Discovery of a new analgesic promises pain relief with fewer downsides, according to the scientists, who say the non-opioid ADRIANA could provide powerful relief without the dangers of addiction.
With successful trials already completed, said the team from Kyoto University, large US studies are now under way, raising hopes for a safer future in pain treatment.
While opioids like morphine are widely used, they carry the risk of serious adverse effects such as respiratory depression and drug dependence.
For this reason, Japan has strict regulations in place to ensure that these medications are prescribed only by authorised physicians.
In the United States, however, the opioid OxyContin triggered a surge in the misuse of synthetic opioids like fentanyl – and the number of deaths from opioid overdose surpassed 80 000 in 2023, escalating into a national public health crisis.
Opioids may soon have a rival, though. The Japanese researchers recently discovered a novel analgesic, or pain reliever, which exerts its effect through an entirely different mechanism. Clinical development of their drug ADRIANA is currently under way as part of an international collaborative effort, they report in PNAS (Proceedings of the National Academy of Sciences).
“If successfully commercialised, ADRIANA would offer a new pain management option that does not rely on opioids, contributing significantly to the reduction of opioid use in clinical settings,” said corresponding author Masatoshi Hagiwara, a specially-appointed professor at Kyoto University.
The research team was first inspired by substances that mimic noradrenaline, which is released in life-threatening situations and activates α2A-adrenoceptors to suppress pain.
However, these pose a high risk of cardiovascular instability. After observing noradrenaline levels and α2B-adrenoceptors, the team hypothesised that selectively blocking α2B-adrenoceptors could elevate noradrenaline levels, leading to activation of α2A-adrenoceptors and resulting in pain relief without causing cardiovascular instability.
To identify selective inhibitors of α2B-adrenoceptors and measure the activity of individual α2-adrenoceptor subtypes, the researchers employed a novel technology known as the TGFα shedding assay and conducted compound screening leading to their discovery of the world’s first selective α2B-adrenoceptor antagonist.
After success in administering the compound to mice and conducting non-clinical studies to assess its safety, physician-led clinical trials were conducted at Kyoto University Hospital.
Both the phase 1 trial in healthy volunteers and the phase 2 trial in patients with postoperative pain after lung cancer surgery yielded highly promising results.
Building on these outcomes, preparations are now under way for a large-scale phase 2 clinical trial in the United States, in collaboration with BTB Therapeutics, Inc, a Kyoto University-originated venture company.
As Japan’s first non-opioid analgesic, ADRIANA has the potential not only to relieve severe pain for patients worldwide but could also play a meaningful role in addressing the opioid crisis – a pressing social issue in the United States – and thus contribute to international public health efforts.
“We aim to evaluate the analgesic effects of ADRIANA across various types of pain and ultimately make this treatment accessible to a broader population of patients suffering from chronic pain,” said Hagiwara.
Study details
Discovery and development of an oral analgesic targeting the α2B adrenoceptor
Masayasu Toyomoto, Takashi Kurihara, Takayuki Nakagawa et al.
Published in Proceedings of the National Academy of Sciences (PNAS) on 7 August 2025
Significance
Control of pain is a global social health issue because severe pain strongly affects patients’ quality of life. Although opioids are the strongest painkillers, continuous use of opioids often leads to addiction with numerous adverse effects, including respiratory depression, constipation, and hyperalgesia. An emerging alternative to opioid-based analgesics is dexmedetomidine, an α2-adrenergic receptor agonist. We found that administration of an α2B-specific antagonist, adrenergic inducer of analgesia (ADRIANA), induced noradrenaline release in the spinal dorsal horn and suppressed pain through an α2A-dependent pathway without causing hemodynamic instability. ADRIANA did not cause addiction or any behavioural change in mice and monkeys. A phase I/II clinical trial of the ADRIANA oral tablet is under way to test its effectiveness in reducing postoperative pain.
Abstract
Noradrenaline is a major monoaminergic neurotransmitter involved in pain modulation through an α2A-adrenergic receptor. Hence, α2-adrenergic agonists such as clonidine and dexmedetomidine exhibit analgesic and opioid-sparing effects. However, their use is restricted to hospital settings due to potential risks of acute hypertension/hypotension and bradycardia. Here, we report that (Z)-1-(3-ethyl-5-fluorobenzo[d] thiazol-2(3H)-ylidene)propan-2-one [adrenergic inducer of analgesia (ADRIANA)], a newly identified α2B subtype-specific antagonist, specifically promotes noradrenaline release in the murine spinal dorsal horn and produces analgesic effects by stimulating the α2A-dependent pain inhibitory pathway. Orally administered ADRIANA has potent analgesic effects in several nociceptive pain models of mice and non-human primates without cardiovascular effects. Mice with genetic loss of the α2B adrenoceptor showed normal responses to mechanical pain, but the analgesic effect of ADRIANA was not significantly detected. These findings reveal that the α2B adrenoceptor is a promising target for non-opioid analgesics through the activation of the α2A-dependent descending pathway.
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