U-47700: A Clinical Review of the Literature

The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–11, 2017 Ó 2017 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2017.05.034

Selected Topics: Toxicology

U-47700: A CLINICAL REVIEW OF THE LITERATURE Kerry Anne Rambaran, PHARMD, BCPS,* Steven W. Fleming, MS, F-ABFT, TC-NRCC,† Jie An, PHD,† Samantha Burkhart, BS,† Jakub Furmaga, MD,‡§ Kurt C. Kleinschmidt, MD, FACEP, FACMT,‡§ A. Michael Spiekerman, PHD,†k and Saeed K. Alzghari, MS, MBA (HOM), PHARMD, BCPS† *Department of Clinical and Administrative Sciences, School of Pharmacy, Keck Graduate Institute, Claremont, California, †Gulfstream Diagnostics, LLC, Dallas, Texas, ‡UT Southwestern Medical Center, Dallas, Texas, §North Texas Poison Control Center, Parkland Health and Hospital System, Dallas, Texas, and kDepartment of Clinical Pathology, Baylor Scott & White Health, Temple, Texas Reprint Address: Saeed K. Alzghari, MS, MBA (HOM), PHARMD, BCPS, Gulfstream Diagnostics, LLC, 9301 N. Central Expressway, Tower 2, Suite 335, Dallas, TX 75231

, Abstract—Background: U-47700 is a synthetic opioid developed by The Upjohn Company in the 1970s, which has recently appeared in the news and medical literature due to its toxicity. Currently, there are no clinical trial data assessing the safety of U-47700. Objective: To describe the signs and symptoms of ingestion, laboratory testing, and treatment modalities for U-47700 intoxication. Discussion: We searched PubMed, Embase, Web of Science, and EBSCO for articles using the term ‘‘U-47700’’ and ‘‘47700.’’ The following inclusion criteria were used: had to be in English; full text; must involve humans; must be either a randomized control trial, prospective trial, retrospective analysis, case series, or case report; and must include clinical findings at presentation. We identified and extracted data from relevant articles. Ten relevant articles were included with 16 patients. Patients that died after overdose with U-47700 typically presented to the hospital with pulmonary edema. Patients who survived an overdose presented with decreased mental status and decreased respiratory rate suggestive of an opioid toxidrome. Patients also commonly had tachycardia. Immunoassays failed to identify U-47700, and the identification of U-47700 required the use of chromatographic and spectral techniques. Conclusion: We report the first clinical review of U-47700 intoxication. Ó 2017 Elsevier Inc. All rights reserved.

INTRODUCTION Drug overdose is the leading cause of accidental death in the United States. Lethal drug overdoses have increased unprecedentedly in recent years; in 2015, there were 52,404 deaths caused by drug overdose (both opioid and non-opioid), among which 20,101 cases involved prescription pain relievers (1). Opioids are the most common drug of addiction in the United States. From 2010 through 2014, six of the top 10 drugs involved in lethal drug overdose were opioids: heroin, oxycodone, methadone, morphine, hydrocodone, and fentanyl (2). Opioids are analgesics that in some people produce euphoria. However, these agents also have multiple side effects, including drowsiness, nausea, constipation, and respiratory depression (3). There are several different types of opioids, including natural products (e.g., morphine, codeine), semi-synthetic opioids (e.g., hydrocodone, oxycodone) and synthetic opioids (e.g., fentanyl, sufentanil) (4). Recently, there has been a re-emergence in the distribution and abuse of novel synthetic opioids. U-47700 (3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide) is a non-fentanyl-based synthetic opioid that acts as a selective agonist of the m-opioid receptor (Figure 1) (5). It was developed by the pharmaceutical company The Upjohn Company in

, Keywords—U-47700; drugs of abuse; novel psychoactive substance; synthetic opioid; opioid poisoning; overdose; opioid toxidrome

RECEIVED: 27 January 2017; FINAL SUBMISSION RECEIVED: 16 May 2017; ACCEPTED: 30 May 2017 1

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keywords ‘‘U-47700’’ or ‘‘47700.’’ We examined the reference lists of each article for additional resources that fit the selection criteria. Selection Criteria

