Peripheral and Central Sensitisation in Osteoarthritis – Implications for Treatment

A major problem in designing new therapies to treat musculoskeletal pain, and osteoarthritis (OA) pain in particular, is that the underlying mechanisms driving musculoskeletal pain are not fully understood. A hallmark of OA is progressive degeneration of articular cartilage and subsequent joint space narrowing. In the majority of patients, the aetiology of OA is not known. Among the known risk factors are age, significant trauma, obesity, altered gait, altered biomechanics (e.g. varus or valgus deformity) and excessive loading.

Experimental and clinical observations suggest that the structural integrity of articular cartilage is dependent on normal subchondral bone turnover, intact chondrocyte function and ordinary biomechanical stresses.¹ An increasing line of evidence suggests that there are strong communication and interaction between the subchondral bone and the articular cartilage.² As bone and cartilage are closely interrelated, interventions affecting pain related to bone turnover may, in addition, be related to pain relevant to osteoarthritis. Pain is a central part of the clinical presentation of OA and the main reason for patients to seek consultation. Many and diverse structural features of the joint have been suggested to be involved in OA-associated pain, including, but not limited to, the presence of osteophytes in the patellofemoral compartment, focal or diffuse cartilaginous abnormalities, subchondral cysts, bone marrow oedema, subluxation of the meniscus, meniscal tears and Baker cysts.³ However, pain perception is often highly individual, and so far none of the features have demonstrated a robust correlation with pain. It has always been a puzzle why radiological joint changes do not correlate with the clinical pain intensity,^4,5 although a recent large clinical trial showed a relationship between Kellgren and Lawrence severity of OA and clinical pain intensity.⁶

The Fundamentals of Osteoarthritis Nociception

Free nerve endings are widely distributed throughout most of the articular structures. The majority remain silent during normal conditions, but become active when the articular tissue is subjected to damaging mechanical deformations and to certain chemical substances. These chemosensitive units are activated by certain ions and inflammatory mediators, such as serotonin, histamine, bradykinin and prostaglandins. The sensation of acute deep-tissue pain from muscles and joints is the result of activation of group III (Aδ fibre) and group IV (C-fibre) polymodal muscle nociceptors.⁷ The nociceptors can be sensitised by release of neuropeptides from the nerve endings. This may eventually lead to peripheral hyperalgesia and central sensitisation of dorsal horn neurons manifested as prolonged neuronal discharges, increased responses to defined noxious stimuli, response to non-noxious stimuli and expansion of the receptive field.⁸ Continuous and intense nociceptive input from the knee joint in animals may drive central sensitisation,⁹ which most likely also plays an important role in human OA.^10,11 Such peripheral and central pain mechanisms may be the reason for the often observed discrepancy between joint damage and clinical pain intensity. Further achievements in acquiring knowledge are hampered by the fact that animal models of OA translate very inadequately into human conditions which, in turn, slows down the development of novel therapies to treat musculoskeletal pain. In humans, little information is available on the peripheral neuronal correlate of pain from musculoskeletal structures, and only a few microneurographic studies have been published where those nociceptors are characterised,¹² due to difficulties in recording and directly activating the nociceptors.

Osteoarthritis Pain in Humans
Normal adult human articular cartilage is thought to be avascular and aneural. However, very recently, sympathetic and sensory nerves were both found to be present within vascular channels in articular cartilage in both mild and severe OA. Perivascular and free nerve fibres and nerve trunks have also been observed within the subchondral bone marrow and within the marrow cavities of osteophytes. Nerve endings localised in damaged human articular cartilage¹³ suggest that vascularisation and the associated innervation of articular cartilage may contribute to tibiofemoral pain in OA across a wide range of structural disease severity. The implications of these findings are that the musculoskeletal pain associated with osteoarthritis may result from a combination of the hitherto accepted central and bone-derived effects. A mechanism-based understanding of the factors involved in generating OA pain has gained acceptance and will further develop the area.¹⁴ Developing both an understanding of the mechanisms that drive persistent OA pain and novel mechanism-based therapies to treat these unique pain states would address a major unmet clinical need and have significant clinical, economic and societal benefits.