Development and Clinical Validation of a Sensitive Lateral Flow Assay for Rapid Urine Fentanyl Screening in the Emergency Department.

BACKGROUND: Rapid identification of fentanyl at the point-of-care is critical. Urine fentanyl concentrations in overdose cases start at single-digit nanograms per milliliter. No fentanyl point-of-care assay with a cutoff at single-digit nanograms per milliliter is available. METHODS: A competitive lateral flow assay (LFA) was developed using gold nanoparticles and optimized for rapid screening of fentanyl in 5 minutes. Urine samples from 2 cohorts of emergency department (ED) patients were tested using the LFA and LC-MS/MS. The 2 cohorts consisted of 218 consecutive ED patients with urine drug-of-abuse screen orders and 7 ED patients with clinically suspected fentanyl overdose, respectively. RESULTS: The LFA detected fentanyl (≥1 ng/mL) and the major metabolite norfentanyl (≥10 ng/mL) with high precision. There was no cross-reactivity with amphetamine, cocaine, morphine, tetrahydrocannabinol, methadone, buprenorphine, naloxone, and acetaminophen at 1000 ng/mL and 0.03%, 0.4%, and 0.05% cross-reactivity with carfentanil, risperidone, and 9-hydroxyrisperidone, respectively. In 218 consecutive ED patients, the prevalence of cases with fentanyl ≥1 ng/mL or norfentanyl ≥10 ng/mL was 5.5%. The clinical sensitivity and specificity of the LFA were 100% (95% CI, 75.8-100%) and 99.5% (95% CI, 97.3-99.9%), respectively. The positive and negative predictive values were 92.3% (95% CI, 66.7-98.6%) and 100% (95% CI, 98.2-100%), respectively. The concordance between the LFA and LC-MS/MS was 100% in the 7 suspected fentanyl overdose cases (5 positive, 2 negative). CONCLUSIONS: The LFA can detect fentanyl and norfentanyl with high clinical sensitivity and specificity in the ED population with rapid fentanyl screening needs.

Rational Urine Drug Monitoring in Patients Receiving Opioids for Chronic Pain: Consensus Recommendations.

Objective: To develop consensus recommendations on urine drug monitoring (UDM) in patients with chronic pain who are prescribed opioids. Methods: An interdisciplinary group of clinicians with expertise in pain, substance use disorders, and primary care conducted virtual meetings to review relevant literature and existing guidelines and share their clinical experience in UDM before reaching consensus recommendations. Results: Definitive (e.g., chromatography-based) testing is recommended as most clinically appropriate for UDM because of its accuracy; however, institutional or payer policies may require initial use of presumptive testing (i.e., immunoassay). The rational choice of substances to analyze for UDM involves considerations that are specific to each patient and related to illicit drug availability. Appropriate opioid risk stratification is based on patient history (especially psychiatric conditions or history of opioid or substance use disorder), prescription drug monitoring program data, results from validated risk assessment tools, and previous UDM. Urine drug monitoring is suggested to be performed at baseline for most patients prescribed opioids for chronic pain and at least annually for those at low risk, two or more times per year for those at moderate risk, and three or more times per year for those at high risk. Additional UDM should be performed as needed on the basis of clinical judgment. Conclusions: Although evidence on the efficacy of UDM in preventing opioid use disorder, overdose, and diversion is limited, UDM is recommended by the panel as part of ongoing comprehensive risk monitoring in patients prescribed opioids for chronic pain.

Ambient mass spectrometry for rapid diagnosis of psychoactive drugs overdose in an unstable patient.

