19 Nov 2018
Barriers and challenges to treating canine OA – part 2
Danielle Marturello and Karen Perry investigate the problems of treating and managing this condition, using examples of available products. Includes video content.
Figure 1. An intraoperative photograph of a patient with septic peritonitis. This particular patient had already undergone one surgery to treat intestinal perforation, suspected to be secondary to ulceration precipitated by NSAID use. This second surgery became necessary when the previous end-to-end anastomosis site broke down four days postoperatively.
Canine OA is a prevalent disease and can be a complicated one to treat successfully. In part one (VT47.49), the authors discussed the dearth of epidemiological data on canine OA and a lack of attention to patient monitoring – and how these can exacerbate the challenge of OA treatment.
In this part, the authors investigate additional challenges, including the limitations of products available for treatment and the fear, of both owners and vets, of adverse effects associated with medical management options. By raising awareness of the barriers encountered in OA treatment, it may be possible to improve the welfare of a substantial percentage of dogs suffering with OA-related discomfort.
In the first (VT47.49) of this three-part series investigating barriers to canine OA treatment, the authors addressed how the limited information regarding the epidemiology of OA, and the lack of attention to and difficulty in monitoring patients with the condition, could contribute to management difficulty.
In this part, the authors will investigate the additional challenges, including the limitations of products available for treatment and the fear of adverse effects associated with management options.
Products available
This barrier can be broken down into two components. Firstly, limitations exist in products on the market. While novel medications and treatments are being developed, they are often not immediately available to the clinician.
Secondly, although safety data of new medications is typically published prior to a product’s release, efficacy studies with large case series are often lacking. This can lead to understandable reluctance to try new things.
Often, it is easier to rely on standard treatments for known conditions, and much more difficult to branch out into something new.
The most commonly used products for management of OA pain are NSAIDs. These medications mediate their effects through COX inhibition. In-depth review articles on specific medications are available (McLaughlin, 2000) and are beyond the scope of this article. However, studies suggest long-term use of NSAIDs (more than 28 days) is beneficial for alleviating chronic OA pain, and patients are at a low risk for serious adverse side effects (Innes et al, 2010).
While numerous studies exist looking at NSAID medications and their efficacy/safety, the quality of these studies, when systematically reviewed, is called into question. Innes et al (2010) reviewed literature on the safety and efficacy of NSAID medications used for the long-term treatment of canine OA. They found only 8 out of 15 (53%) could be classified as type-one studies (randomised, controlled clinical trial with in vivo data).
Furthermore, only another 8 out of 15 were considered “high quality” studies. Having said this, substantially more evidence exists to support the use of NSAIDs in OA management than for any other treatment modality.
As mentioned in part one, the wide range of factors affecting joint health and pain status make it difficult to provide a specific recommendation for the treatment of OA applicable in all situations, and, to achieve satisfactory relief, multimodal therapy is often advocated.
In the authors’ experience, multimodal therapy is certainly more efficient than monotherapy in cases with moderate-to-severe OA, but a paucity of peer-reviewed evidence supports this. As owners become more discerning in the treatment of their pets, vets more frequently have to communicate this lack of evidence to owners. Understandably, this can lead to owner reluctance in pursuing (and paying for) medications with a limited evidence base.
To limit this barrier, practitioners can choose medications with supportive evidence as their first-line treatment where possible. Nutraceuticals are often chosen as the second, and sometimes primary, treatment modality for patients with OA.
The benefits of nutraceuticals in the management of OA are widely debated and meta-analyses are generally poorly supportive of the direct efficacy of these adjunctive therapies (Reichenbach et al, 2007; Vandeweerd at al, 2012). In this regard, the use of nutraceuticals can carry a significant financial burden for owners, particularly of large breed dogs. Therefore, it is difficult to justify their use over products where evidence of efficacy exists.
The use of amantadine with NSAIDs is the only multimodal management regime for which we have satisfactory evidence when considering treatment of canine OA. Amantadine is an antiviral agent found to have NMDA antagonistic activity when studied in humans (Lascelles et al, 2008).
Its oral formulation was shown to improve chronic back pain in humans by reducing central sensitisation (Kleinböhl et al, 2006). Accordingly, its effectiveness was studied in dogs in a randomised, blinded clinical trial. Investigators found amantadine was successful at reducing OA pain in dogs refractory to NSAIDs, and physical activity was improved in treated dogs (Lascelles et al, 2008).
In cases managed by the authors, amantadine is the first product added to a multimodal treatment plan. Not only can the authors justify this to owners based on peer-reviewed evidence, but the clinical experience of the authors has also been very good.
Other medications used as components of the multimodal management regime have limited evidence to support their use and, therefore, the order in which they are trialled is up to the individual clinician. Gabapentin is a human anticonvulsant drug that acts by binding to the α2-δ1 subunit of presynaptic voltage-gated calcium channels. This causes inhibition of the release of excitatory neurotransmitters, such as substance P.
