14 Dec 2015
Painful Joints associated with osteoarthritis in dogs
Breed, age and weight are known factors in development of osteoarthritis.
Osteoarthritis (OA) is a common, painful condition of dogs that can be challenging to manage successfully in practice. Non-surgical options focus on pharmacotherapy for chronic pain.
Use of adjunctive techniques, such as acupuncture, hydrotherapy and massage, are beyond the scope of this article, but may be useful in the context of a holistic approach to pain management in the arthritic patient.
Pharmacotherapy for managing OA pain
NSAIDs
NSAIDs form the backbone of treatment for OA-associated pain because they are licensed, efficacious and safe in the majority of animals (KuKanich et al, 2012).
As a drug class, NSAIDs produce analgesia through inhibition of cyclooxygenase enzymes and a reduction in production of eicosanoids, particularly prostaglandin E2, which is associated with vasodilation of blood vessels, sensitisation of nociceptors and enhanced nociceptive processing in the dorsal horn of the spinal cord and higher brain centres.
Lascelles et al (2009) demonstrated both COX-1 and COX-2 enzyme are upregulated in the synovium of dogs with naturally occurring OA. However, inhibition of eicosanoid production is also associated with the side effects of NSAIDs, which are well known and stated clearly on the summary of product characteristics of all licensed NSAID molecules.
Particularly relevant to the long-term administration of NSAIDs to dogs is their potential to affect the gastrointestinal (GI) tract, including decreased mucus production, increased gastric acid secretion, decreased secretion of bicarbonate in the duodenum and decreased turnover of mucosal cells. Collectively these effects can contribute to a predisposition to GI injury, including a risk of GI perforation (Lascelles et al, 2005).
Numerous studies have compared the relative effectiveness of different NSAIDs for the management of OA-associated pain and have failed to show a systematic difference between NSAIDs in analgesic efficacy (Edamura et al, 2012; Walton et al, 2014). However, anecdotally some dogs appear to respond better (both in terms of efficacy and side effect profile) to one NSAID than another, which probably reflects the pharmacogenetics of an individual animal.
When starting NSAID therapy in a dog with OA, it is worthwhile discussing this possibility with the dog owner, so they are aware if the first NSAID treatment is not effective at relieving the joint pain it is worth trying a different NSAID to see if it is more effective.
Limited data is available on the ideal “wash-out” period to leave between different NSAID therapies; however, it is recommended at least 48 hours is left between stopping one treatment and starting another if lack of efficacy is the reason for the NSAID switch.
Switching NSAIDs may also be indicated if one drug is associated with adverse effects (for example, vomiting); however, it is prudent to leave a longer time interval between stopping one NSAID and starting another NSAID if adverse effects are documented, and a precautionary approach should be adopted if the adverse effect was serious (for example, evidence of GI ulceration or haemorrhage). This may involve leaving a one to two-week period between stopping and starting the next NSAID or avoiding further NSAID treatment completely.
There has been a drive to develop NSAIDs with a more favourable side effect profile, with the focus of attention being on development of NSAIDs that are more selective for the COX-2 enzyme, leaving the COX-1 enzyme spared from inhibition.
NSAIDs with a high selectivity for the COX-2 enzyme relative to COX-1 inhibition are termed coxibs, while COX-2 preferential drugs show some selectivity for the COX-2 receptor. In veterinary medicine, coxibs include firocoxib, robenacoxib, mavacoxib and cimicoxib, although mavacoxib is considered to be borderline between preferential and selective for COX-2 inhibition (Lees et al, 2015).
Carprofen and meloxicam are widely considered to be COX-2 preferential drugs. However, it is difficult to be certain whether a drive towards COX-2 selectivity is associated with increased tolerability of NSAIDs because limited data describe the relative risk of side effects associated with administration of different NSAID molecules in dogs.
Monterio-Steagall et al (2013) performed a systematic review of NSAID-induced adverse effects in dogs and concluded most studies were not appropriately designed to determine the safety of NSAIDs, with many of them involving a healthy population of non-geriatric research dogs, which is not analogous to the majority of dogs treated with NSAIDs in the canine population.
Hunt et al (2014) analysed pharmacovigilance data relating to reported NSAID-related side effects in dogs and found overall the incidence of side effects associated with NSAID administration was relatively low.
A higher incidence of side effects was associated with coxib compared with non-coxib NSAIDs, but this was attributed to change in reporting habits of pharmacovigilance data over time and the fact coxib drugs have more recently received market authorisation than non-coxib drugs, rather than being a true reflection of increased side effects associated with coxib administration.
Dose titration of NSAIDs is commonly recommended to ensure the lowest effective dose of NSAID possible is administered, therefore potentially reducing the likelihood of NSAID-related adverse effects. Although administering higher than the licensed dose of NSAID is associated with an increased risk of adverse events (Lascelles et al, 2005), there is no evidence dose titration is associated with a lower risk of adverse events.
