A new study in rhesus monkeys clarifies one aspect of how the new drug cebranopadol relieves pain and finds that this effective analgesic has milder side effects than fentanyl and morphine.
Pure mu opioid receptor agonists like fentanyl and morphine are the most widely used analgesic drugs in medical settings. However, their severe side effects and high abuse potential have prompted the need for alternatives. Treatment with drugs that simultaneously target nociceptin receptors and mu receptors has been shown to limit mu receptor-related side effects. Cebranopadol, an effective pain reliever in rodents and humans, targets nociceptin receptors and various opioid receptors. But whether the mu opioid receptor subtype is the most important for cebranopadol analgesia is unknown, and the associated side effects haven’t been investigated in nonhuman primate models.
To better evaluate cebranopadol as an analgesic alternative to pure mu agonists, researchers compared it with fentanyl and morphine. Specifically, they compared the potency, abuse potential, and respiratory depressant and itch-inducing side effects of the drugs in rhesus monkeys. The results are published in the journal Anesthesiology.
Pain response tests suggested that cebranopadol is a more potent analgesic than fentanyl. Compared with fentanyl, cebranopadol blunted the tail withdrawal reflex of the monkeys in response to warm water at a lower dose. In addition, cebranopadol didn’t cause itching, while fentanyl did. Pretreating monkeys with specific opioid receptor inhibitors revealed that the mu receptor subtype was the most important for the pain-relieving effects of cebranopadol.
Reinforcement experiments reflected some capacity for abuse, as monkeys tended to self-administer both cebranopadol and fentanyl over saline. However, the reinforcing strength of cebranopadol was weaker, indicating a lower abuse potential for cebranopadol than for fentanyl.
At higher doses, systemic cebranopadol did not cause the respiratory depression observed with fentanyl treatment.
Intrathecally administered cebranopadol was also very effective in delaying tail withdrawal in response to warm water. Moreover, it did not cause the characteristic scratching behavior evoked by intrathecal morphine. These findings suggest the potential of cebranopadol as an alternative spinal analgesic.
Notably, the study did not test whether intrathecal cebranopadol induced respiratory depression. The lack of this side effect should be confirmed in future studies. More importantly, as cebranopadol did exhibit potential for abuse, its further development and clinical use will require caution.
Despite these limitations, the results of this study clarify the molecular targets of cebranopadol and suggest that this effective analgesic may have a better side-effect profile than commonly used opioids.