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The family of phenylpiperidines (characterized by a phenyl moiety directly linked to a piperidine) includes also the NSO fentanyl (synthesized by P. Janssen in the 1960s) and its analogs, up to 1000 times more potent as analgesic than meperidine and differing in structure from the latter for a phenethyl group on the piperidine nitrogen in place of a methyl group (Elbaridi et al., 2017; Raffa et al., 2018). While extensive literature has been published in regards to pharmacology and toxicology of fentanyl and its illicit analogs (Bäckberg et al., 2015; Mounteney et al., 2015; Dwyer et al., 2017; Giorgetti et al., 2017; Guerrieri et al., 2017; Helander et al., 2017a; Pichini et al., 2017a,b; Shoff et al., 2017; Suzuki and El-Haddad, 2017), the pharmacological and toxicological properties of non-fentanyl derived NSOs have not yet been reviewed in detail. Compounds such as U-47700, U-51754, U-49900, U-448800, AH-7921 from the chemical family of benzamide, U-50488 and U-51754 from the acetamide family and MT-45 from the piperazine family are the NSOs most recently reported as health threats for opioids consumers (Mohr et al., 2016; Amin et al., 2017; Baumann et al., 2017; Domanski et al., 2017; Fabregat-Safont et al., 2017; Prekupec et al., 2017; Marchei et al., 2018). Indeed, this new generation of derivatives has been involved in a number of recent overdose deaths worldwide (Drug Enforcement Administration [DEA], 2016; Baumann et al., 2017; Domanski et al., 2017; Fabregat-Safont et al., 2017). Clandestine manufacturing of NSOs has been pirated from scientific literature or patent filings published by pharmaceutical companies attempting to search for new therapeutic drugs without addiction-related adverse effects (Logan et al., 2017). In a similar manner to fentanyl derivatives, these NSOs are being partly used as heroin adulterants or as constituents of counterfeit pain pills and they can be bought directly by users from online vendors via conventional web or cryptomarket (European Monitoring Centre for Drugs, and Drug Addiction [EMCDDA], 2016; Armenian et al., 2017b; Baumann et al., 2017; Van Hout and Hearne, 2017). Similarly to morphine and heroin (opiates) or to semi-synthetic opioids (like hydro- and oxycodone, hydro- and oxymorphone), these compounds produce CNS depressants effects such as respiratory depression, analgesia, hypothermia, sedation, euphoria, anxiety, sweating, disorientation, drowsiness, nausea, and miosis (Carroll et al., 2012; Guerrini et al., 2013; Hill and Thomas, 2016; Armenian et al., 2017b), and although the effects of tolerance and dependence may rapidly reach high levels, elevated risks of overdose and death are frequent for these compounds (United Nations Office on Drugs and Crime [UNODC], 2017b). Furthermore, the typical rewarding characteristics and the easy availability induce users to abuse of these opioids (Carroll et al., 2012). The main NSOs AH-7921, MT-45, and U-47700 have been identified in Europe between 2013 and 2016, and over 40 deaths were reported to the European Monitoring Centre for Drugs and Drug Addiction in a short time after that AH-7921 and MT-45 were found out on the European drug market (EMCDDA) (European Monitoring Centre for Drugs, and Drug Addiction [EMCDDA], 2017). Moreover, in 2016 U-47700 has been the cause of at least 46 confirmed fatalities as well as the subject of 88 reports from forensic laboratories submissions in the United States (Fabregat-Safont et al., 2017). Since the popularity of these substances is rapidly increasing and evolving over time, there is a great need to update all possible information, particularly with respect to their subjective and side effects and to tackle unsolved issues, including limited analytical methods to disclose and monitor different compounds (Katselou et al., 2015; Lucyk and Nelson, 2017). To fill this gap, we here sought to report the latest information available on non-fentanyl derived NSOs U-47700, U-50488, U-51754, U-49900, U-48800, AH-7921, and MT-45 with particular regard to their pharmacotoxicology and adverse effects on users (see Figure 1). We report a method for the detection and quantitation of 12 drugs and 2 metabolites in the same structural class as the illicit mu-opioid agonist U-47700 in human whole blood. These substances are either known or suspected to be present as potential novel opioids in illicit drug markets. The general class of these drugs was developed in pharmaceutical research programs in the 1970s, but these drugs have recently become of concern for overdoses and death in opioid users in the USA and internationally. The scope of analysis included the following compounds: methylenedioxy U-47700, ethylenedioxy U-47700, ethylenedioxy U-51754, U-69593, U-47931E (bromadoline), U-47700, U-48800, U-49900, U-51754, U-50488, propyl U-47700 and isopropyl U-47700. Additionally, two metabolites N,N-didesmethyl U-47700 and desmethyl U-47700 were also included in the scope. Drugs were extracted from human whole blood using solid-phase extraction, and the extracts were analyzed by liquid chromatography--tandem mass spectrometry. The assay was validated with respect to bias, carryover, interference, within-run and between-run precision, and accuracy. Eight medicolegal death investigation cases that had screened positive for U-48800 by liquid chromatography--time-of-flight mass spectrometry were successfully confirmed and quantified using this method. The mean and median concentrations of U-48800 in these cases were 2.5 (±2.1) and 1.8 ng/mL, respectively, with a range of concentrations of 0.27–6.2 ng/mL. Case history information including the presence of other drugs in combination are described and discussed.