While opioid analgesics have been shown to be effective in the treatment of chronic pain, they are also associated with risk of addiction. Little is known about what significance a patient's initial experience with opioid medications may have in predicting future development of addiction. This case-control study proposes to generate hypotheses to identify risk factors at the time of initial exposure to opioids for pain. Cases were individuals in an inpatient substance abuse treatment center for primary prescription opioid abuse. Controls, individuals who were using prescribed opioids for at least 3 months who had not developed addiction, were from a pain management center. Subjects completed a number of measures to capture data from the individual's first exposure to prescription opioids. Between-group differences on the instruments as well as on the individual items were compared using t-tests for continuous variables and Fisher's exact test for categorical variables. The ARCI, designed to measure euphoria and other drug effects, showed the most significant between-group difference. Those items significant for morphine showed a difference between means of 5.68 (95% CI 3.58,7.78) with a t-value of 5.31 (p-value <.0001) Item analysis of the ARCI showed significant differences (cases 81%, controls 0) between groups: “A thrill had gone through me” and “I feared I would lose the contentment that I had then.” Euphoria and other differences in the subjective response to opioids suggest the hypotheses that (1) a subgroup of patients with pain does develop euphoria when taking opioids for pain, and (2) this experience of euphoria may be a risk factor for the eventual development of prescription opioid addiction.