Figure 1. Chemical structure of U-47700.

the 1970s as a novel opioid analgesic drug and is a structural isomer of AH-7921, an earlier opioid analgesic developed by Allen & Hanburys Ltd., but was never made commercially available for medical use (6). The U.S. Food and Drug Administration never approved this experimental selective m-opioid receptor agonist, nor was it studied in humans. Based on the data obtained from animal models, U-47700 has about 7.5 times the potency of morphine (5,7). The animal data also indicate that this drug produces effects similar to other potent opioid agonists, such as analgesia, sedation, and euphoria, but also causes other common opioid side effects, including constipation, nausea, and respiratory depression. It is marketed as a ‘‘research chemical’’ and is readily available on the Internet (8). Since 2015, the Drug Enforcement Administration (DEA) has received reports for 46 deaths associated with U-47700 in six states: New Hampshire (n = 1), New York (n = 31), North Carolina (n = 10), Ohio (n = 1), Texas (n = 2), and Wisconsin (n = 1) (8). On November 14, 2016, the DEA issued the final order to temporarily place U-47700 and its isomers, esters, and ethers into Schedule I to avoid the forthcoming hazard to the public safety (8). All available data indicate that U-47700 has a high abuse potential and can be addictive due to its opioid effects. It does not have any accepted medical or safety data for its use in the United States (8). Its pattern of abuse is similar to that of heroin and prescription opioid analgesics, leading to similar public health risks such as large numbers of drug treatment admissions, emergency visits, and fatal overdoses. In this review, we summarize the reported cases related to U-47700 and describe the clinical and analytical implications associated with this drug to help clinicians become aware of this growing epidemic. DISCUSSION Literature Search We searched PubMed, Embase, Web of Science, and EBSCO for articles from 2015 to the present, using the

We utilized the following criteria for article selection: 1) articles written in English; 2) must be full-text articles; 3) must involve humans; 4) must be either a randomized controlled trial, prospective trial, retrospective analysis, case series, or case report; and 5) must include clinical findings at presentation. Data Extraction The senior author (SKA) identified relevant articles reporting the outcomes of interest. Two authors (KAR, SF) extracted data independently and blinded to each other from all case reports. Extracted data were crossreviewed by KAR and SF; SKA resolved any discrepancies. We utilized standardized tables to extract the following variables if a patient was deceased at presentation: 1) drug(s) consumed, 2) route, 3) cumulative dose, and 4) presentation. Furthermore, we used standardized tables to extract the following variables if a patient was alive at presentation: 1) drug(s) consumed, 2) route, 3) presentation, 4) duration of toxicity, and 5) treatment/ treatment outcome. RESULTS In total, we initially identified 11 articles. After applying the inclusion criteria, nine relevant articles remained. Further review of the reference lists of each article identified an additional article for inclusion. In total, 10 relevant articles were identified for this review, with a total of 16 patients (Figure 2) (4,6,9–16). Clinical and Analytical Implications of U-47700 Of the 16 cases found, 10 were fatalities, with the subjects’ ages ranging from 20–46 years (Table 1) (4,6,11,13,15). Additionally, all of the subjects were male, and eight of the 10 deaths occurred in the United States. Only three cases mentioned the route of exposure, with insufflation being reported in two of the three cases and vaporization on foil being the third (10,12,14). Similarly, only four cases reported on concomitant use of other pharmaceutical agents, of which two subjects either had a history of utilizing or was currently using recreational drugs. Because the findings reported were primarily postmortem, the duration of toxicity is unknown. Nine of the ten cases reported postmortem findings of pulmonary edema, two

U-47700

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Figure 2. Search flow diagram.

