The authors review the opioid literature for evidence of increased analgesia and reduced adverse side effects by combining muopioid-\r\nreceptor (MOR) agonists, kappa-opioid-receptor (KOR) agonists , and nonselective low-dose-opioid antagonists (LD-Ant).\r\nWe tested fentanyl (MOR agonist) and spiradoline (KOR agonist), singly and combined, against somatic and visceral pain models.\r\nCombined agonists induced additive analgesia in somatic pain and synergistic analgesia in visceral pain. Other investigators report\r\nsimilar effects and reduced tolerance and dependence with combined MOR agonist and KOR agonist. LD-Ant added to either a\r\nMOR agonist or KOR agonist markedly enhanced analgesia of either agonist. In accordance with other place-conditioning (PC)\r\nstudies, our PC investigations showed fentanyl-induced place preference (CPP) and spiradoline-induced place aversion (CPA).\r\nWe reduced fentanyl CPP with a low dose of spiradoline and reduced spiradoline CPA with a low dose of fentanyl. We propose\r\ncombined MOR agonist, KOR agonist, and LD-Ant to produce superior analgesia with reduced adverse side effects, particularly\r\nfor visceral pain.
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