Smith Hypothesis



100% of the deaths associated with the Opioid Crisis were premature and mostly preventable deaths.
Methylation of certain CpG islands within the promoter region of the OPRM1 gene, as seen in response to the exposure to the opioids, results in gene silencing. This gene silencing is not producing a drop in the population of the mu-opioid receptor. Rather, this gene silencing results in the formation of an abnormal mu-opioid receptor. This production of an abnormal mu-opioid receptor is due to a process we are calling partial gene silencing – the receptor was produced but it was an abnormal receptor. This abnormal mu-opioid receptor is no longer able to maintain balance and homeostasis within the Autonomic Nervous System when Opioid Abstinence is attempted. This dysfunction within the Autonomic Nervous System results in a true Neuroendocrine Emergency known as Autonomic Dysfunction. This Autonomic Dysfunction is reflected in the abnormal activity in both branches of the Autonomic Nervous System, the Sympathetic Nervous System and the Parasympathetic Nervous System. Autonomic dysfunction, and the Catecholamine Surge that results, is a condition of extreme duress and cannot long be endured by the human body. The full agonist opioids offer a partial and temporary relief. But this partial and temporary relief comes with the associated risk of the full agonist opioids. The partial agonist, Buprenorphine, is able to maintain a more complete and longer lasting relief from the autonomic dysfunction but, due to the Ceiling Effect of Buprenorphine, at a higher level of safety. Untreated, there is concern that autonomic dysfunction could be a risk factor for the development of Opioid Induced Adrenal Insufficiency. In addition, a Catecholamine Surge is known to be associated with Cardiomyocyte Necroptosis. Therefore, cardiac related death rates would be expected to be increased dramatically in any vulnerable populations which also experienced a simultaneous increase in opioid overdose deaths. These cardiac deaths would mistakenly be attributed to a non opioid related etiology.