A patient with pain associated with metastatic leiomyosarcoma received escalating doses of opioids. Upon discontinuation of intravenous morphine, transdermal fentanyl was initiated, and after several days, the dose was increased to 200microg/hour for persistent, severe pain. The patient became somnolent, and further dose adjustments and route change were carried out. She then exhibited severe allodynia, myoclonus, and delirium thereafter fentanyl was stopped. All symptoms resolved with discontinuation of fentanyl and subsequent introduction of a weak opioid. Pain was well controlled. Gradually increasing standard doses of fentanyl may lead to severe neurotoxicity, which may respond to opioid discontinuation and/or rotation. Vigilant scrutiny of all possible causes of apparent analgesic failure followed by consideration of opioid reduction and rotation is warranted in cases of neurotoxicity accompanying opioid treatment.