Opioid abuse has been a global menace for centuries, but the proliferation of synthetic opioids and their use within this current decade have created epidemic-level harms in some countries. According to the United Nations Office on Drugs and Crime, almost 12 million years were estimated loss of "healthy" life resulting in premature death and disability attributable to global opioid abuse just in 2015. Law enforcement and regulatory authorities have been particularly challenged abating the spread of synthetic opioids because soon after controlling the currently recognized abused opioids, their structures are tweaked, and new entities replace them. Drug racketeers have most often exploited the fentanyl phenylpiperidine structure in this regard, but non-fentanyl-like and classical morphinan-like structures have been pirated as well. A growing number of anecdotal reports identify respiratory depression induced by these newer synthetic opioids to be especially refractive to reversal by antagonists, with consequently high levels of lethality. This review examines three of these synthetic opioids representing three chemical classes (U-47700, MT-45, and acetylfentanyl) that have emerged to be of such menace that they have been brought under international control in recent years and addresses factors that could make synthetic opioids especially untreatable by opioid antagonists.