U-47700: A Not So New Opioid (2024)

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Abstract

Introduction

U-47700 (3,4-Dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide) is a selective agonist of the μ-opioid receptor which was developed by the Upjohn Co. in the 1970s (1). In vitro μ-opioid receptor studies have demonstrated that U-47700 binds to the receptor and acts as an agonist (2). Szmuszkovicz (1982) demonstrated that this opioid agonist had analgesic activity (3) and Cheney et al. (1985) found that U-47700 was 7–8 times more potent than morphine in binding affinity to the μ-opioid receptor (4). It is the methyl analog of AH-7921, arecently controlled synthetic opioid.

There have not been any human studies on the pharmacological effects of U-47700 cited in the scientific or medical literature. However, anecdotal information from user reports and drug forums suggest typical opioid pharmacology: analgesia, sedation, euphoria, constipation, itching, respiratory depression and death (5). Sold on the street under the name “pink” and sometimes referred to as “synthetic cocaine” many illicit drug users are ingesting U-47700, often without their knowledge when it is added to or substituted for other illicit drug preparations. An internet user forum (5) lists suggested “dosing” (Table I) and “pharmaco*kinetics” (Table II) of U-47700. These anecdotal dosing guidelines may be, in part, the cause of fatalities associated with the drug. The concentration or purity could vary widely; thus, the same amount of powder ingested could lead to significant differences in drug dose.

From 2015 to 2016, the DEA reported at least 46 confirmed fatalities linked to the use of U-47700, with the vast majority of the deaths occurring in New York and North Carolina (6). As a response to this increasing public health threat, U-47700 received emergency scheduling and was placed into Schedule 1 of the Controlled Substances Act effective 14 November 2016 (7).

There has been a paucity of case reports involving U-47700 that give the circ*mstances of the death as well as blood concentrations; many of these reported deaths involved other intoxicants including acetyl fentanyl, alprazolam, amphetamine, butyryl fentanyl, diphenhydramine, ethanol, etizolam, furanyl fentanyl, hydrocodone, morphine, 6-acetylmorphine, oxycodone and tramadol (8–11). Mohr (2016) reported on a series of deaths (n = 16) which involved U-47700 (10). In this series, five cases had U-47700 as the only significant toxicological finding. Four of these cases reported peripheral blood concentrations with a mean of 0.302 mg/L (range 0.242–0.382). The fifth case reported a U-47700 blood concentration of 0.453 mg/L with an unspecified draw site. McIntyre (2017) reported on a fatality involving U-47700 with other drugs and provided a tissue distribution of U-47700, with peripheral blood concentration of 0.19 mg/L, central blood concentration of 0.34 mg/L and a tissue distribution ranging from 0.17 mg/L in vitreous to 1.7 mg/kg in liver tissue (Table III) (11). That case was certified as “acute U-47700 and alprazolam abuse”.

This case report presents the distribution of U-47700 in blood and tissues in a lethal intoxication due solely to U-47700, and the first instance of a death attributed to this compound in south-central Kansas. The availability of tissue distribution data in a U-47700 fatality in the absence of other central nervous system depressants is valuable to aid in the interpretation of toxicological findings in the course of death investigation.

Case History

A 26-year-old white male was found dead in his bedroom. The decedent had been living in a major East Coast city until he moved back to south-central Kansas 6 months prior to his death. He was last seen alive the evening before his death, and was reported to have a prior history of illicit drug use.

The decedent was found lying in his bed clad in a pair of shorts. There was no external trauma observed at the scene. However, the decedent did have “white foam” exuding from his mouth. During the scene investigation, a box was found that contained apparent drug paraphernalia including two spoons with residue, two syringes, and a “cook can” (cut-off bottom of a soda can). The spoons and “cook can” were collected and submitted to the Center for examination.

A complete autopsy examination was conducted at the Sedgwick County Regional Forensic Science Center the following morning. The body was that of a well-developed adult male who weighed 310 pounds, was 74 inches in height (BMI 39.8), and appeared to be compatible with the stated age of 26 years. There were no apparent needle puncture sites identified. Internal examination revealed moderately congested and edemous lungs (right 710 g and left 640 g) as well as an enlarged heart weighing 500 grams. The urinary bladder contained 270 mL of clear yellow urine. There was no other significant pathology noted. The following specimens were collected and submitted for toxicological evaluation: blood (heart and femoral), vitreous fluid, liver, brain, urine and gastric contents. Heart blood, femoral blood and urine were collected in tubes preserved with 2% sodium fluoride. Vitreous was collected in a standard gray-top tube containing sodium fluoride and potassium oxalate. Liver tissue, brain tissue and gastric contents were unpreserved. All specimens were refrigerated until the time of analysis.

Toxicological Analyses

A comprehensive toxicological evaluation was conducted. The postmortem heart blood specimen was screened for volatile compounds (ethyl alcohol, methanol, isopropanol, acetone, difluoroethane and toluene) by headspace gas chromatography with a flame ionization detector (GC-FID). Urine was screened by EMIT (Siemens Healthcare Diagnostics, Inc; Newark, DE, USA) [amphetamines, barbiturates, benzodiazepines, benzoylecgonine, cannabinoids, opiates, methadone, methamphetamine and phencyclidine (PCP)], and heart blood was screened using a fifteen panel ELISA (Immunalysis Corporation; Pomona, CA, USA) (amphetamine, barbiturates, benzodiazepines, benzoylecgonine, cannabinoids, carisoprodol, fentanyl, ketamine, methamphetamine, methadone, opiates, oxycodone, phencyclidine, tramadol and zolpidem). An alkaline drug screen was conducted on the heart blood utilizing solid-phase extraction followed by gas chromatography with nitrogen-phosphorus detection (GC-NPD) and confirmation via gas chromatography/mass spectrometry (GC/MS). Colorimetric tests were conducted on heart blood for salicylates and acetaminophen.

