Researchers at the National Institutes of Health (NIH) have identified a new, highly potent opioid that shows potential as a treatment for both pain and opioid use disorder. In a study published in Naturethe team observed the effect of the new drug on laboratory animals. They showed that it has high analgesic effects without causing respiratory depression, tolerance or other indicators of potential addiction in humans.
Opioid pain relievers are necessary for medical purposes, but they can lead to addiction and overdose. Developing a highly effective pain medication without these drawbacks would have enormous public health benefits.”
Nora D. Volkow, MD, Director of NIH’s National Institute on Drug Abuse (NIDA)
The team investigated formulations of an understudied class of synthetic opioid compounds known as nitazenes. Nitazenes selectively engage mu-opioid receptors, primary targets for opioid drugs in the brain and peripheral nervous system. However, nitazenes were withdrawn in the 1950s due to their excessive activity. The scientific team re-examined this class of compounds with an emphasis on exploiting their selectivity for the mu opioid receptor and building new nitazenes with a safer pharmacological profile.
“Our goal was to study the profile or pharmacology of these drugs,” said Michael Michaelidis, Ph.D., senior author and NIDA investigator. “We wanted to lower the potency and create a potential therapeutic. What we discovered exceeded our expectations.”
The team initially focused on a chemical compound called FNZ that could be administered to rats and labeled with a radioisotope for positron emission tomography (PET). PET imaging allows real-time drug monitoring throughout the rat brain. The team found that FNZ entered the brain only briefly, for about five to 10 minutes. However, the pain relief, known as analgesia, lasted for at least two hours. Knowing that nitazenes can have active metabolites or byproducts, the team investigated whether an FNZ metabolite might be responsible for the prolonged effect. This research revealed DFNZ, another opioid that has been called a “superagonist” for its extremely high efficacy at the mu opioid receptor.
While FNZ carries serious risks, including respiratory depression and a high potential for addiction, DFNZ appears to sidestep these obligations.
At preclinical therapeutic doses, DFNZ produced a moderate and sustained increase in brain oxygen rather than depressing respiration. Repeated doses of the drug did not result in tolerance, drug dependence, or significant withdrawal effects. Among 14 classic opioid withdrawal symptoms, the researchers observed only irritability, as measured by vocalization, when handling DFNZ-treated rats.
To test the drug’s rewarding effects, an important component of its addictive potential, the team studied its effects on rats trained to press a lever for a dose of the painkiller. They found that the animals readily self-administer DFNZ, indicating that it produces some rewarding effect. However, when the drug was replaced with saline, the animals stopped the drug-seeking behavior. The immediate behavioral change contrasts with what researchers see with other opioids such as heroin, morphine and fentanyl. In these cases, the animals usually persist in seeking the drug even after its removal.
Further research revealed a possible neurochemical explanation. While DFNZ increases the release of slow-acting dopamine in the brain’s reward circuitry, it does not trigger the fast bursts of dopamine associated with the formation of strong drug associations, the conditioned responses that drive craving and addiction relapse.
“DFNZ has an unprecedented pharmacology for an opioid,” Michaelides said. “It’s a potent and highly effective analgesic, but in some contexts it resembles some agonists, drugs that activate the receptor with low efficacy, which scientists believe is needed for safety. Its ability to be given in therapeutic doses without causing respiratory depression is very important.”
The teams’ findings challenge the prevailing view that highly potent mu-opioid receptor drugs are unsuitable for development as safe analgesics. In fact, the paper’s authors argue that DFNZ should be investigated for use in the treatment of opioid use disorder and may be preferable to current opioid agonist medications, which have an associated risk of causing respiratory depression.
The research team will pursue additional preclinical studies to support an application for regulatory approval to conduct human studies of DFNZ. They believe that several patient populations may benefit from DFNZ, including those in surgical settings and with cancer-related or chronic pain who have a particularly high need for effective pain treatment.
This research was supported in part by the NIH Intramural Research Program and by NIH/NIDA grant DA056354.
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