Generalized itch is commonly reported in up to 90% of the patients receiving spinal opioids and in only 1% when used systemically. Pruritus may significantly interfere with patients' compliance and willingness to use opioids despite poor analgesia. Opioids induce itching by binding to specific opiate receptors in the central and peripheral nervous system, thus mimicking the physiologic effects of endorphins and enkephalins or by acting on the mast cells of the skin. A 15-year-old male with desmoplastic small round cell tumor of the pelvis developed mouth pain due to grade two mucositis after chemotherapy. The initial analgesic regimen used was hydromorphone titrated rapidly up to 0.8 mg every four hours as needed (PRN). Due to nausea, vomiting and suboptimal analgesia hydromorphone was changed to morphine sulfate 5 mg intravenously every three hours PRN. After the first dose of morphine the patient reported severe generalized pruritus, which did not improve despite the use of high dose antihistamines. The rotation to PCA fentanyl and hydromorphone did not alleviate itching. Only after changing the opioid to oxycodone oral solution 45 mg every three hours PRN and adding naloxone 0.25 mcg/kg/hr itching diminished and resolved completely within 24 hours, allowing the patient to use opioids liberally. Pain control remained optimal until discharge. The pathogenesis of opioid-induced itching may be explained by an imbalance between the over-expression of μ-opioid receptors over the κ-opioid receptors. In the case described above oral oxycodone, probably by a stronger κ activity than morphine, along with naloxone, a μ antagonist might have had a combined effect reestablishing the balance between μ and κ-opioid receptors at central levels and resolving the itch. Further studies are required to investigate the types of μ antagonists and κ agonists that have antipruritic effects against itch evoked by opioids and other pruritogenic agents in humans.