Overdose deaths are often viewed as the leading edge of the opioid epidemic which has gripped the United States over the past two decades (Skolnick, 2018a). This emphasis is perhaps unsurprising because opioid overdose is both the number-one cause of death for individuals between 25 and 64 years old (Dezfulian et al., 2021) and a significant contributor to the decline in average lifespan (Dowell et al., 2017). Exacerbated by the COVID 19 pandemic, it was estimated there were 93,400 drug overdose deaths in the United States during the 12 months ending December 2020, with more than 69,000 (that is, >74%) of these fatalities attributed to opioid overdose (Ahmad et al., 2021). However, the focus on mortality statistics (Ahmad et al., 2021; Shover et al., 2020) tends to obscure the broader medical impact of nonfatal opioid overdose. Analyses of multiple databases indicate that for each opioid-induced fatality, there are between 6.4 and 8.4 non-fatal overdoses, exacting a significant burden on both the individual and society. Over the past 7–8 years, there has been an alarming increase in the misuse of synthetic opioids (“synthetics”), primarily fentanyl and related piperidine-based analogs. Within the past 2–3 years, a structurally unrelated class of high potency synthetics, benzimidazoles exemplified by etonitazene and isotonitazene (“iso”), have also appeared in illicit drug markets (Thompson, 2020; Ujvary et al. 2021). In 2020, it was estimated that over 80% of fatal opioid overdoses in the United States now involve synthetics (Ahmad et al., 2021). The unique physicochemical and pharmacological properties of synthetics described in this review are responsible for both the morbidity and mortality associated with their misuse as well as their widespread availability. This dramatic increase in the misuse of synthetics is often referred to as the “3rd wave” (Pardo et al., 2019; Volkow and Blanco, 2020) of the opioid epidemic. Among the consequences resulting from misuse of these potent opioids is the need for higher doses of the competitive antagonist, naloxone, to reverse an overdose. The development of more effective reversal agents such as those described in this review is an essential component of a tripartite strategy (Volkow and Collins, 2017) to reduce the biopsychosocial impact of opioid misuse in the “synthetic era”.

过量死亡通常被视为过去二十年来席卷美国的阿片类药物流行病的前沿（Skolnick，2018a）。这种强调可能并不令人惊讶，因为阿片类药物过量既是 25 至 64 岁人群的头号死因（Dezfulian 等人，2021 年），也是平均寿命下降的重要原因（Dowell 等人，2017 年） ）。在 COVID 19 大流行的影响下，据估计，在截至 2020 年 12 月的 12 个月中，美国有 93,400 人因药物过量而死亡，其中超过 69,000 人（即 >74%）归因于阿片类药物过量（Ahmad 等人）等人，2021）。然而，对死亡率统计的关注（Ahmad 等人，2021 年；Shover 等人，2020 年）往往会掩盖非致命性阿片类药物过量的更广泛医学影响。对多个数据库的分析表明，对于每起阿片类药物引起的死亡，有 6.4 到 8.4 次非致命性过量服用，这给个人和社会都带来了沉重的负担。在过去的 7-8 年中，滥用合成阿片类药物（“合成物”）的情况惊人地增加，主要是芬太尼和相关的基于哌啶的类似物。在过去的 2-3 年内，非法药物市场中也出现了一类结构上不相关的高效合成物苯并咪唑，例如依托尼他烯和异烟肼（“iso”）（Thompson，2020 年；Ujvary 等人，2021 年）。据估计，到 2020 年，美国超过 80% 的致命阿片类药物过量使用现在涉及合成物（Ahmad 等人，2021 年）。本综述中描述的合成物独特的物理化学和药理学特性是与其滥用相关的发病率和死亡率以及它们的广泛可用性的原因。这种滥用合成物的急剧增加通常被称为阿片类药物流行的“第三波”（Pardo 等人，2019 年；Volkow 和布兰科，2020 年）。滥用这些强效阿片类药物的后果之一是需要更高剂量的竞争性拮抗剂纳洛酮来逆转过量服用。开发更有效的逆转剂（例如本综述中描述的那些）是三方战略（Volkow 和 Collins，2017 年）的重要组成部分，以减少“合成时代”阿片类药物滥用的生物心理社会影响。