In preclinical testing, a new vaccine hindered the often-abused prescription opioids oxycodone and hydrocodone from entering the brain and suppressed one of the drugs’ signature central nervous system (CNS) effects. According to vaccinologists Dr. Marco Pravetoni, Dr. Paul Pentel, and colleagues at the University of Minnesota, the findings warrant continued development of the vaccine as a potential aid in the treatment of oxycodone and hydrocodone abuse and dependence.
The vaccine aims to lower motivation to take the prescription opioids by blocking their rewarding and reinforcing effects. The recent experiments showed that the vaccine attenuates the drugs' antinociceptive (pain-suppressing) effect—an indication that it may also reduce reinforcement, since both effects depend on drug concentrations in the brain. In these tests, the researchers measured how quickly rats became uncomfortable enough to withdraw their paws from a moderately heated plate, first when drug free and then with oxycodone (2.25 mg/kg) or hydrocodone (6.75 mg/kg). Each opioid enabled both vaccinated and unvaccinated rats to keep their paws on the plate longer than when drug free, but the vaccine reduced oxycodone’s antinociceptive effect by 80 percent and hydrocodone’s antinociceptive effect by 73 percent.
Like other anti-drug vaccines, the new vaccine induces antibodies that bind its target drugs, resulting in drug-antibody complexes that are too large to cross the blood-brain barrier (see Figure). In the trials, vaccinating rats before injecting them with oxycodone reduced the amount of drug reaching the brain by an average of 86 percent after a 0.1 mg/kg dose, and 54 percent after a 0.5 mg/kg dose. Vaccination reduced brain penetration of hydrocodone to a similar extent. The drug doses used in the experiments produce peak serum levels comparable to those attained by people taking the drugs orally.
The vaccine could help individuals seeking to recover from addiction to other opioids as well, Dr. Pentel says. In addition to oxycodone and hydrocodone, the antibodies it induces bind to oxymorphone and several other abused opioids.
When fully developed, the vaccine could be used in conjunction with opioid pharmacotherapy with methadone, buprenorphine, or naltrexone, potentially enhancing the effectiveness of both approaches, according to Dr. Pravetoni. Tests of antibody affinity showed that the vaccine-induced antibodies do not bind strongly to those medications, which would remain free to enter the brain and exert their therapeutic effects. In addition, vaccinated patients could still obtain pain relief from opioids such as fentanyl.
The Minnesota team is currently testing how the vaccine affects self-administration of oxycodone by rats. These studies will provide more clues as to whether the vaccine can effectively aid recovery from prescription opioid abuse and dependence.
This study was supported by NIH grants: DA026300 and DA026300.
Pravetoni, M., et al. An oxycodone conjugate vaccine elicits oxycodone-specific antibodies that reduce oxycodone distribution to brain and hot-plate analgesia. Journal of Pharmacology and Experimental Therapeutics 341(1):225-232, 2012. Full Text
Pravetoni M et al. Reduced antinociception of opioids in rats and mice by vaccination with immunogens containing oxycodone and hydrocodone haptens. Journal of Medicinal Chemistry 56(3):915-23, 2013. Abstract