Wernham et al (2011) investigated the analgesic efficacy of a dose titration of meloxicam in dogs with spontaneous OA and found dogs receiving the reduced dose of meloxicam were more likely to drop out of the study due to inadequate pain control than dogs receiving the licensed dose of meloxicam. However, the majority of dogs in the reduced dose group tolerated a 15% reduction in meloxicam dose without an increase in pain level, suggesting in many dogs a modest dose reduction can be achieved without an associated reduction in analgesic efficacy. This study also indicates any dose reduction must be carried out with careful assessment of analgesic efficacy.
Similarly to dose reduction, a question mark exists over the benefits of continuous dosing of NSAIDs in dogs compared to intermittent dosing during OA flare-ups, which may be commonly practised by owners in an attempt to reduce the likelihood of NSAID-related side effects.
Episodes of breakthrough pain, where pain management is inadequate, contribute to maintenance of central sensitisation and an upregulated pain state and make effective management of pain more difficult in the longer term (Moore, 2011). This principle has led to the concept of preventive analgesia for acute pain, whereby analgesic strategies that limit central sensitisation are recommended (Vadivelu et al, 2014) and the same principle is likely to apply to chronic pain states.
At an effective dose, NSAIDs act both peripherally (through a reduction in inflammation and therefore peripheral sensitisation of C and A delta fibre nociceptors) and centrally (via a reduction in nociceptive transmission in the spinal cord and brain; KuKanich et al, 2012) to limit central sensitisation. It is arguable continued dosing of NSAIDs at the licensed dose and dose interval will be more effective at preventing central sensitisation and will therefore provide superior pain relief compared to reduced dosing regimens where there is a risk the effect site NSAID concentration will fall below the level required for therapeutic efficacy.
This theory has been tested in people, with studies comparing intermittent to continuous dosing with the NSAID celecoxib in patients with OA (Luyten et al, 2007; Strand et al, 2011; Sands et al, 2013). Intermittent therapy was defined as NSAID administration when needed to treat an OA flare.
Continuous therapy was significantly more efficacious at preventing OA flares than intermittent therapy in patients with hip and knee OA (Strand et al, 2011) and resulted in lower WOMAC scores (a measure of pain, stiffness and physical function; Sands et al, 2013).
Innes et al (2010) reviewed the safety and efficacy of long-term (defined as treatment longer than 28 days) NSAID administration in dogs and, although data were limited, found longer-term treatment had benefits in analgesic efficacy compared with short-term treatment and was not associated with an increased adverse event rate.
These data suggest continuous dosing NSAID regimens should be recommended to manage OA-associated pain in dogs.
Paracetamol (acetaminophen) and codeine
Although the licensed preparation of paracetamol and codeine is authorised for a treatment course of only five days, it is used for the long-term management of pain in dogs with OA. There are, however, no studies investigating the safety or efficacy of this preparation for management of OA pain.
There appears to be a general perception paracetamol is better tolerated by dogs than NSAIDs, but no data support this contention. It is important to be aware that due to a high first pass metabolism of codeine by the liver in dogs (KuKanich, 2010), the codeine in this preparation is highly unlikely to be bioavailable and therefore provide analgesia to dogs.
Tramadol
Tramadol is a centrally acting synthetic analogue of codeine that has two different principal analgesic modes of action.
Tramadol and O-desmethyl metabolites exert an agonist effect at opioid receptors as well as inhibiting norepinephrine and serotonin reuptake in the CNS, thereby modulating descending analgesia pathways.
Despite not being licensed for administration to dogs, there has been a huge increase in the popularity of tramadol as a longer-term analgesic for dogs with chronic pain, probably because it is perceived to be safe and devoid of NSAID-related side effects. However, it is important to be aware very limited data describes the efficacy of oral tramadol for the management of OA pain in dogs.
Malek et al (2012) investigated the analgesic efficacy of tramadol 4mg/kg three times daily in client-owned dogs with OA and found it to be equally efficacious to carprofen for some outcome measures.
Anecdotally, this dose of tramadol is considerably higher than is commonly prescribed for the management of OA pain in dogs, suggesting many dogs may not receive benefit from tramadol administration at a lower dose, although higher doses (such as 4mg/kg three times daily) may be associated with dysphoria or sedation in some animals.
Interestingly, Malek et al (2012) also measured plasma concentrations of tramadol and found they were significantly decreased after two weeks of treatment, indicating drug metabolism is altered with prolonged dosing.
In conclusion, tramadol may play a role in the management of OA-associated pain in dogs, but further data are required to support dose and dosing interval. Tramadol should not be used in preference to NSAID therapy in dogs, unless NSAIDs are contraindicated or poorly tolerated by an individual patient.
Amantadine
Amantadine is an oral N-methyl-D-aspartate receptor antagonist that may therefore be effective in limiting or reversing central sensitisation that occurs as a result of OA.
Lascelles et al (2008) investigated the analgesic efficacy of amantadine combined with an NSAID (meloxicam) in dogs with spontaneous OA and pain that was refractory to NSAID therapy alone and found pain scores were decreased compared to dogs that continued on meloxicam therapy only.
The dose of amantadine evaluated in this study was 3mg/kg to 5mg/kg once daily. No behavioural, biochemical or haematological abnormalities were noted after 42 days, although amantadine is excreted by the kidneys in dogs and caution is advised when using amantadine in human patients with kidney disease. These limited data suggest amantadine may be a useful adjunct to NSAID therapy in dogs with pain caused by OA.
