U-47700: A Clinical Review of the Literature

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.

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 μ-opioid receptor (Figure 1) (5). It was developed by the pharmaceutical company The Upjohn Company in 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 μ-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.