In North America, opioid use has become a public health crisis with policy makers declaring it a state of emergency. Opioid substitution therapy (OST) is a harm-reduction method used in treating opioid use disorder. While OST has shown to be successful in improving treatment outcomes, there is still a great degree of variability among patients. This cohort of patients has shifted from young males using heroin to a greater number of older people and women using prescription opioids. The primary objective of this review is to examine the literature on the association between the first exposure to opioids through prescription versus illicit use and OST treatment outcomes.