Characterization of the Discriminative Stimulus Effects of Binary Mixtures of Mu Opioid Receptor Agonists in Rats Discriminating Fentanyl

Drug overdose deaths involving synthetic opioids, primarily fentanyl, have risen dramatically over the past decade and are currently the driving force of the opioid epidemic in the United States. Fentanyl analogs with greater potency than fentanyl (e.g., carfentanil) pose serious risk to public health. Although fentanyl analogs are primarily encountered by humans as constituents of a mixture of drugs, research has primarily evaluated the effects of these drugs alone. The present study characterized interactions between opioid receptor agonists in seven male Sprague-Dawley rats trained to discriminate 10 g/kg fentanyl from saline while responding under a fixed-ratio 10 schedule of food presentation. Dose-effect curves were determined for each drug alone and in binary mixtures (fentanyl:heroin, fentanyl:carfentanil, and heroin:carfentanil) at fixed-dose ratios of 3:1, 1:1, and 1:3 relative to the ED for each drug when given alone. Dose addition analyses were used to determine the nature of the drug-drug interaction for each mixture. Additive interactions were observed for all binary mixtures at each fixed dose ratio, except the 1:3 fentanyl:carfentanil mixture, which exhibited supra-additive effects at the 80% effect level. These results suggest a lack of a significant interaction between the discriminative stimulus effects of these opioid receptor agonists at the doses tested in this study. Future studies expanding these findings to the respiratory depressant effects of these drugs are of significant importance to rule out possible interactions directly relevant to opioid overdose that occur at doses much larger than those tested in this study. SIGNIFICANCE STATEMENT: In the United States, drug overdose deaths involving synthetic opioids, primarily fentanyls including superpotent fentanyl analogs (e.g., carfentanil), have increased 12-fold over the past decade. Although previous studies have evaluated the effects of carfentanil alone, fentanyl analogs are encountered by humans as a mixture with other drugs; this study determined the effects of mixtures of carfentanil and other opioids (fentanyl and heroin) to characterize interactions between these drugs that might contribute to their apparent increased lethality in humans.