The present invention provides a method for treating cancer pain by administering to an individual in need of such treatment with a pharmaceutically effective amount of a blocking reagent for ephrinB-EphB signaling. Also provided is a method for reducing opioid tolerance in treating cancer pain thereby rescuing analgesic effect of morphine treatment of cancer pain by administering to an individual in need of such treatment with a pharmaceutically effective amount of a blocking reagent for ephrinB-EphB signaling. The blocking reagent can be an EphB receptor blocker such as EphB1-Fc and EphB2-Fc.