A 25-year-old man suffered from consciousness change was sent to our emergency department by friends who reported that they were not sure what had happened to him. Physical examination revealed bilateral pupils dilatation, lethargy, slurred speech, and ataxia. Computer-aided tomographic scan of the brain revealed no definite evidence of intracranial lesions. Routine laboratory tests revealed total physiological turmoil. Despite immediate commencement of aggressive treatment, the patient's condition deteriorated long before the traditional drug screen provided an answer for the identities of the multiple drugs overdose. It ended up with the need for cardiopulmonary resuscitation, but in vain. At the end of the tragic event, under the suggestion of a colleague, a portion of the patient's urine specimen was sent to our university esoteric laboratory for rapid analysis by means of a newly-developed thermal desorption-electrospray ionization-mass spectrometry. Ketamine, 3,4-methylenedioxymethamphetamine, and 3,4-methylenedioxyamphetamine were identified in the urine sample within 30s. Conventional toxicological testing techniques like gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry are currently used for identifying abused drugs. One concern is their time-consuming sample pretreatment which leads to relatively low efficiency in terms of turnaround time for revealing the identity of the consumed drugs particularly when the patients are severely overdosed. We learned a lesson from this case that a more efficient toxicological identification technique is essential to expedite the process of emergency care when the patients are so heavily overdosed that they are under critical life-threatening conditions.

[The determination of pyrovaleron in the urine by gas chromatography in the combination with the method of extractive chilling-out and centrifugation]. / Gazokhromatograficheskoe opredelenie pirovalerona v moche metodom ékstraktsionnogo vymorazhivaniia v sochetanii s tsentrifugirovaniem.

The express-method for the determination of pyrovaleron in the urine based on the combination with the method of extractive freezing-out and centrifugation of the samples as the preliminary stage of the preparation of a biological object for the analysis. The identification and quantitative determination of the substance of interest were performed using gas chromatography with nitrogen-selective detection. The preparation of the samples was carried out as a single-step procedure no longer than 30 min in duration. The limit of alpha-pyrovaleron detection in the urine was estimated at 1 mcg/ml. Its concentration after extraction from the urine increased by a factor of more than nine.

The limited utility of screening laboratory tests and electrocardiograms in the management of unintentional asymptomatic pediatric ingestions.

BACKGROUND: Suspected ingestions are a common chief complaint to the emergency department although the majority of ingestions by children are insignificant. OBJECTIVE: Assess the utility of screening laboratory tests and Electrocardiograms (ECGs) in unintentional asymptomatic pediatric poisonings. METHODS: Retrospective chart review at a tertiary care children's hospital and a regional poison center of patients less than 12 years of age using ICD-9 codes from January 2005 through December 2008. Laboratory or ECG results requiring intervention and/or direct treatment, a non-RPC subspecialty consultation, and/or prolonged Emergency Department stay was considered changed management. RESULTS: Five hundred ninety five suspected ingestions met our criteria. The median age was 2.6 years (IQR 1.6, 3.0 years) and 56% were male. One laboratory test or ECG was obtained in 233 patients (39%). Of 24 screening ECGs, 32 complete blood counts and 34 blood gases, none were clinically significant. Fifty-two patients received screening metabolic panels, 3 were abnormal and 2 changed management (anion gap metabolic acidosis with unsuspected salicylate ingestions). None of the 127 (21%) screening acetaminophen levels changed management. Two of sixty-five (13%) screening salicylate levels changed management. Three screening urine toxicology tests on patients with altered mental status were positive without ingestion history. No patient under the age of 12 years with normal vital signs and normal mental status had positive screening tests. CONCLUSIONS: Screening laboratory tests and ECGs were of limited utility and rarely changed management despite being ordered in a significant number of patients. Screening tests are rarely indicated in unintentional overdoses in children who are asymptomatic.

[Intoxication or false-positive acetaminophen result of toxicological determinations? Two case reports]. / Zatrucie paracetamolem czy falszywie dodatni wynik analizy toksykologicznej? Opis 2 przypadków.

The aim of this study was to show the diagnostic procedure used in the two cases with false-positive serum acetaminophen results in suspected acetaminophen poisoning. The determination of serum acetaminophen were carried out using a UV/VIS spectrophotometer (Specord 40 Analytik Jena), coupled with an analytic computer station WinASPECT. The employed method of determination was based on the acetaminophen reaction with sodium nitrite, which yields yellow colour of solution in the presence of sodium hydrate. The intensity of the yellow colour depends on the concentration of acetaminophen in serum. The relationship between absorbance and concentration was linear at concentrations in the range 50-600 microg/mL, with relative standard deviation of +/- 2.1% and detection limit of 30 microg/mL. To confirm or reject the doubtful results of colorimetric assays, the serums of patients were measured with high performance liquid chromatography with mass spectrometry detection and gas chromatography with mass spectrometry detection. The analysis of presented cases leads to a conclusion that acetaminophen results should be confirmed either by scanning urine for p-aminophenol presence (which is a routine procedure in our laboratory) or by using a different method of measuring acetaminophen serum levels.