reported findings of cerebral edema, and two reported findings of cardiomegaly (4,10,12,14,16). The remaining 6 patients who lived after using U-47700 are discussed in Table 2 (9,10,12,14,16). These subjects were between the ages of 22 and 41 years, and were in the United States at the time of the incident; there was an equal number of males and females that lived. For these subjects, the most common route reported was insufflation followed by intravenous use. The dose of U-47700 utilized may affect the clinical presentation of subjects; however, none of these case reports provided a dose. In theory, the intravenous route would provide a more pronounced effect and presentation when compared with insufflation or ingestion; however, the differences were unremarkable. As such, the subjects generally presented with a Glasgow Coma Scale score of 3, hypoxia, and respiratory depression suggestive of an opioid toxidrome. Furthermore, the subjects also presented with tachycardia. Intravenous naloxone seems to reverse the coma and bradypnea caused by U-47700 (9,12,14). It is of note that the total naloxone doses for reversal of U-47700 ranged from 0.4–4 mg, whereas cases associated with carfentanil, another abused synthetic opioid, may require up to 2 mg/kg of naloxone to reverse carfentanil’s effects (17). Chest x-ray studies may show patchy infiltrates or consolidation, but that was not a common finding in all of the reports. Of note, no reported findings of pulmonary or cerebral edema or cardiomegaly occurred in the 6 subjects that lived. Table 2 describes the duration of toxicity from each case report. Armenian et al.’s report of a patient taking street NorcoÒ is significant in that clinicians must be wary of ‘‘fake pills,’’ and cannot always assume that illegally obtained prescription medications on which patients overdose are pure (9). In this particular case, fentanyl and U-47700 were found in the patient’s system after what the patient thought was combination acetaminophen-hydrocodone, leading to

an unexpected presentation. In all 6 of the cases, patients made a full recovery. With regard to analytical findings, the matrix typically recovered for testing were blood and urine samples (Table 3) (4,6,9–16). None of the immunoassays utilized could detect U-47700. Thus, the reported cases turned to untargeted and targeted approaches to detect U-47700. Untargeted approaches detect unexpected peaks with chromatographic and spectral techniques, whereas targeted approaches detect expected peaks for known agents with chromatographic and spectral techniques. All cases used an untargeted approach followed by a targeted approach to identify U-47700, except Mohr and colleagues, who solely utilized targeted methodologies because those patients overdosed on U-47700 (4). Limitations The limitation of this clinical summary is that it relies on case reports, which have their own inherent limitations. Furthermore, the small number of case reports may not generalize the entire population exposed to U-47700. Information about co-ingestions was significantly lacking in most reports. Additionally, in some cases, the subjects utilized benzodiazepines and alcohol, which could have further confounded the clinical picture. Of note, the majority of cases did not specify the dose of U-47700 utilized, which can significantly affect the presentation of the patient. Furthermore, the route utilized amongst individuals taking U-47700 varied, thus making it difficult to ascertain the peak onset of action. Because these are case reports, one cannot infer causality from an uncontrolled observation. An analytical limitation of diagnosing novel psychoactive substance intoxication is the inability to test for these new substances. Many laboratories use a targeted approach and may miss detecting the presence of these novel psychoactive substances, such as U-47700. As mentioned previously, clinical experience with U-47700

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Table 1. Case Reports Identified in Which Use of U-47700 Resulted in Death Date

Country

Age, Years

Coopman et al. (6)

May 2016

Belgium

30

M

Fentanyl, U-47700

Vaporization on foil

Approximately 36 g

Elliott et al. (11)

Mar 2016

UK

27

M

Insufflation

None provided

McIntyre et al. (13)

Oct 2016

USA

46

M

Possibly mirtazapine History using: cannabis, ketamine, methcathinone, ‘‘legal highs’’ U-47700

Insufflation

None provided

Mohr et al. (4)

Sept 2016

USA

25

M

U-47700

Not specified

None provided

Mohr et al. (4)

Sept 2016

USA

29

M

U-47700, Chiesel 60% Sativa, 1G322

Not specified

None provided

Mohr et al. (4)

Sept 2016

USA

29

M

U-47700

Not specified

None provided

Mohr et al. (4)

Sept 2016

USA

30

M

U-47700

Not specified

None provided

Mohr et al. (4)

Sept 2016

USA

26

M

Not specified

None provided

Spargo (15)

2015

USA

27

M

U-47700, hydrocodone/ acetaminophen, alprazolam, venlafaxine U-47700

Not specified

None provided

Spargo (15)

2015

USA

20

M

U-47700

Not specified

None provided

EMS = emergency medical services.

