Continuous Therapy for Osteoarthritis: Efficacy and Safety of Long-Term NSAID Therapy
The Rationale for the Long-Term Treatment of Osteoarthritis
Our knowledge of the clinical presentation and pathophysiology of arthritis is continually evolving. In the chronic phase of arthritis what we see is chronic pain with intermittent flare-ups. From human medicine we know that one can "get used to" living with chronic pain but that this leads to a substantial deterioration in quality of life (never ending pain /pain that dominates everything). In companion animals, this phenomenon is characterized by behavioural changes that owners often misinterpret as normal signs of ageing.
Perception of pain is worsened by the development of central sensitization (involving COX-2) which is characterized by allodynia and secondary hyperalgesia. Once present, central sensitization is difficult to reverse and the increased pain that results will tend to worsen clinical signs. Central sensitisation can also worsen the disease in the joint.
In osteoarthritis we see progressive changes involving all the components of the joint: cartilage, synovial membrane, synovial fluid, the joint capsule, sub-chondral bone, ligaments and muscles. Even though therapy may have little direct effect on these tissues (e.g., cartilage), the length of treatment must be long enough if we want to influence these processes indirectly by reducing pain and thereby improving joint function.
Efficacy of Long-Term Treatment with NSAIDs
Efficacy can be seen clinically in the spectacular improvements in the behaviour of animals in their normal daily lives which is generally seen when they are given long-term treatment. This kind of improvement is not obtained after only short course of NSAIDs, or when observance is not correctly achieved. By using daily or continuous treatment owners can see that the level of pain in their pet can be further improved and this generally convinces them to treat their animal long-term.
Efficacy has also been proved experimentally. In a number of different studies involving different NSAIDs, run by pharmaceutical companies, efficacy was seen to improve after 3 months of continuous treatment compared to only 30 days.
In a recent publication* Innes et al. investigated the published literature and concluded that "the balance of evidence for the efficacy of NSAIDs supports longer-term use of these agents for increased clinical effects."
Safety of Long-Term Treatment with NSAIDs
Whatever the NSAID or the length of treatment being used, the general rules for avoiding contra-indications and reducing adverse effects still apply. Informing the pet owner of the risks of potential adverse events and what to do if they occur is fundamental. A major risk associated with NSAIDs is renal toxicity and it is essential to ensure a normal circulating volume / hydration status (and correct if necessary) and to check that there is no renal insufficiency.
When considering the use of long-term treatment the question is: Are we increasing the risk of having an adverse event by increasing the length of treatment?
In the Innes et al. paper, mentioned above, the authors calculated the Experimental (adverse) event rates (EER). They found that there was no correlation between the duration of treatment and the EER. No publication suggested a reduction in safety associated with long-term treatment. According to the authors "Overall studies reported EERs between 0 and 0.31 (mean 0.11), but there was not a significant correlation between study (treatment) length and EER."
One can also look at the regulatory dossiers submitted by Pharmaceutical companies in order to obtain marketing authorisations for "long-term products". We tend to be suspicious about information given by Pharmaceutical companies about to launch a product. However, the efficacy and especially the safety (toxicity) of a product are criteria that are very closely monitored by the regulatory agencies both before and after launch. This is even more the case now that products are launched over a wider geographic area (whole Europe or Europe and USA).
With our current understanding of arthritis the long term use of NSAIDs for chronic arthritis seems to be appropriate. Innes et al. can again be quoted; "The current evidence suggests that there is a clinical benefit of longer-term NSAID use for dogs with chronic osteoarthritis and that this is associated with a low risk of adverse events."
We also need to keep in mind that even if NSAID treatment remains the underlying basis for the treatment of arthritis, overall management should be based on a multi-modal approach including weight control of the animal, prescription of regular controlled physical exercises combined with functional rehabilitation, the use of additional analgesic therapy and in some cases the use of palliative surgery.
1. Innes JF, Clayton J, Lascelles BDX, Review of the safety and efficacy of long-term NSAID use in the treatment of canine osteoarthritis. The Veterinary Record, 2010, 166,226-230.