[Acute methoxetamine intoxication--a case report with serum and urine concentrations]. / Ostre zatrucie metoksetamina--opis przypadku z wyznaczonymi stezeniami w surowicy i moczu.

Methoxetamine (MXE) is a novel synthetic drug, structurally related to phencyclidine, with ketamine-like properties. Available in Poland since 2010, with no legal control, is adverti. sed as the "ideal dissociation drug". The aim of this study was to present a case of nasal methoxetamine acute poisoning in a 28-year-old man, the course of treatment, and the method of identification of this substance in serum and urine. In the course of this intoxication extreme agitation and aggression with slight response to benzodiazepines were observed. The patient was confused, hallucinated. In addition, the physical examination re. vealed tachycardia 120/min and normal blood pressure (130/80 mm Hg). The period of acute poisoning was covered by amnesia. The MXE concentrations in serum and urine were determined using liquid chromatography-mass spectrometry (LC-MS-MS) method, and were respectively 270 ng/ml and 660 ng/ml. Confirmed MXE poisoning increases our knowledge about this new substance, providing relevant clinical and analytical data.

[Suicidal intoxication with sodium azide--a case report]. / Smiertelne samobójcze zatrucie azydkiem sodu--opis przypadku.

Sodium azide (NaN3) is an inorganic matrix compound with a very high toxicity. Mechanism of action is not clarified, and it is assumed to interfere with the processes of oxidative phosphorylation. The acute intoxications with sodium azide are extremely rare. We described a case of 19-year-old man who was found dead. In the course of prosecution the empty container, with label "NaN3, 20 g", was found near the body. There were traces of white powder detected in the container. Azide ions were determined by derivatization, i.e. they were transformed to pentafluorobenzaldehyde azide compound. Analysis of the final extract after derivatization was performed by gas chromatography coupled with mass spectrometry GC/MS. The largest concentration of azide ions were determined in the stomach content and vitreous humour, and much less one in whole blood, urine and kidney fluid.

Correlation of Fentanyl Positive Drug Screens with Other Medications in Patients from Pain, Rehabilitation and Behavioral Programs.

Fentanyl has been associated with many drug overdose deaths; its presence in many street drugs has been postulated to be increasing. We examined 1.3 million urine drug tests from April 2016 to April 2019 for fentanyl and other drugs. The highest relationship was observed with heroin. Approximately 30%-40% of the drug tests positive for the heroin metabolite 6-monacetylmorphine (6-MAM) were also positive for fentanyl. There was a large variance over time, but the percent positive in 2016 and 2019 were similar. In contrast, there was a definite increase in the presence of fentanyl with cocaine and methamphetamine. There was not a large increase over time associated with methadone, buprenorphine, and marijuana.

Methemoglobinemia associated with massive acetaminophen ingestion: a case series.

Background: Acetaminophen is a common pharmaceutical ingestion reported to US poison centers. In overdose, toxic metabolites are known to cause hepato- and nephrotoxicity. While G6PD deficiency may be a risk factor for methemoglobin production in the setting of acetaminophen overdose, it is rarely reported in patients who do not have this condition.Methods: We present two cases of methemoglobinemia following massive acetaminophen ingestion with no known history of G6PD deficiency or other substances known to induce methemoglobinemia. The two cases had peak methemoglobin measurements of 32% and 12% respectively, and both were treated with methylene blue.Discussion: A number of mechanisms may be involved in production of methemoglobin in the setting of massive acetaminophen ingestion including NAPQI-induced oxidation, depletion of glutathione stores, and production of oxidant-metabolites including paraaminophenol. While it is unlikely that the majority of acetaminophen overdoses result in any clinically significant methemoglobinemia, massive acetaminophen overdose may be complicated by development of methemoglobinemia.Conclusion: Physicians should be aware of the possibility that massive acetaminophen ingestion may be complicated by methemoglobinemia in rare instances. Further studies should aim to characterize the metabolic pathways leading to possible methemoglobinemia in humans after large acetaminophen ingestions.

