Opioid addiction is classified as a Substance Use Disorder (SUD), a complex and chronic health condition with physical, social, and psychological consequences. While there is no cure for it, we present a novel approach towards preventing a hallmark feature of addiction-- the opiate withdrawal syndrome. Opioids exert numerous effects, acutely and chronically, on the nervous system with physical dependence, tolerance, and withdrawal being the most adverse chronic features. The degree of opioid dependence can be quantified by the frequency and/or intensity of the behavioral expression of withdrawal seen after abrupt termination of opioid consumption or after treatment with an opioid antagonist such as naloxone. Although the Central Nervous System (CNS) is the primary area of opioid impact, the involvement of the immune system in modifying CNS phenomena was suggested nearly two centuries ago and proved by several groups within the last few decades. Through a series of studies with immunomodulators alpha interferon, cyclosporine A, and cortisol, preclinical experiments show that administration of these agents prior to chronic morphine exposure prevents the expression of opiate withdrawal a hallmark feature of addiction. This review provides updates on current developments in the management of the opioid epidemic and an overview of studies on preventative immunomodulation prior to repetitive opioid administration as a means of addressing one of the underlying symptomatology driving the epidemic.