The treatment of chronic pain has been challenging due to partial efficacy or severe side effects of approved pain relievers. Management of severe pain depends on opioids, which despite their great analgesic potency induce dangerous adverse effects and are subject to analgesic tolerance and dependence. We chemically modified the endogenous opioid peptide Leu-Enkephalin (LENK) to enhance its metabolic stability and membrane permeability. The resulting LENK-like peptide KK-103 produced sustained antinociception and an antidepressant effect in mice. The common adverse effects of opioids, including constipation, respiratory depression, analgesic tolerance, and physical dependence, were not observed with KK-103.