Treating Chronic Knee  Osteoarthritis Pain ADB-102 

Knee osteoarthritis (OA) is one of the primary causes of chronic pain and disability worldwide. Not surprisingly, the high disease burden of chronic lower extremity OA pain is accompanied by frequent opioid prescriptions. Importantly, chronic OA pain remains a major contributor to loss of quality-adjusted life-years; and treating pain and related disabilities may lessen the increased mortality attributed to lower extremity OA. 

It is well-accepted that pain processing and transmission in OA is reliant on specialized ‘nociceptors’ that require the function of various ion channels. These ion channels determine resting membrane potential, neurotransmitter release, and sensory neuronal excitability. Alterations in ion channel expression and/or function can lead to nociceptor hyperexcitability (so-called peripheral sensitization) associated with both chronic neuropathic and inflammatory pain common place in OA.   

Peripheral sensitization involves lowering the threshold for nociceptor electrical signals that transmit pain (action potentials or AP) increasing the likelihood that larger numbers of APs will reach sensory terminals enhancing the release of pain mediators and neurotransmitters that propagate pain transmission. The inflammatory milieu evident in OA not only lowers the threshold for AP of pain sensory fibers, it causes peripheral sensitization by unmasking (activating) otherwise ‘silent’ nociceptors. The resulting torrent of pain signals in chronic OA, can lead to central sensitization (hyperexcitability and enhanced responsiveness in the central nervous system). Only a subset of specialized nociceptive fibers is considered necessary and sufficient to cause persistent OA pain.