The aim of this study was to examine the usefulness of opioid initiation therapy with oral tramadol (TD) by comparing its efficacy and safety with that of sustained-release oxycodone (OXC). Although the complexity of clinical setting seemed to make difficult to carry out strict evaluation of TD initiation therapy, a higher number of patients experienced unmanageable pain with TD initiation therapy than with OXC. Almost half the TD-initiated patients switched from TD to another analgesic in earlier phase than those on OXC did. However, the number of patients who changed the initiation opioid because of side effects was larger with OXC than it was with TD. The incidence of nausea and sleepiness was significantly lower with the TD initiation therapy than it was with OXC. Additionally, cases of nausea observed after OXC administration were also significantly fewer in patients who switched opioids from TD to OXC than in the OXC-initiated patients. In the case of OXC-initiation, the number of onset of side effects was the highest immediately following opioid initiation, and then it gradually decreased. However, in switched case from TD to OXC, they mostly did not develop side effects after OXC administration. These results suggest that opioid initiation with TD could be a useful alternative for pain management with fewer side effects; however, careful monitoring of pain relief is essential, especially in the early phase of TD initiation.