For humans, gabapentin is a first-line medication for chronic neuropathic pain (Lamont, 2008). For canine patients, no trials are available in the literature that evaluate the drug’s safety and efficacy, but as chronic OA is likely to result in neuropathic pain, gabapentin may have a role to play in management.
Additionally, a study by Boileau et al (2005) examined a similar ligand in an experimentally induced canine OA model, and found the compound was able to slow the progression of cartilage changes.
Tramadol is a centrally acting analgesic and has been advocated for use when more substantial pain is present, such as following a surgical procedure or in cases of severe OA. While it has been demonstrated to be effective for treatment of OA in people, no published clinical trials have demonstrated clinical efficacy for the treatment of OA in dogs.
Human studies have proven that, without production of the metabolite O-desmethyltramadol, the drug has little analgesic effect (Stamer et al, 2007). In canine studies, researchers have established dogs do not produce substantial amounts of O-desmethyltramadol and, as such, effectiveness is predicted to be weak at best (Kukanich and Papich, 2011).
An alternative medication to use is codeine, a mu-opioid agonist used for relief of mild-to-moderately severe pain in humans. In dogs, codeine has a 4% bioavailability, with the primary metabolite being morphine (Findlay et al, 1979).
Studies have demonstrated little morphine is produced from codeine, but large amounts of codeine-6-glucuronide are formed, which may provide some analgesic effects (Yeh and Woods, 1971; Kukanich, 2010). No reports are available of oral codeine efficacy in clinical cases or controlled clinical studies of OA, but it remains a low-cost option that can be trialled. Ultimately, however, oral opioid and opioid-like medications can be expected to have relatively poor efficacy and patients taking these medications should be monitored closely for pain control.
Many other medications are available, including pregabalin, amitriptyline and corticosteroids, but evidence to support their use specifically in the management of OA is largely lacking beyond textbook chapters and review articles.
Fear of adverse effects
A broad range of licensed and other candidate therapies are available for use in OA management, and the efficacy and safety of these products certainly varies. Unfortunately, again, a lack of peer-reviewed evidence exists comparing the safety of these products. Evidence, however, does support that both owner and vet fears of adverse effects associated with NSAID use acts as a barrier in the treatment of OA.
A study carried out by Belshaw et al (2016) highlighted awareness of, and concern about, the risk of adverse events associated with NSAID administration in dogs with OA is high in vets, nurses and owners alike (Figure 1). This study also showed vets struggled with recognising, managing and avoiding adverse events associated with NSAID administration. When noted, management strategies varied, but included dose reduction, a brief drug respite or complete cessation of the medication.
Methods used in attempts to avoid these events included screening blood tests and dose reduction. However, the evidence base supporting these methods in avoiding and treating adverse events is limited, and a major concern – raised by this study and supported by the authors – is the risk to animal welfare if affected dogs are not receiving adequate analgesia (Belshaw et al, 2016).
More evidence is warranted; however, based on that available, it appears the concerns regarding adverse events, and the resultant barrier to appropriate OA treatment may be higher than justified.
A study by Innes et al (2010) suggested the incidence of serious adverse effects associated with NSAID use of 28 days or more is low and the risk of adverse effect did not increase with duration of treatment. The authors of this study suggested adverse events may have more to do with an individual animal’s inherent response to NSAIDs rather than dose and duration of treatment (Innes et al, 2010). While the authors are not advocating the risk of adverse effects be ignored, it should also not be overstated.
The study by Belshaw et al (2016) demonstrated the source of most owner concerns regarding NSAID administration came from information given by a vet; as such we may be building our own barrier to OA treatment. Informed owner consent is critical, but the risks can be kept in perspective and the risk of leaving an animal in chronic pain should be weighed carefully against the risk of adverse events.
Another route forward is a more targeted approach for OA treatment. Grapiprant represents an advance in this area, being a highly selective prostaglandin E2 (PGE2) antagonist. PGE2 is the most abundant prostaglandin in the synovium and, as such, plays a crucial role in the development of inflammation and subsequent joint pain.
Grapiprant specifically blocks the prostaglandin E2 receptor 4, effectively hindering the prostaglandin pathway, which allows the cyclooxygenase-2 enzyme to maintain its role in normal organ function (Rausch-Derra et al, 2015).
In a study evaluating 36 dogs over nine months, none of the treated animals experienced adverse clinical effects or demeanour changes, and no pathological tissue changes were noted (Rausch-Derra et al, 2015).
In the final part of this article the authors will investigate some additional limitations and, where possible, propose ways to ameliorate these. One of these, certainly applicable to all canine patients with OA, is suboptimal client compliance. The other barriers described in the final part are those largely applicable to surgical treatment options for canine OA.
Other articles in this series
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