Osteoarthritis (OA) is recognized by degeneration of articular cartilage, synovitis, remodeling of subchondral bone and atrophy/weakness of joint muscles. Clinical presentation is dominated by pain during joint use and often at rest. There are circadian variations in pain severity in both knee and hand OA, with pain worsening in the evening [1
]. Pain frequency and intensity has been related to obesity, helplessness and education as well as a significant co-morbid association with anxiety and depression [3
There are major distinctions between physiological and pathophysiological (chronic) pain. Physiological pain is a necessary defense mechanism, related directly to the degrees of existing or imminent tissue damage, and is essential for survival. On the other hand, chronic pain serves no defensive or helpful function, since neither the intensity nor quality of chronic pain is related to the degree of tissue damage and may persist long after the resolution of any initial insult. Chronic pain (nociceptive or neuropathic) is now recognized as a manifestation of an aberrant functioning of a pathologically altered nervous system. Pain therapy, and the emerging pharmacology, is seen in terms of symptomatic treatment (through modulation of aberrant function, that is, neural excitability) and disease modification (through neural restoration of physiological pain processing). This is the context in which we will develop new therapies and will be the focus of this review. However, this does not deny that disease modifying approaches, for example, to resolve joint or cartilage degeneration, may also impact on OA pain.
Pain in OA, like other chronic pain conditions, is a complex integration of sensory, affective and cognitive processes that involves a number of abnormal cellular mechanisms at both peripheral (joints) and central (spinal and supraspinal) levels of the nervous system. The relative contribution of these processes in the OA population appears to be strongly segmented. Intra-articular anesthetic studies in hip and knee OA support a peripheral drive to pain in approximately 60% to 80% of patients, depending on the affected joint [3
]. In some individuals, however, central mechanisms, for example, dysfunction of descending inhibitory control [5
] or altered cortical processing of noxious information, may play a greater role [6
With such patient heterogeneity, identifying pharmacological targets of the future is fraught with issues. Biomarker development and patient stratification will need to be progressed in parallel to ensure 'tailor-made treatment'. More narrow titration of preclinical activities, for example, animal models, in vitro assays and so on, to specific patient subsets may also be required to improve predictability in humans. Nevertheless, rational mechanistic approaches can be taken. Alterations in the physiology of sensory pathways, such as sensitization (reduced threshold for stimulation), hyper-excitability (amplification or prolongation of nerve discharge) or spontaneous nerve activity, can be associated with specific molecular changes.
In this review we have selected examples of emerging pharmacology for the treatment of OA pain (Figure ). Where appropriate, examples of inflammatory and neuropathic pain pharmacology have been highlighted, since there is continuing discussion as to whether components of osteo-arthritic pain are also neuropathic (see [7
] for a review). Ultimately, in any patient, multiple algogenic mechanisms may underpin the pain experience. Combinations of pharmacological approaches may, therefore, be a requirement for effective pain management. However, 'chasing' efficacy with combinations will need to be balanced against the cumulative safety burden of treatments. Indeed, OA patients (particularly the elderly) may be willing to forgo efficacy in favor of lower adverse event risk [8
Figure 1 Key elements of osteoarthritis (OA) pain pathophysiology and examples of pharmacological intervention points. Observations of pain resolution following intra-articular local anesthetic and following joint replacement would implicate a peripheral drive (more ...)