Opioid drugs, acting with the opioid receptors, are commonly used in clinical anesthesia and analgesia, but there is no effective preventive strategies for its side effects such as respiratory depression, hyperalgesia, and opioid tolerance. Naloxone and Nalmefene , these two drugs are mainly used for postoperative snooze and respiratory depression relieve. In recent years, it has been reported that preadministration of ultralow‑dose opioid receptor antagonists can significantly alleviate postoperative opioid tolerance and hyperalgesia. This review summarized research advances of the effect and potential mechanism of ultralow‑dose opioid receptor antagonist on adverse reactions induced by opioid receptor agonists. With further study of opioid agonists combined with ultralow‑dose antagonists, new ideas will be generated for prevention of side effects caused by opioid drugs.