Transdermal fentanyl (TDF) has been increasingly administered for the management of cancer pain. Occasionally, some patients fail to obtain poor analgesic effects with its dose escalation. We discuss a case of a 44-year-old male diagnosed with lung cancer with back pain caused by bone metastasis. He was administered a TDF of 75 microg/hr with good pain relief on admission. With time, the dose escalation to 300 microg/hr induced neuroexcitatory adverse effects without pain improvement. The conversion to 150 microg/hr TDF and sustained-release oral morphine 360 mg/day provided effective pain control. This clinical phenomenon demonstrated a possible association with the development of opioid tolerance. Although several experimental approaches regarding partial opioid substitution or combining different opioids for better pain control were suggested, the basic studies of opioid tolerance do not justify conclusions. In this case, partial opioid rotation and opioid combination were beneficial approaches to pain management.