Novel Approach to Therapy of Pain and Opioid Addiction | Wolfgang Sadee

Summary :
⁣Opioid analgesics are effective pain medications but cause addiction and other adverse effects, significantly reducing their therapeutic value. Main strategies for improving pain therapy include development of non-opioid analgesics and opioids with reduced addiction liability; however, the latter approach has met with only partial success. Taking advantage of multiple conformations with distinct signaling pathways attributable to the μ opioid receptor (MOR), biased opioid agonists or agonist-antagonist combinations have promise to treat pain with reduced adverse effects, but addiction liability remains largely unresolved. We have developed 6-naltrexol (6BN), a neutral opioid antagonist with moderate potency and peripheral selectivity, to treat peripheral adverse opioid effects (e.g., constipation). Beyond this application, we now report that 6BN has exceptional potency in selectively preventing the formation of opioid dependence: at low doses (<0.05 mg/kg), 6BN potently prevents the formation of opioid dependence in guinea pigs and mice (Oberdick et al., JPET 350:22 (2016) and Safa et al. Front. Pharmacol. DOI: 10.3389/fphar.2020.613328 (2021)). To account for these results, we have developed a novel receptor model proposing a MOR conformation with high 6BN affinity (Sadee, Molecules 25, 4163; doi:10.3390/ molecules25184163 (2020)). Further results indicate that low-dose 6BN acts as an addiction modulator rather than an antagonist, affording novel opportunities to develop safer pain therapy, well tolerated opioid use maintenance, facilitated detoxification protocols, and prevention of neonatal opioid withdrawal syndrome. Supported by grants from the NIH: NICHD R21, NIDA SBIR, NCATS HEAL CRADA