This study aimed to evaluate the efficacy of immediate-release (IR) oxycodone in combination with sustained-release (SR) oxycodone titration for managing moderate-to-severe cancer pain in opioid-tolerant patients. Participants were selected based on a numerical rating scale (NRS) score of ≥4 and a daily oxycodone dose of ≥50 mg. IR oxycodone was administered orally as a rescue medication for breakthrough pain (BTP). Pain intensity scores, frequency of BTP, daily doses of SR and IR oxycodone, and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Advanced Cancer (EORTC QLQ-C15-PAL) scores were assessed over a three-day period. Adverse effects were also recorded. A total of 109 patients were enrolled in the study. Pain relief rates were 32% (35/109) on day 1, 44%(48/109) on day 2, and 67% (73/109) on day 3. Compared to baseline, the average NRS score decreased significantly on day 1 (p = 0.0030), day 2 (p < 0.0001), and day 3 (p < 0.0001). On day 1, 100% of patients experienced ≤2 BTP episodes per day, while 95%had ≤1 episode per day by day 3. There was a significant reduction in BTP episodes on days 2 and 3 compared to day 1 (p = 0.0187 and p < 0.0001, respectively). All eight EORTC QLQ-C15-PAL items showed significant improvements (p < 0.0100) from baseline. The incidence of adverse events was 42%. The combination of IR oxycodone with SR oxycodone titration is both feasible and tolerable for opioid-tolerant patients with moderate-to-severe cancer pain.