Peripherally mediated opioid combination therapy in mouse and pig.

The concomitant epidemics of chronic pain and opioid misuse in the United States have led to a call for novel analgesics with limited abuse potential. Previously, we have shown that co-delivery of a novel combination targeting both μ- and δ-opioid receptors in the peripheral and central nervous systems can produce synergistic analgesia. Loperamide, a peripherally restricted μ-opioid agonist, and oxymorphindole, a δ-opioid receptor partial agonist, synergize in multiple mouse models of hyperalgesia. We predicted this effect would generalize across species and therefore assessed this combination for analgesic synergy in a mouse model of post-incisional hypersensitivity. In mice, oxymorphindole and loperamide displayed significant analgesic synergy. Similar synergy was observed with N-benzyl-oxymorphindole and loperamide. In cross-bred pigs, we compared the analgesic effects of either morphine alone or the combinations of oxymorphindole and loperamide or the combination of N-benzyl-oxymorphindole and loperamide. Both combinations showed increased potency as compared to morphine sulfate and effectively reduced hypersensitivity following injury without side effects. From these data we conclude that the combination of oxymorphindole and loperamide or the combination of N-benzyl-oxymorphindole reverse incisional hyperalgesia, likely by acting in the periphery, in a large animal model without adverse effects on respiration or heart rate. PERSPECTIVE: This article presents novel opioid combinations, the μ-opioid agonist loperamide with a δ-opioid agonist, either oxymorphindole (OMI) or N-benzyl-oxymorphindole (BOMI), that relieve pain in mice and pigs without adverse side effects. These therapies could help clinicians manage pain in patients while reducing overall opioid burden and limiting side effects.