Discussion

Introduction:
Osteoarthritis (OA) is the most important chronic musculoskeletal disorder in horses. Joint pain (often intermittent) is one of the hallmarks of OA and the major cause of lameness.
Numerous processes in the course of OA can contribute to joint pain and very rarely can the precise tissue origin of pain be identified. Synovitis is an important factor, activating mechanoreceptors through joint effusion, swelling and/or fibrosis, and nocireceptors through direct chemical stimulation.

Pathways of inflammatory pain:
Nociception is induced by the chemical stimulation of nerve afferents by endogenous mediators during inflammation. Interleukin-1 (IL-1) and Tumour Necrosis Factor alpha (TNF-alpha) are the 2 major cytokines in OA, which increase synthesis of prostaglandin E2 (PGE2). The role of prostaglandins is not as unambiguous as it seems. In a study comparing PGE2 levels in synovial fluid in lame horses that did or did not respond to intra- articular analgesia, no significant difference was found (De Grauw et al. 2006). Substance P is also related to pain associated with OA (Fortier and Nixon 1997) and was the only mediator that could be directly linked to outcome of intra-articular analgesia (De Grauw et al. 2006).

Management of joint pain:
Chronic pain due to OA is mostly managed pharmacologically. It should be realised that treatment aimed at pain reduction does not necessarily treat the underlying primary disease process and may even interfere negatively with it.

Systemic treatment of joint pain:
The nonsteroidal anti-inflammatory drugs (NSAIDs) are the most important class of compounds with phenylbutazone, flunixin and meloxicam most often used. They inhibit the enzyme cyclooxygenase (COX) in the arachidonic acid cascade, thus impeding prostaglandin production. Most of the older NSAIDs inhibit both COX-1 and -2 iso-enzymes, and therefore also affect constitutive prostaglandin production by COX-1, which protects mucosal barriers in the gastrointestinal tract. Newer NSAIDs are more selective COX-2 inhibitors and have a superior gastro- intestinal safety profile.
Phenylbutazone (PBZ) is the most widely used drug in equine practice and is deemed most cost-effective for OA (Goodrich and Nixon 2006). It may, however, have severe adverse health effects on humans and has been withheld official registration for equine use in some countries. Whilst proven effective, comparative research on clinical efficacy vs. other NSAIDs in horses is limited and information on the effects on the primary disease process is even scarcer and conflicting.
Flunixin is mostly used in the treatment of abdominal pain, but is also effective for the alleviation of lameness. Little is known of the effects on joint homeostasis.
Meloxicam, a COX-2 inhibitor, is the only NSAID with data on in vivo effects on cartilage metabolism. De Grauw et al. (2009) demonstrated lower matrix metalloproteinase activity in synovial fluid with lower levels of markers of proteoglycan breakdown and collagen II turnover, indicating mitigation of the catabolic effects of acute joint inflammation.

Local treatment of joint pain:
Local treatment consists mostly of intra-articular injection of corticosteroids, but opioids are new and promising.
Corticosteroids inhibit the NF-kB signalling pathway, acting as potent upstream inhibitors of inflammation. They also regulate gene expression levels of matrix genes and hence can affect cartilage turnover and repair.
Intra-articular corticosteroid use has been controversial, but there is now agreement that, if used judiciously with respect to frequency, interval and dose, the benefits outweigh the disadvantages (Goodrich and Nixon 2006). Most commonly used corticosteroids in equine practice are methylprednisolone acetate, betamethasone and triamcinolone. Methylprednisolone acetate is a long-acting corticosteroid with a recommended dose of 40 - 100 mg/joint, of which the lower end is advisable. Doses between 10 - 40 mg have a clear anti- inflammatory effect whilst preserving the normal joint environment.
Betamethasone acetate is a medium to long acting corticosteroid. In vitro there is suppression of proteoglycan synthesis at low-medium doses.
Triamcinolone acetate is most widely used and has a medium duration of action. In vitro studies indicated it may potentially suppress inflammation without negative effects on the transcription of extracellular matrix genes (Richardson and Dodge 2003). Opioids are analgesic drugs par excellence. In the horse Santos et al. (2009) showed that IA morphine had a stronger and longer analgesic effect than ropivacaine, albeit with a slower onset. Van Loon et al. (2010) showed a significant effect of IA morphine on lameness, joint effusion, and behavioural expression of pain and on synovial fluid inflammatory mediators in an LPS arthritis model. There was no effect on biomarkers of cartilage metabolism, or on substance P release. Epidural administration did have an analgesic, but not a local anti-inflammatory effect (Van Loon et al. 2012).

Conclusion:
Pain is the most important clinical hallmark of OA. Pain relief alone may have a favourable (short- to mid-term) clinical effect, but could potentially also have adverse effects on the underlying disease process and hence on long-term outcome. The intra- articular use of opioids is novel and promising in equine orthopaedics.