Effect of positive urine fentanyl screen on attitudes toward heroin use.

BACKGROUND: It is unknown if targeted risk reduction counseling in the health care setting, after documented exposure to fentanyl, can affect behavior change to reduce risks and increase utilization of evidence-based overdose prevention strategies. METHODS: We conducted a retrospective analysis of results (7/2018-6/2019) from questionnaire-facilitated counseling by recovery coaches in the emergency department (ED) and primary care settings following disclosure of a urine toxicology positive for fentanyl. RESULTS: Seventy-five percent of N = 101 respondents were neither aware of nor expecting fentanyl in their substances of use. Fifty-three (70 %) of those initially unaware answered that learning about exposure to and the risks from fentanyl changed their thoughts about reducing or abstaining from use. A greater proportion of patients seen in the ED expressed desire to stop or reduce opioid use as compared to ambulatory clinic patients (91 % vs. 46 %, p < 0.001). Of those not already engaged in treatment, 18 % and 15 % were interested in medication and behavioural health treatment, respectively, and each of them indicated a change in thought based on the counseling. Forty-five percent of individuals not yet receiving naloxone endorsed interest in receiving it, and 22 % of all respondents were somewhat or very interested in access to safe consumption sites. CONCLUSION: This study suggests a novel clinical utility in toxicology screens to inform behavior in the setting of illicit fentanyl exposure. In addition to linkages to evidence-based treatment, linkages to harm-mitigating strategies associated with ongoing substance use may be critical to a comprehensive overdose prevention strategy in the clinical setting.

Naloxone Dosing After Opioid Overdose in the Era of Illicitly Manufactured Fentanyl.

INTRODUCTION: Illicitly manufactured fentanyl (IMF) is responsible for a growing number of deaths. Some case series have suggested that IMF overdoses require significantly higher naloxone doses than heroin overdoses. Our objective was to determine if the naloxone dose required to treat an opioid overdose is associated with the finding of fentanyl, opiates, or both on urine drug screen (UDS). METHODS: A retrospective chart review was conducted at a single emergency department and its affiliated emergency medical services (EMS) agency. The charts of all patients who received naloxone through this EMS from 1/1/2017 to 6/15/2018 were reviewed. The study included patients diagnosed with a non-suicidal opioid overdose whose UDS was positive for opiates, fentanyl, or both. Data collected included demographics, vital signs, initial GCS, EMS and ED naloxone administrations, response to treatment, laboratory findings, and ED disposition. The fentanyl-only and fentanyl + opiate groups were compared to the opiate-only group using the stratified (by ED provider) variant of the Mann-Whitney U test. RESULTS: Eight hundred and thirty-seven charts were reviewed, and 121 subjects were included in the final analysis. The median age of included subjects was 38 years and 75% were male. In the naloxone dose analysis, neither the fentanyl-only (median 0.8 mg, IQR 0.4-1.6; p = 0.68) nor the fentanyl + opiate (median 0.8 mg, IQR 0.4-1.2; p = 0.56) groups differed from the opiate-only group (median 0.58 mg, IQR 0.4-1.6). CONCLUSION: Our findings refute the notion that high potency synthetic opioids like illicitly manufactured fentanyl require increased doses of naloxone to successfully treat an overdose. There were no significant differences in the dose of naloxone required to treat opioid overdose patients with UDS evidence of exposure to fentanyl, opiates, or both. Further evaluation of naloxone stocking and dosing protocols is needed.

Overdose in infant caused by over-the-counter cough medicine.

Each year consumers purchase about 95 million units of over-the-counter medications for pediatric use, an unsafe application that can cause life-threatening effects. Despite a warning from the Food and Drug Administration, many parents or caregivers continue to administer these remedies to children. This report describes the case of a 4-month-old infant presenting to the emergency department with acute life-threatening intoxication including altered mental status, impaired coordination of movements, as well as a positive urine drug test for phencyclidine and an elevated serum ethanol level. Further evaluation uncovered that the actual reason for all clinical symptoms and laboratory test results was over-the-counter cough syrup.

