Effects of Combined Opioids on Pain and Mood in Mammals

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