The pathophysiology of knee OA pain is complex. Altered processing of nociceptive inputs at spinal and higher brain centers may help explain discrepancies between pain severity and pathological abnormalities in OA. Central sensitization is described as an increased responsiveness of nociceptive neurons at spinal and supraspinal levels to normal or sub-threshold afferent input leading to hyperalgesia. It may also include dysfunction of endogenous pain control systems. Furthermore, peripheral pro-inflammatory mediators and neuropeptides in knee OA can sensitize nociceptors, lowering their threshold for activation. This increased responsiveness of peripheral nociceptors is referred to as peripheral sensitization.