Sex

Drug(s)

Route

Cumulative Dose

Presentation Found deceased Pulmonary edema reported, no apparent injection sites. Found deceased

Postmortem findings: Lungs showed edema, congestion, and expanded alveoli, with terminal clubbing of the septa. Liver and spleen were enlarged. Microscopically the liver showed macrovesicular steatosis, but no significant fibrosis, and the spleen showed sinusoidal congestion. Found deceased. Pulmonary edema was present. U-47700 peripheral blood concentration was 334 ng/mL. Subject complained of a headache and then collapsed. EMS attempted resuscitation. Postmortem findings: cerebral and pulmonary edema. U-47700 peripheral blood concentration was 453 ng/mL. Found deceased. Pulmonary edema was present. Postmortem peripheral blood concentration of U-47700 was 242 ng/mL. Found deceased. Postmortem findings: pulmonary edema, gastritis and chronic hepatitis. Found deceased. Postmortem findings: cerebral and pulmonary edema. Found deceased. Postmortem findings: pulmonary edema and cardiomegaly. Found deceased. Postmortem findings: pulmonary edema, cardiomegaly and hepatosplenomegaly.

K. A. Rambaran et al.

Author

Author

Date

Country

Age, Years

Sex

Drug(s)

Route

Presentation

Duration of Toxicity

Armenian et al. (9)

Nov 2016

USA

41

F

3 tablets of U-47700 Home medications: baclofen, gabapentin, sertraline Alcohol Smokes Marijuana Methamphetamine abuse history

Ingestion

Arrival to ED: depressed level of consciousness. Pinpoint pupils mildly responsive to sternal rub. 10 min after naloxone: BP 141/ 98 mm Hg, pulse 134 beats/ min, RR 19, SPO2 100 on nonrebreather mask. Serum chemistry 48 min into ED arrival was significant for acetaminophen < 10 mg/mL and glucose 64 mg/dL. No drug abuse screen was performed

1.5 h

Domanski et al. (10)

Jul 2016

USA

26

M

Alcohol Alprazolam U-47700

Insufflation

EMS: Face down with agonal breathing, cyanotic with O2 sat of 50% on ambient air. ED: GCS of 3, pinpoint pupils. HR 125 beats/min, BP 150/ 63 mm Hg, RR 14 breaths/ min, T 97.4 F or 36.3 C, ABG pH 6.97, PCO2 > 90, PO2 80, HCO3 21.4. CXR showed bilateral consolidation, CT showed patchy consolidation on right upper lobe and bilateral lower lobes. SCr 1.5 mg/dL, lactate 4.4 mmol/L, WBC 11.2 K/ mL, Glu 94 mg/dL, CK 130 U/L. ECG showed sinus tachycardia at 125 beats/ min with normal intervals and nonspecific ST changes. Ethanol level of 55 mg/dL.

3h

Treatment/Treatment Outcome

U-47700

Table 2. Case Reports Involving the Use of U-47700 and the Outcome

Two minutes into ED arrival received 0.4 mg naloxone i.v., which resulted in arousal and regain of consciousness. Pruritus and anxiety occurred shortly after naloxone and was resolved after receiving lorazepam 1 mg i.v. and diphenhydramine 50 mg i.v. She remained somnolent for 2 h but then recovered to normal coherent state. She attempted to DAMA and was discharged home 4 h after arrival with a complete recovery. Intubation by EMS: ketamine, lorazepam, rocuronium. From ED, he was transferred to ICU where he was sedated on propofol and given antibiotics for presumed pneumonia. He self-extubated in the ICU and was discharged 3 days after presentation with a normal examination.