[Determinations of the presence of drugs in traffic users in the material of the Department of Forensic Medicine, Medical University of Bialystok]. / Badania nad obecnoscia srodków odurzajacych i substancji psychotropowych w organizmach uczestników ruchu drogowego w materiale Zakladu Medycyny Sadowej UM w Bialymstoku.

In recent years, there has been observed an increasing number of traffic users being under influence of psychoactive substances that affect the central nervous system. A total of 198 blood samples and 23 urine samples collected from traffic users (drivers, passengers and pedestrians) suspected of having ingested psychoactive substances were examined. The analysis included blood samples collected from living individuals and blood or urine from the deceased. Ethyl alcohol levels were determined by gas chromatography, while body fluids were examined by Elisa tests for determination of cannabinoids, amphetamines, opium narcotics, cocaine (benzoiloecgonine), benzodiazepines, barbiturates and tricyclic antidepressants. The confirmation of positive results was carried out by gas chromatography with mass detector. Twenty-nine blood samples were positive, what constituted 14.6% of the total number of investigated cases, including 12 (7.8%) of samples originating from living individuals and 17 (37.8)--from the fatalities. In both groups, the most commonly detected substances were cannabinoids (THC and its metabolite carboxy-THC) and amphetamines and its analogues.

A Fatal Case Involving N-Ethyldeschloroketamine (2-Oxo-PCE) and Venlafaxine.

Methoxetamine, 3-methoxyphencyclidine or 3-methoxyeticyclidine are arylcyclohexylamines which have been abused in the past. However, the market for new psychoactive substances, in particular for research chemicals, is rapidly growing and new compounds are being regularly explored by users. Abuse can lead to clinical case and in the worst-case scenario to fatalities. We present the fatal case of a 52-year-old man, who was found dead in the bedroom by his fiancé. He had abused N-ethyldeschloroketamine and venlafaxine prior to his death. These compounds were retrieved from a non-targeted gas chromatography/mass spectrometry-based screening approach of a purified urine sample. In addition, deschloroketamine, bisoprolol and ramiprilate were found in the urine sample, but were either absent or only present at low level in femoral blood. During autopsy a number of tablets were found in the duodenum and identified as venlafaxine. Furthermore, N-ethyldeschloroketamine was quantified in various specimens taken during autopsy and the highest concentration was observed in liver (6,137 ng/g) followed by urine (3,468 µg/L), bile fluid (3,290 µg/L), gastric contents (3,086 µg/L), heart blood (2,159 µg/L) and liquor (1,564 µg/L). The smallest amount was found in femoral blood (375 µg/L). N-ethyldeschloroketamine was also found in the disposable syringes, in a beaker and on the spatula along with deschloroketamine, morphine, metamizole, oxycodone, flupirtin or ibuprofen. The concentrations presented-in particular for femoral blood-are a good starting point for evaluating N-ethyldeschloroketamine intoxications in the future. The other values are helpful for evaluating the post-mortem concentration distribution of this research chemical.

New synthetic opioid cyclopropylfentanyl together with other novel synthetic opioids in respiratory insufficient comatose patients detected by toxicological analysis.