The positive screen results for all compounds were quantitated by GC-NPD and confirmed by GC/MS or confirmed and quantitated by liquid chromatography tandem mass spectrometry (LC–MS/MS) (tetrahydrocannabinol in blood). Instrumental analysis was conducted following solid-phase extraction and, in the case of solid tissues, 1:4 hom*ogenization with deionized water.

The physical evidence was also screened for controlled substances including U-47700. The spoons and “cook can” were individually rinsed with a small volume of methanol, and the resulting solutions were injected onto a GC/MS operating in scan mode. The presence of controlled substances was confirmed by comparing retention time and mass spectral data to known standards.

Results

Heart blood screened positive for cannabinoids by ELISA, urine screened positive for PCP and cannabinoids by EMIT, and the alkaline drug screen on heart blood by GC/MS was positive for U-47700. The GC-NPD data from the alkaline drug screen was compared against a library of relative retention time data to rule out approximately 170 drug compounds and metabolites from a variety of classes. Screening results were negative for all other compounds.The U-47700 was initially detected and confirmed in the heart blood of the decedent by GC-NPD and GC/MS. A quantitative study was undertaken utilizing GC-NPD which obtained the following results: heart blood 0.26 mg/L, femoral blood 0.40 mg/L, vitreous fluid 0.09 mg/L, brain tissue 0.38 mg/kg, liver 0.28 mg/kg and urine 4.6 mg/L. The U-47700 distribution results are reflected in Table IV. The central to peripheral blood ratio (C/P) was 0.65. This method underwent an abbreviated validation procedure and it was linear (r² > 0.9875) over the range 0.025 mg/L to 0.5 mg/L with a precision (% CV) of 2.9%. The limit of detection was administratively set at 0.025 mg/L. Carryover was not present in the negative control following the upper calibration standard at 0.5 mg/L.

Tetrahydrocannabinol was detected and quantitated at a concentration of 19 ng/mL in the heart blood. The urine screened positive for phencyclidine (cut-off 25 ng/mL) and blood had an elevated response compared to the negative control for phencyclidine but below the response of the cut-off at 10 ng/mL; however, the GC/MS confirmation analyses in both matrices were negative (LOD 5 ng/mL). A limited experiment was conducted to determine whether the elevated responses in the PCP immunoassays were due to cross-reactivity with U-47700. Negative urine and blood samples were spiked with 0.50, 1.0 and 5.0 mg/L of U-47700 and screened with the immunoassay kits. The results for both kits were negative.

The analyses of the “cook can” revealed that the presence of methamphetamine and heroin, and one spoon’s residue tested positive for methamphetamine. The other spoon was negative for controlled substances. Each item was also examined for the presence of U-47700 which was not detected.

Based upon the totality of circ*mstances (law enforcement investigation, scene investigation, autopsy and toxicological examinations) the cause of death was certified as “acute U-47700 intoxication,” and the manner of death was accidental.

Discussion

This case of lethal intoxication due to U-47700 had a femoral blood concentration of 0.40 mg/L. The four cases reported by Mohr et al. (10) with a mean peripheral blood concentration of 0.302 mg/L (range 0.242–0.382 mg/L) are slightly lower than this case. This case is approximately double the peripheral blood concentration of the case at 0.19 mg/L reported by McIntyre et al. (11). The lower concentration of U-47700 resulting in death in McIntyre’s case is likely due to the combined effects of alprazolam, another CNS depressant drug. Based upon published literature, the attribution of cause of death in this case of acute U-47700 intoxication is consistent with other reported cases.

The C/P ratio of our case is 0.65, which is nearly the inverse of the ratio found by McIntyre of 1.7 (11). Further differences between the two distributions include the concentration of U-47700 in liver, and urine. The liver concentration was significantly lower than that found by McIntyre, whereas the urine concentration was an order of magnitude higher in this case. These differences may be due to an increase in survival time.

The screen results for PCP are unexplained. The limited experiment in spiking urine and blood with U-47700 suggests that it does not cross-react with either the EMIT or ELISA assays. Interrogation of the alkaline screen data did not reveal any PCP analogs, such as 3-hydroxy-PCP, nor synthetic cathinones, such as methylenedioxypyrovalerone (MDPV) (12), known to have cross-reactivity with the immunoassay kits. A query of the Center’s Illicit Drug laboratory was made to see if any PCP analogs had been submitted for analysis; at this time none had been submitted.

Needle puncture sites were not identified during the autopsy examination, and U-47700 was not detected on the physical evidence collected at the scene. This suggests that the route of administration was something other than intravenous injection. The anecdotal information from Table II suggests that either oral ingestion or insufflation are probable routes of administration. Insufflation of this drug has been reported by others (10, 11, 13).

This case report is the first to provide the tissue distribution of U-47700 in a lethal intoxication due solely to this synthetic opioid in the absence of other CNS depressants.

Acknowledgements

The authors would like to thank the Toxicology laboratory staff of the Regional Forensic Science Center for their participation in the initial screening of the case and examination of the physical evidence.

References

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