Evaluation of a Dual Fentanyl/Heroin Vaccine on the Antinociceptive and Reinforcing Effects of a Fentanyl/Heroin Mixture in Male and Female Rats.

Opioid-targeted vaccines represent an emerging treatment strategy for opioid use disorder. To determine whether concurrent vaccination against two commonly abused opioids (fentanyl and heroin) would confer broader spectrum opioid coverage, the current study evaluated dual fentanyl/heroin conjugate vaccine effectiveness using a warm water tail-withdrawal and a fentanyl/heroin-vs-food choice procedure in male and female rats across a 105-day observation period. Vaccine administration generated titers of high-affinity antibodies to both fentanyl and heroin sufficient to decrease the antinociceptive potency of fentanyl (25-fold), heroin (4.6-fold), and a 1:27 fentanyl/heroin mixture (7.5-fold). Vaccination did not alter the antinociceptive potency of the structurally dissimilar opioid agonist methadone. For comparison, continuous treatment with a naltrexone dose (0.032 mg/kg/h) shown previously to produce clinically relevant plasma-naltrexone levels decreased the antinociceptive potency of fentanyl, heroin, and the 1:27 fentanyl/heroin mixture by approximately 20-fold. Naltrexone treatment also shifted the potency of 1:27 fentanyl/heroin mixture in a drug-vs-food choice self-administration procedure 4.3-fold. In contrast, vaccination did not attenuate 1:27 fentanyl/heroin mixture self-administration in the drug-vs-food choice procedure. These data demonstrate that a vaccine can simultaneously attenuate the thermal antinociceptive effects of two structurally dissimilar opioids. However, the vaccine did not attenuate fentanyl/heroin mixture self-administration, suggesting a greater magnitude of vaccine responsiveness is required to decrease opioid reinforcement relative to antinociception.