Non-fentanyl-derived synthetic opioids emerging during recent years

Abstract

Purpose Since the appearance of fentanyl followed by its many kinds of analogues around 1988, North America has been exposed to fierce synthetic opioid pandemic resulting in more than 130,000 deaths due to their overdoses until May 2019, when China declared to prohibit the licit fentanyl analog production. However, the Chinese announcement did not go into force in USA due to the adroit strategies of tough traffickers. Thus, contrary to the expectation, the number of synthetic opioid products and their poisoning cases in USA has increased by about 30%; especially, various benzimidazole synthetic opioids have revived on the illicit drug market during a recent few years. In this article, the recent abrupt changes in the situations of illicit synthetic opioid market and their current abuses are described. Methods Various databases, such as SciFinder, Google, and Google Scholar, were utilized to collect relevant reports referring old but newly appearing synthetic opioids. Results At the present time, there are several families of new synthetic opioids, which are not fentanyl derivatives; MT-45 and its analogs, benzamide and 2-phenylacetamide opioids (U-series opioids), and benzimidazole opioids. Most of the above substances had been developed in 1950s to 1970s, but had never been used as analgesic medicines, because of their severe adverse effects, such as respiratory depression, physical dependence, and resulting deaths. However, there is possibility that these drugs will become main illicit synthetic opioids in place of the fentanyl analogs during coming several years from this time. Conclusions All of the above non-fentanyl-derived families had been developed 50–70 years ago to establish them as analgesic medicines, but had been unsuccessful. These drugs largely appeared in the illicit drug markets in North America, Europe, and Australia, during recent years. Pharmacological, toxicological, and metabolic studies are insufficient for benzamide and 2-phenylacetamide opioids, and are very scant especially for benzimidazole opioids. This time we should start studying pharmacotoxicology of the newly emerging synthetic opioids to alert forensic toxicologists in the world and to suppress their rapid and wide spread in the world. Supplementary Information The online version contains supplementary material available at 10.1007/s11419-022-00624-y.

Study of metabolism and potential toxicity of nine synthetic opioid analogs using the zebrafish larvae model

“…4,5 In the last years, this class of NPS have been associated with a number of fatalities in several countries, particularly in the USA. 6 Cinnamylpiperazines differ structurally from fentanyl analogs, which are characterized by a piperidine core and a phenethyl chain, for the presence of a piperazine ring and a cinnamyl moiety (Figure 1).…”

In Vitro Functional Profiling of Fentanyl and Nitazene Analogs at the μ-Opioid Receptor Reveals High Efficacy for Gi Protein Signaling

“…In recent years, a new class of nonfentanyl novel synthetic opioid (NSO) known as the 2-benzylbenzimidazole opioids, or nitazenes, has surfaced on recreational drug markets worldwide. − Although first reported in the late 50s and early 60s, nitazenes were never approved for clinical use . Isotonitazene, a nitazene analog that emerged in 2019, was found to be 500 times more potent than morphine and was classified as Schedule I by the Drug Enforcement Administration (DEA) in the following year due to its high risk of intoxication and fatal overdose. , Despite the DEA’s action, nitazenes remain widely available on recreational drug markets and have been detected in illicit heroin and adulterated pain medicines, exacerbating the opioid crisis. ,,, …”

Energetics of high temperature degradation of fentanyl into primary and secondary products

“…Fentanyl was first synthesized in Belgium in the 1950s and introduced to the USA in 1968 for medical purposes. 1 Fentanyl is often used to treat patients with chronic pain, such as cancer patients and those who are physically intolerant to other opioids. 2 Due to its high potential for abuse and addiction, fentanyl is classified as a Schedule II controlled drug.…”