Introduction: Fentanyl derivatives like cyclopropylfentanyl have recently appeared on the recreational drug market. Cyclopropylfentanyl is probably a highly potent opioid, but human toxicological data are not available so far. Similar to other fentanyl derivatives the most serious acute health risk due to the use of cyclopropylfentanyl is likely to be respiratory depression. In case of overdose, this may lead to apnoea, respiratory arrest and death. In this paper, we present three cases of severe intoxication with cyclopropylfentanyl. Methods: Observational case series including three intoxications treated in the Emergency Department at the University Medical Centre in 2017. In all cases, the consumption of any drugs was denied by the patients and relatives. Toxicological analyses using GC-MS, LC-QTOF-MS and LC-MS-MS of serum, urine samples and in one case of a powder sample, found in the hospital room, were performed. Medical records were reviewed to obtain clinical data. Results: Clinical effects of severe opioid intoxications comprising loss of consciousness, bradypnea, hypercapnia, arterial hypotension and miosis were recorded. In all cases, the novel fentanyl analogue cyclopropylfentanyl was detected in body fluids. In two cases further synthetic opioids (U-47700, methoxyacetylfentanyl, butyrfentanyl, 2-fluoroiso- or 4-fluoroisobutyrfentanyl) and mitragynine or desoxypipradrol were found. A discovered powder sample contained cyclopropylfentanyl, cyclopropylnorfentanyl, acetylfentanyl, 4-ANPP, U-47700 and caffeine. Except for acetylfentanyl all ingredients could be detected in the respective blood and urine sample. In two cases a cyclopropylfentanyl serum concentration of 51 and 76 ng/ml was determined. Discussion: In three cases of severe potentially life-threatening intoxication, cyclopropylfentanyl was verified using different analytical procedures. The ingested substance, as well as the excreted metabolites, were detected by application of various mass spectrometric techniques. Conclusions: In cases of intoxication without a medical history, the detailed toxicological analysis may reveal new psychoactive substances which are not detected by standard toxicological screening approaches. The high pharmacological potency of new products with unknown toxicological data and unknown synergistic effects may easily lead to a life-threatening overdose.

Metabolites to parent 3-MeO-PCP ratio in human urine collected in two fatal cases.

In this article, two fatal cases related to the use of 3-methoxyphencyclidine (3-MeO-PCP) are described. This compound is a new psychoactive substance that belongs to the phencyclidine family. In the recent period, this dissociative drug has gained interest because of its proposal as a legally available alternative to phencyclidine in some countries. The scientific literature related to 3-MeO-PCP is very poor. Using standard ultra-performance liquid chromatography-mass spectrometry and ultra-performance liquid chromatography-tandem mass spectrometry, the authors focused on the detection of 3-MeO-PCP and its metabolites in human urine. 3-MeO-PCP metabolism was studied in vitro after drug incubation with human liver microsomes and the identified metabolites were investigated in the urine of the two forensic cases. 3-MeO-PCP metabolites, including O-demethyl-3-MeO-PCP, piperidine-hydroxy-3-MeO-PCP, O-demethyl-piperidine-di-hydroxy-3-MeO-PCP and piperidine-di-hydroxy-3-MeO-PCP, were detectable in the urine from both cases and the ratio between metabolites and parent 3-MeO-PCP, always lower than 1, were calculated to estimate the proportionality of metabolites. At this stage, one can conclude that testing for 3-MeO-PCP metabolites does not increase the window of detection of the drug.

Fentanyl exposure and preferences among individuals starting treatment for opioid use disorder.

BACKGROUND: Fentanyl has become widespread in the illicit opioid supply, and is a major driver of overdose mortality. METHODS: This study used a medical records review at a community opioid use disorder treatment program to examine patient-level correlates of fentanyl exposure as measured by urine testing at admission (N= 1,174). Additionally, an anonymous survey was conducted with 114 patients about their experiences and preferences regarding fentanyl. RESULTS: Overall, 39% of patients entering treatment tested positive for fentanyl. Prevalence of fentanyl exposure differed based on other drug test results (fentanyl-positive = 81.1% vs. 15.4% among participants positive vs. negative for heroin/opioids, p < .001; 59.0% vs. 38.3% among participants positive vs. negative for methadone, p = .001; 53.8% vs. 24.9% among participants positive vs. negative for cocaine, p < .001), prior addiction treatment (40.6% vs. 32.0% among participants with vs. without prior treatment, p < .05), and mental health (36.7% vs. 43.1% among participants with vs. without co-occurring psychiatric diagnosis, p < .05). Most participants reported knowingly using fentanyl (56.1%) and knowing people who prefer fentanyl as a drug of choice (65.8%). Preference for fentanyl (alone or mixed with heroin) was expressed by 44.7% of participants. Participants thought fentanyl withdrawal had faster onset (53.5%), greater severity (74.8%), and longer duration (62.0%) than heroin withdrawal. CONCLUSIONS: Recent opioid and cocaine use were strongly associated with fentanyl exposure in this sample. Although fentanyl exposure is often unintentional, there may be a subgroup of individuals who come to prefer fentanyl. Future research should examine the relationship between fentanyl use, patient preferences for fentanyl, and treatment outcomes.