Systemic and neuraxial opioid–induced pruritus are separately modulated. Systemic (oral, subcutaneous, and parenteral) morphine may drive pruritus through the engagement of mas-related G protein–coupled receptor X2 (MRGPRX2) on mast cells. Neuraxial (epidural and intrathecal) opioid-induced pruritus, on the other hand, is likely driven by spinal neurons containing the μ-opioid receptor, because less than 0.01% of the peak concentration detected in the cerebrospinal fluid is detected in the plasma after neuraxial opioid administration.