2 microg/L) in right and 20.9 microg/L (<2 microg/L) in left femoral blood, 37.6 microg/L (4.2 microg/L) in right and 33.9 microg/L (4.4 microg/L) in left ventricular blood, 282.9 microg/L (121.2 microg/L) in urine, 688.2 microg/L in stomach contents, 122.5 microg/L (25.4 microg/L) in bile, 19.5 microg/L (< 2 microg/L) in vitreous humour, 203.0 microg/kg (26.6 microg/kg) in liver and 78.6 microg/kg (46.3 microg/kg) in kidney. We concluded that the woman's death was caused by acute intoxication with fentanyl. The manner of death was presumed to be suicide due to excessive administered Durogesic transdermal therapeutic systems.
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