Purpose <p>The administration of intrathecal morphine frequently induces pruritus as an adverse reaction. Xiaofeng Granules (XF) is a compound preparation improved from the ancient formula “Xiaofeng Powder”. It has been proven to relieve skin itching caused by various reasons in clinical practice. The aim of the study was to evaluate the effect of XF on pruritus caused by intrathecal morphine and possible mechanism.</p> Methods <p>Male C57BL/6 mice were intrathecally injected with morphine to induce scratching behavior. The effects of XF on intrathecal morphine-induced pruritus and analgesia were evaluated. The number of scratching response was counted within 30&#xa0;min after morphine injection. The warm-water tail immersion test was conducted to measure the tail flick latency (TFL) within 120&#xa0;min after morphine injection. The maximum possible effect percentage (%MPE) and area under the curve (AUC) were calculated based on TFL to evaluate the analgesic effect. Western blot was performed to evaluate the phosphorylation levels of NR2B, PKC and CAMK II in the dorsal horn of the lumbar spinal cord of mice.</p> Results <p>Compared with control treatment, intrathecal morphine elicited obvious scratching response when providing analgesic effect in a dose dependent manner. Gavage administration of XF can significantly reduce intrathecal morphine-induced scratching behavior without affecting its analgesic efficiency; besides, XF can inhibit the phosphorylation of NR2B, PKC, and CAMK II induced by intrathecal morphine, which can be reversed by intrathecal injection of NMDA.</p> Conclusions <p>XF can relieve intrathecal morphine-induced pruritus and may be related to the inhibition of the NR2B/PKC/CAMK&#xa0;II signaling pathway.</p>