(Continued )

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Table 2. Continued

Country

Age, Years

Date

Sex

Drug(s)

Route

Domanski et al. (10)

Jul 2016

USA

24

F

Alcohol Alprazolam U-47700

Insufflation

Jones et al. (12)

Aug 2016

USA

23

F

U4 or U-47700

i.v. injection The previous two times via insufflation but it caused epistaxis.

Schneir et al. (14)

Jul 2016

USA

22

M

250 mg of U-47700 divided into five separate doses. Only utilized one, utilized two in the past without adverse effect

Mixed with water and applied into nostril

Presentation ED: she reported anxiety, nausea, and abdominal pain. T 97.8 F or 36.5 C. Drowsy upon physical examination but no dyspnea. HR 97 beats/min, BP 111/77 mm Hg, RR 18 breaths/min, O2 sat at 100 on room air. Ethanol level of 11 mg/dL. CXR normal. ECG normal sinus rhythm at 87 beats/min with normal intervals, no ST changes EMS: She was cyanotic with RR of 4 breaths/min and O2 saturation of 60%. ED: HR 104 beats/min, O2 sat 77 % on 5L O2 via nasal cannula, RR 30 breaths/ min. PE: normal with dried blood at nares and mouth, increased respiratory effort and crackles in both lung bases. CXR: patchy infiltrates and mild congestion consistent with pulmonary edema. BMP, CBC normal with WBC 18.3, VBG with venous O2 saturation of 65.4% Urine screen was negative for recreational drugs. EMS: Found him cyanotic with agonal respirations at 4 breaths/min and pulse oxygenation of 60%. BP 138/88 mm Hg, pulse 134 beats/min and GCS 3. ED: BP 112/71 mm Hg, pulse 92 beats/min, T 97.6 F or

Duration of Toxicity

Treatment/Treatment Outcome

3h

Kept for 24 h observation then discharged

Minutes

EMS: Given naloxone 2 mg intranasal without response followed by 2 mg naloxone i.v., whereby she became more responsive ED: Placed on BiPAP, which improved O2 saturation to 100 and decreased RR to normal limits. She came off BiPAP later that night and was discharged the following day after her pulmonary function improved.

Time prior to being found was not reported.

2 mg of naloxone was given by the EMS, which reversed the coma and bradypnea. He was discharged after staying 5 h in the ED. Oneweek follow-up revealed he was asymptomatic.

K. A. Rambaran et al.

Author

Nov 2016

USA

29

M

U-47700 on the day of presentation and phenazepam a few days prior

i.v.

U-47700

Vo et al. (16)

36.4 C, pulse oxygenation 97% on room air. CXR: normal, ECG unremarkable with normal QRS width and QTc 442 ms. Leukocytosis 16,000/mm3 with a differential: 88% neutrophils, 8% lymphocytes, 2% monocytes, and 1% eosinophils. Urine tested positive for benzodiazepine as a class. Initially was unresponsive but regained consciousness prior to transport to ED. ED: BP 157/105 mm Hg, HR 112 beats/min. PE unremarkable, CBC normal except for elevated neutrophils 79.6%. Elevated SCR 1.4 mg/dL with estimated normal GFR.

3h

Monitored in ED and was provided with oral hydration, which resulted in improvement of vital signs. He was discharged 3 h post observation.

ABG = arterial blood gases; BiPAP = bilevel positive airway pressure; BMP = basic metabolic panel; BP = blood pressure; CBC = complete blood count; CK = creatine kinase; CT = computed tomography; CXR = chest x-ray; DAMA = discharge against medical advice; ECG = electrocardiogram; ED = emergency department; EMS = emergency medical services; GCS = Glasgow Coma Scale score; GFR = glomerular filtration rate; Glu = glucose; HCO3 = bicarbonate; h = hour; HR = heart rate; ICU = intensive care unit; i.v. = intravenous; O2 = oxygen; PCO2 = partial pressure of carbon dioxide; PE = physical examination; PO2 = partial pressure of oxygen; RR = respiratory rate; SCr = serum creatinine; SPO2 = peripheral capillary oxygen saturation; T = temperature; USA = United States of America; VBG = venous blood gas; WBC = white blood cells.

