New non-addictive painkiller precisely targets sites of chronic pain and does not induce tolerance

Good news! We have been waiting for it for decades! Is this finally the breakthrough!

"Researchers have developed a non-addictive painkiller that remains inactive until it reaches sites of chronic pain. Instead of dulling the nerves that send the pain signals like other analgesics, this new pain pill directly addresses the underlying cause. Its makers are currently working towards testing the compound in human trials.

Different from other medications, a prodrug remains inactive until it encounters a specific circumstance in the body that activates it. ..."

"... The mechanism of action for the targeted prodrug involves activation of the active drug by a chemical reaction with reactive oxygen species such as hydrogen peroxide, which are present in much higher amounts at sites of pain than the rest of the body. ...

The prodrug was tested in both chemical and preclinical models and found to provide localised relief of sciatic nerve injuries, as well as other models of chronic pain featuring oxidative stress like osteoarthritis, chemotherapy-induced peripheral neuropathy and diabetic neuropathy. ...

“This showed us that the compound did not induce a tolerance, which is a major limiting factor to powerful painkillers like morphine,” ..."

From the abstract:

"Treatment of diseases of oxidative stress through activation of the antioxidant nuclear factor E2-related factor 2 (NRF2) is limited by systemic side effects. We chemically functionalize the NRF2 activator monomethyl fumarate to require Baeyer–Villiger oxidation for release of the active drug at sites of oxidative stress. This prodrug reverses chronic pain in mice with reduced side effects and could be applied to other disorders of oxidative stress."

New painkiller precisely targets sites of chronic pain

Researchers discover localised pain relief using known chemical reaction (original news release) "A team of international researchers including those from the University of Adelaide have taken a well-known chemical reaction as the basis of a new generation of targeted pain relief medication."

Site-specific drug release of monomethyl fumarate to treat oxidative stress disorders (open access)

Fig. 1: Pathological peroxides are required for compound 1c to activate NRF2 in vitro.