The relationships of characteristics of the initial opioid prescription and pain etiology with the probability of opioid discontinuation were explored in this retrospective cohort study using health insurance claims data from a nationally representative database of commercially insured patients in the U.S. We identified 1,353,902 persons aged ≥14 with no history of cancer or substance abuse, with new opioid use episodes and categorized them into 11 mutually exclusive pain etiologies. Cox Proportional Hazards models were estimated to identify factors associated with time to opioid discontinuation. After accounting for losses to follow-up, the probability of continued opioid use at one year was 5.3% across all subjects. Patients with chronic pain had the highest probability for continued opioid use followed by patients with inpatient admissions. Patients prescribed doses above 90 morphine milligram equivalents (HR=0.91, CI: 0.91–0.92); initiated on tramadol (HR=0.90, CI: 0.89–0.91) or long-acting opioids (HR=0.78, CI: 0.75–0.80); were less likely to discontinue opioids. Increasing days’ supply of the first prescription was consistently associated with a lower likelihood of opioid discontinuation (HRs, CIs: 3–4 days’ supply = 0.70, 0.70–0.71; 5–7 days’ supply = 0.48, 0.47–0.48; 8–10 days’ supply = 0.37, 0.37–0.38; 11–14 days’ supply = 0.32, 0.31–0.33; 15–21 days’ supply = 0.29, 0.28– 0.29; ≥22 days supplied = 0.20, 0.19–0.20). The direction of this relationship was consistent across all pain etiologies. Clinicians should initiate patients with the lowest supply of opioids to mitigate unintentional long term opioid use.