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Table 3. Analytical Findings of Case Reports Involving the Use of U-47700 Author

Matrix Tested

Presumptive Immunoassay Tests and Results

Additional Testing Results for U-47700

Antemortem serum

N/A

Untargeted LC/QToF U-47700: 7.6 and 6.0 ng/mL at 13 and 44 min post arrival, respectively

Coopman et al. (6)

Postmortem blood and urine

N/A

Domanski et al. (10)

Antemortem urine from male

Negative ED drug screen 28-panel enzyme immunoassay positive for benzodiazepines, cannabinoids, ketamine

Domanski et al. (10)

Antemortem urine from female

*7-panel ED drug screen positive for cannabinoids 28-panel enzyme immunoassay positive for cannabinoids

Elliott et al. (11)

Postmortem urine and blood

N/A

Jones et al. (12)

Antemortem urine and blood

Negative rapid immunoassay

Targeted U-47700 UPLC/MS/MS: blood (13.8 ng/mL) and urine (71 ng/mL) Untargeted HPLC/PDA: Subclavian blood-Sertraline (180 ng/L) Untargeted GC/MS scan: Urine - fentanyl, sertraline Targeted LC/MS/MS: U-47700 (0.1 ng/mL), lorazepam, cotinine, ketamine, norketamine Untargeted LC/QToF: Acetaminophen, ketamine, ketorolac, ofloxacin, piperacillin, U-47700 Untargeted: GC/MS scan propofol and acetaminophen Targeted LC/MS/MS: Cotinine Untargeted LC/QToF: Acetaminophen, ketorolac, piperacillin, theobromine and U-47700 Untargeted HPLC/PDA: Urine-quetiapine, amphetamine, mexedrone, ketamine. Blood-quetiapine, amphetamine, naproxen U-47700 targeted LC/MS/MS: detected in both femoral blood (1460 ng/mL) and urine Untargeted LC/QToF: U-47700, N-desmethyl-U-47700, N, N-didesmethyl-U-47700 Untargeted UPLC/ToF: U-47700 Targeted UPLC/MS/MS Urine: U-47700, buprenorphine, norbuprenorphine, and mitragynine Serum – U-47700

Poly drug use with acetaminophen, benzoylecgonine, fentanyl, gabapentin, hydrocodone, sertraline. ToF analysis screened for 581 drugs including 303 designer drugs Used SWGDRUG Library 2.4 and did not get a hit for the GC/MS scan Used European Reitox EWS and was able to identify the substance as U-47700. Targeted analysis included 79 analytes that include opioids, benzodiazepines, sedative hypnotic agents, skeletal muscle relaxants, and gabapentin.

Targeted analysis included 79 analytes that include opioids, benzodiazepines, sedative hypnotic agents, skeletal muscle relaxants, and gabapentin. If using targeted approach, transition 329 > 81 and 204 will provide appropriate specificity with respect to AH-7921 and like compounds. Suspected metabolites identified by ToF without reference standards using accurate mass.

N/A

K. A. Rambaran et al.

Armenian et al. (9)

Additional Comments

Postmortem blood (peripheral and central), vitreous, liver, urine and gastric

†12-panel ELISA screen

Mohr et al. (4)

Postmortem blood

N/A

Schneir et al. (14)

Antemortem urine

‡9-panel Immunoassay positive for benzodiazepines

Spargo (15)

Postmortem femoral blood and urine

3-panel ELISA screen (cannabinoids, opiates, cocaine metabolite)

Spargo (15)

Postmortem subclavian blood and urine Antemortem urine and serum

3-panel ELISA screen (cannabinoids, opiates, cocaine metabolite) Immunoassay screen positive for benzodiazepines

Vo et al. (16)

