Abstract: Pain is a kind of feedback of body injury which produces unpleasant subjective feelings, alerting the individual of actual or potential tissue damage. The mainstream drugs for the treatment and relief of pain are opioid receptor agonists. However, opioid-like side effects (addiction, tolerance, respiratory depression, etc.) of traditional opioid agonists limit their widespread use. Researchers have developed many effective strategies to avoid the side effects. In this article, the traditional and novel strategies to eliminate opioid side effects during the design and application of μ-opioid receptor agonists were highlighted, and the recent research progress of κ-opioid receptor agonists was briefly introduced, so as to provide new ideas for the development of analgesics and clinical treatment of pain.