A Fatality Related to the Synthetic Opioid U-47700: Postmortem Concentration Distribution

Journal of Analytical Toxicology, 2017;41:158–160 doi: 10.1093/jat/bkw124 Advance Access Publication Date: 26 October 2016 Case Report Case Report A Fatality Related to the Synthetic Opioid U-47700: Postmortem Concentration Distribution County of San Diego, Medical Examiner’s Department, 5570 Overland Ave., Suite 101, San Diego, CA 92123, USA *Author to whom correspondence should be addressed. Email: Abstract In this case report, we present an evaluation of the distribution of postmortem concentrations of 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) in a fatality attributed principally to the drug. A man who had a history of drug abuse was found unresponsive and not breathing on his bed. Drug paraphernalia, indicating drug insufflation, was located in the decedent’s room. Toxicology screening tests in peripheral blood initially identified U-47700 using an alkaline drug screen with gas chromatography-mass spectrometry (GC-MS) following solid-phase extraction. It was subsequently confirmed and quantitated by GC-MS-specific ion monitoring analysis following liquid–liquid extraction. The U-47700 peripheral blood concentration was quantitated at 190 ng/mL compared to the central blood concentration of 340 ng/mL. The liver concentration was 1,700 ng/g, the vitreous was 170 ng/mL, the urine was 360 ng/mL and the gastric contained only a trace amount (<1 mg). Other drugs detected in peripheral blood were alprazolam (0.12 mg/L), nordiazepam (<0.05 mg/L), doxylamine (0.30 mg/L), diphenhydramine (0.14 mg/L), ibuprofen (2.4 mg/L), salicylic acid (<20 mg/L) and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (2.4 ng/mL). The cause of death was certified as acute U-47700 and alprazolam abuse, and the manner of death was certified as accident. Introduction 3,4-Dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is a strong synthetic µ-opioid analgesic, which was derived from, and is a structural isomer of, another opioid, AH7921. In recent times, it has been encountered as an illicitly used narcotic in Europe, and the USA. Although not presently scheduled in the USA, it is controlled in Finland and Sweden. U-47700, which also has no currently recognized medical use, has been reported to be approximately 7- to 8-fold more potent than morphine in affinity binding to µ-opioid receptors (1). Although the pharmacological effects of U-47700 have not been specifically investigated clinically in humans, anecdotal evidence from user reports found on the Internet suggest that it has effects very similar to morphine and heroin. There have now been reports of overdose in at least 10 states within the USA, including hospitalizations identified by local law enforcement in Florida and Northern Texas, since the first US incident was discovered in Knoxville, Tennessee, in June 2015. U-47700 was identified as the sole opioid of intoxication in two individuals in Texas who obtained the drug over the Internet (2). Recently, fatalities associated with the drug were described in the UK (3) and Belgium (4). Although there are sparse descriptions of biological analysis of U-47700, Elliott et al. (3) first reported a death resulting from mixed drug intoxication with a femoral blood concentration of 1,460 ng/mL. The case also involved concomitant use of other drugs of abuse: mexedrone, amphetamine and ketamine, and therapeutic medications: quetiapine, amitriptyline and naproxen. Around the same time frame, Coopman et al. (4) described a fatality (combined with fentanyl and sertraline) with blood and urine U-47700 concentrations of 13.8 and 71.0 ng/mL, respectively. A non-fatal intoxication in central California has been presented with a hospital admission serum concentration of 7.6 ng/mL—again in combination with fentanyl and other drugs including benzoylecgonine, sertraline, gabapentin, hydrocodone and acetaminophen (5). In this report, postmortem concentrations are described for peripheral blood, central blood, liver, vitreous humor, urine and gastric contents in a death certified principally to acute U-47700 abuse. An © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: 158 Iain M. McIntyre*, Ray D. Gary, Sandra Joseph, and Robert Stabley 159 A Fatality Related to the Synthetic Opioid U-47700 analytical procedure was developed using a gas chromatographymass spectrometry (GC-MS)–specific ion monitoring (SIM) method. Methods Case report Postmortem specimen collection All specimens analyzed were collected during autopsy at the San Diego County Medical Examiner’s Office. Peripheral blood (~20 mL) was drawn from the right common iliac vein (blood returning from the leg and visually identified in the pelvis during autopsy) and stored in standard glass tubes containing sodium fluoride (100 mg) and potassium oxalate (20 mg). Central blood was collected directly from the heart and placed in identical tubes. Sections of the right lobe of liver were collected and stored in an opaque plastic 4-ounce container without preservative. Vitreous humor samples were withdrawn from the eyes with a syringe and stored in a glass tube without preservative. Urine was collected into in an opaque plastic 4-ounce container without preservative. Entire gastric content (450 mL) was measured and transferred into opaque 12-ounce containers without preservative. All samples were stored at 4°C until analyzed. All toxicological analyses were completed within 4 months of specimen collection. Toxicology A comprehensive toxicological screening regimen was performed. Postmortem blood was screened for alcohol and volatile compounds (GC-FID headspace), 12 drugs of abuse panel by ELISA (cocaine metabolite, opiates, methamphetamine, benzodiazepines, cannabinoids, fentanyl, phencyclidine, oxycodone, methadone, zolpidem, carisoprodol U-47700 confirmation analysis Materials All solvents and chemicals were purchased from Fisher Scientific (Pittsburgh, PA, USA) and were analytical grade or better. Test tubes made of borosilicate glass used for all phases of the extraction procedure were purchased through VWR International (Radnor, PA, USA). The U-47700 drug standard used in the calibration formulations was obtained from Cayman Chemical Co. (Ann Arbor, MI, USA), and the D3–hydrocodone internal standard was purchased from Cerilliant Corporation (Round Rock, TX, USA). Extraction U-47700 was confirmed and quantitated utilizing minor modifications to a previously described procedure for fentanyl using GC coupled with an MS SIM procedure (6). The analysis included whole-blood (porcine) calibrators (20, 50, 100, 250 and 500 ng/mL), case samples (whole blood, liver, vitreous, urine and gastric), positive controls and negative controls that were subjected to an alkaline liquid–liquid extraction procedure. Case specimens were extracted using appropriate dilutions (as required) to ensure that the quantitation was within the range of the calibration curve. To 1 mL of s (...truncated)