Untargeted GC/MS scan: U-47700 in peripheral blood U-47700 Targeted GC/MS (SIM): Peripheral – 190 ng/mL Central – 340 ng/mL Vitreous – 170 ng/mL Liver – 1700 ng/mg Urine – 360 ng/mL Gastric – Trace amounts Peripheral – alprazolam (0.12 mg/L), doxylamine (0.3 mg/L), diphenhydramine (0.14 mg/L), ibuprofen (2.4 mg/L) U-47700 targeted LC/MS/MS: Cases ranged from 17–490 ng/mL Targeted 8-panel benzodiazepine LC/MS/MS: negative Untargeted LC/ToF: U-47700, desmethyl-U-47700 Untargeted GC/MS scan: bloodibuprofen, U-47770 and urine – U-47700, oxymetazoline, demethyldiazepam, olanzapine Untargeted GC/MS scan: U-47700 detected in both urine and blood Untargeted LC/ToF: Serum – U-47700 (240 ng/mL), phenazepam (1.4 mg/L) Urine – U-47700

Used Cayman Spectra Library to identify U-47700 by GC/MS.

U-47700

McIntyre et al. (13)

Majority of the cases involved poly drug abuse Analysis revealed that U-47700 cross-reacted with the benzodiazepine screen at a high concentration of 107 ng/mL. The assay has a cutoff of 100 ng/mL. Polydrug abuse with diazepam (0.60 mg/L), demethyldiazepam (0.52 mg/L), oxazepam (0.076 mg/ L) and temazepam (0.108 mg/L) N/A Positive benzodiazepines screen may be attributed to novel psychoactive substances such as seen in this case with phenazepam

ELISA = enzyme-linked immunosorbent assay; ED = emergency department; EWS = early warning system; GC = gas chromatography; HPLC = high-performance liquid chromatography; LC = liquid chromatography; MS = mass spectrometry; PDA = photodiode array; QToF = quadrupole time-of-flight; SIM = selected ion monitoring; ToF = time-of-flight; ug/ L = micrograms per milliliter; UPLC = ultra-performance liquid chromatography. * Seven-panel drug screen includes amphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine metabolite, opiates, phencyclidine. † Twelve-panel drug screen includes benzodiazepines, buprenorphine, cannabinoids, carisoprodol, cocaine metabolite, fentanyl, methadone, methamphetamine, opiates, oxycodone, phencyclidine, zolpidem. ‡ Nine-panel drug screen for amphetamines, barbiturates, benzodiazepines, cocaine (benzoylecgonine), methadone, opiates, oxycodone, phencyclidine, and tetrahydrocannabinol.

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is limited. Analytical challenges include the unknown stability of the drug in different matrices and storage conditions. McIntyre and colleagues noted that U-47700 is not stable in ethyl acetate, which is a widely used extraction solvent in toxicology laboratories (13). Also demonstrated in the case reports is the need to have an up-to-date library that is current with worldwide drug trends. This limitation can determine if an unknown peak is identified as shown by Coopman and colleagues (6). CONCLUSION We reported the first clinical review of U-47700 as a guide for practitioners to bring awareness to the presentation and management of individuals taking this agent. The most common routes of ingestion were by insufflation and intravenous injection. In cases where the individual died, pulmonary edema was the most common finding. Individuals that survived a U-47700 overdose generally had decreased mental status and respiratory depression on presentation, suggestive of an opioid toxidrome. Patients alive at presentation also experienced tachycardia. Intravenous naloxone was able to reverse overdose symptoms of decreased mental status and bradypnea. Nontargeted approaches were the primary mode of identification of U-47700. The recent scheduling of U-47700 by the DEA is a call to action to prevent this agent from causing further morbidity and mortality as presented in this review. REFERENCES 1. American Society of Addiction Medicine. Opioid addiction 2016 facts & figures. Available at: http://www.asam.org/docs/defaultsource/advocacy/opioid-addiction-disease-facts-figures.pdf. Accessed January 26, 2017. 2. Warner M, Trinidad JP, Bastian BA, Minino AM, Hedegaard H. Drugs most frequently involved in drug overdose deaths: United States, 2010-2014. Natl Vital Stat Rep 2016;65:1–15.

