Abstract

Today's management of osteoarthritis (OA) consists mainly of symptomatic treatment of pain although traditional analgesics such as NSAIDs may offer only weak pain relief and risk serious adverse reactions. New safe and more efficient treatment regimes are needed for OA, but such a development requires a solid fundamental understanding of the peripheral and central pain mechanisms involved in OA.

OA is characterized by a progressive erosion of articular cartilage and bone remodelling which can be accompanied by pain, local inflammation, and joint degeneration. The main biological factors thought to be responsible for cartilage degradation are the matrix metalloproteinases (MMP) and aggrecanases. Biochemical markers of OA pathophysiology have received increasing attention due to their superior sensitivity in comparison with conventional structural (e.g. radiological) endpoints.

In the individual patient, little association is found between joint damage, local inflammation, and pain. Recently cytokine levels, degree of sensitization (local and spreading), descending pain control, comorbidities, and pain duration are some of the individual factors playing a role for pain severity. With the expected demographic and lifestyle changes, the incidence of joint pain will continue to increase. Better understanding of the individual fundamental pain mechanisms may improve patient profiling, help individualizing management, suggest new treatment options and thereby advance the development of new therapies.

The sources pain in OA and mechanisms responsible are not well understood. Joint nociception can lead to peripheral and central sensitization. It has consistently been shown that pain intensity, pain durations, and the number of OA locations are important drivers for sensitization in OA.

Various animal models of OA have been established to investigate the consequences of experimental OA on pain processing and various pain mechanisms, but they do not translate well into humans. As a consequence, data derived from these models for drug development programs are not always predictive of efficacy, and new strategies are needed for developing translational pain biomarkers. In clinical OA conditions, the poor relationship between joint pathology and pain is found, and better understanding and characterization of the underlying mechanisms of pain are important. Techniques for assessing pain mechanisms in OA patients provide biomarkers capable of quantifying pain mechanisms such as temporal summation, descending inhibition, spreading sensitisation, and primary and secondary hyperalgesia. Such pain biomarkers can help to phenotype OA patients based on the contribution of peripheral and central pain sensitization. Biomarkers are currently being explored as tools to facilitate better understanding of pain mechanisms and to predict pain outcomes after e.g. total knee replacement surgery. Preoperative pain intensity, acute postoperative pain, and pain sensitization have been shown to be predictors for the development of chronic postoperative pain after knee joint replacement.

Relating clinical benefit of a given therapy with quantitative assessment of the pain mechanisms involved provides new opportunities for tailored and individualized management regimes. The use of biological biomarkers in combination with techniques such as comprehensive quantitative sensory testing that explore OA pain mechanisms has increased the understanding of dynamic pathological events that lead to patients' symptoms.