3. Mattoo SK, Singh SM, Bhardwaj R, Kumar S, Basu D, Kulhara P. Prevalence and correlates of epileptic seizure in substanceabusing subjects. Psychiatry Clin Neurosci 2009;63:580–2. 4. Mohr AL, Friscia M, Papsun D, Kacinko SL, Buzby D, Logan BK. Analysis of novel synthetic opioids U-47700, U-50488 and furanyl fentanyl by LC-MS/MS in postmortem casework. J Anal Toxicol 2016;40:709–17. 5. Cheney BV, Szmuszkovicz J, Lahti RA, Zichi DA. Factors affecting binding of trans-N-[2-(methylamino)cyclohexyl] benzamides at the primary morphine receptor. J Med Chem 1985;28:1853–64. 6. Coopman V, Blanckaert P, Van Parys G, Van Calenbergh S, Cordonnier J. A case of acute intoxication due to combined use of fentanyl and 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-Nmethylbenzamide (U-47700). Forensic Sci Int 2016;266:68–72. 7. Harper NJ, Veitch GB, Wibberley DG. 1-(3,4Dichlorobenzamidomethyl)cyclohexyldimethylamine and related compounds as potential analgesics. J Med Chem 1974;17: 1188–93. 8. Drug Enforcement Administration, Department of Justice. Schedules of controlled substances: temporary placement of U-47700 into schedule I. Final order. Fed Regist 2016;81:79389–93. 9. Armenian P, Olson A, Anaya A, Kurtz A, Ruegner R, Gerona RR. Fentanyl and a novel synthetic opioid U-47700 masquerading as street ‘‘Norco’’ in central California: a case report. Ann Emerg Med 2017;69:87–90. 10. Domanski K, Kleinschmidt KC, Schulte JM, et al. Two cases of intoxication with new synthetic opioid, U-47700. Clin Toxicol (Phila) 2017;55:46–50. 11. Elliott SP, Brandt SD, Smith C. The first reported fatality associated with the synthetic opioid 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) and implications for forensic analysis. Drug Test Anal 2016;8:875–9. 12. Jones MJ, Hernandez BS, Janis GC, Stellpflug SJ. A case of U47700 overdose with laboratory confirmation and metabolite identification. Clin Toxicol (Phila) 2017;55:55–9. 13. McIntyre IM, Gary RD, Joseph S, Stabley R. Fatality related to the synthetic opioid U- 47700: postmortem concentration distribution. J Anal Toxicol 2017;41:158–60. 14. Schneir A, Metushi IG, Sloane C, Benaron DJ, Fitzgerald RL. Near death from a novel synthetic opioid labeled U- 47700: emergence of a new opioid class. Clin Toxicol (Phila) 2017;55:51–4. 15. Spargo EA. Two fatalities involving the use of the synthetic opioid U-47700. Toxtalk 2016;40:9–13. 16. Vo KT, van Wijk XM, Wu AH, Lynch KL, Ho RY. Synthetic agents off the darknet: a case of U-47700 and phenazepam abuse. Clin Toxicol (Phila) 2017;55:71–2. 17. Haymerle A, Fahlman A, Walzer C. Human exposures to immobilising agents: results of an online survey. Vet Rec 2010;167(9): 327–32.

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ARTICLE SUMMARY 1 Why is this topic important? U-47700 is an emerging synthetic opioid associated with significant morbidity and mortality. No formal studies have shown the clinical utility or safety of U-47700. 2 What does this review attempt to show? This review evaluates the signs and symptoms of ingestion, laboratory testing, and treatment modalities for U-47700 intoxication. 3 What are the key findings? The key findings associated with U-47700 include pulmonary edema in those who died from its use, an opioid toxidrome in patients that survived a U-47700 overdose including respiratory depression, decreased mental status, tachycardia in those that survived a U-47700 overdose, reversal of overdose symptoms with intravenous naloxone, and the failure of immunoassays to identify U-47700. 4 How is patient care impacted? This is the first clinical review of cases associated with U-47700 to inform and guide treatment decisions for clinicians that may encounter a U-47700 overdose.