Gabapentin
Due to the probable neuropathic component to OA-mediated pain, gabapentin may be a useful adjunct to therapy. The drug is a structural analogue of gamma-aminobutyric acid, but its analgesic action is attributed to binding to the alpha-2/delta subunit of the voltage gated calcium channel, thereby decreasing the release of excitatory neurotransmitters. However, it is important to be aware no published studies have investigated administration of gabapentin for OA-associated pain, therefore recommended dosing regimens are somewhat empirical. Pharmacokinetic studies suggest a dose of 10mg/kg to 20mg/kg gabapentin every eight hours is required in dogs to provide analgesia (KuKanich, 2013).
Adverse effects of gabapentin include sedation and drowsiness that may limit its use in some animals. It is also not recommended to stop the drug abruptly after chronic administration due to the risk of seizures, with the recommendation to reduce the dose of the drug over a period of one week (KuKanich, 2013).
Nutraceuticals
Nutraceuticals are commonly used for the management of OA-associated pain and include products such as glucosamine, chondroitin sulphate, green-lipped mussel powder and dietary supplementation with omega-3 fatty acids. Vandeweerd et al (2012) conducted a systematic review of nutraceuticals to alleviate clinical signs of OA and reported serious methodological issues with the studies available for evaluation. For example, there were limited numbers of rigorous randomised controlled trials, the number of animals included in studies was generally low and there was a lack of standardisation of doses and duration of treatment between trials.
These limitations make it very difficult to effectively appraise the evidence base for nutraceutical-based treatments, but Vandeweerd et al (2012) concluded there was a good evidence base to support a positive treatment effect of dietary supplementation of omega-3 fatty acids in dogs. The proposed mechanism is that omega-3 fatty acids may lower arachidonic acid concentrations and alter the production of eicosanoids to less inflammatory forms. The evidence for other nutraceutical treatments was poor.
Novel agents for management of OA-associated pain
Anti-nerve growth factor antibody
Nerve growth factor (NGF) is essential for the development and maintenance of normal nociceptors. At inflammatory sites different cell types produce NGF, contributing to hyperalgesia. Further roles of NGF include increasing the expression of receptors to inflammatory neurotransmitters in the dorsal root ganglion of sensory nerve fibres and stimulating inflammatory cells to release inflammatory compounds.
Due to the importance of NGF in nociceptor function, a number of human and laboratory animal studies have investigated the analgesic efficacy of antibodies to NGF in the management of OA pain and produced encouraging results.
More recently, a canine specific anti-nerve growth factor antibody has been evaluated in dogs with OA (Webster et al, 2014; Lascelles et al, 2015).
In a placebo-controlled trial, Lascelles et al (2015) used validated clinical metrology instruments and activity monitors to assess pain and activity in dogs with OA for up to 28 days after an intravenous injection of caninised anti-NGF antibody and found improvements in pain scores and activity that were comparable to effects expected from administration of an NSAID, without concurrent side effects. These data indicate the future potential of canine anti-NGF antibody for the management of OA pain in dogs.
Intra-articular botulinum toxin A
Botulinum toxin A injected intra-articularly has the potential to provide analgesia in dogs with OA because it inhibits the release of neurotransmitters (for example, substance P, calcitonin and gene-related peptide) that are important in the pain pathway.
In a relatively small study of 36 dogs with OA, Heikkila et al (2014) investigated the analgesic efficacy of this treatment and found improvements in pain score and gait in the treatment compared with the placebo group. No side effects were reported resulting from toxin injection.
Although sedation or anaesthesia is required to inject into the joint, botulinum toxin A may be efficacious in the management of OA pain for up to three months after injection. Further studies in larger numbers of animals are required to support these preliminary findings.
Assessment of analgesic efficacy
Assessing the efficacy of any analgesic treatment is fundamental to good analgesia practice and a number of owner questionnaires can be used for this purpose. Asking the owner to complete the questionnaire before starting treatment and at regular intervals afterwards (such as every two weeks) can confirm there has been a good response to treatment and pain levels are decreased as well as serving to motivate the owner to maintain treatment compliance.
It is also essential to use these questionnaires when practising dose titration to ensure analgesia is maintained despite a reduced NSAID dose.
Three recommended questionnaires are the Canine Brief Pain Inventory (Brown et al, 2008), the Helsinki Chronic Pain Index (Hielm-Björkman et al, 2009) and the Liverpool Osteoarthritis in Dogs (LOAD; Walton et al, 2013) questionnaire. All three are “owner friendly”, relatively quick to complete and intuitive to use (Panel 1).
Conclusions
Effective analgesia is the goal of conservative management of patients with OA and this can be achieved through a combination of surgical and non-surgical options. NSAIDs are the major drug class used for pain management because they are licensed and efficacious, although adjunctive agents such as tramadol, gabapentin and amantadine, are required in some cases.
Although beyond the scope of this article, a holistic approach to pain management comprising attention to weight control, physiotherapy and potentially acupuncture and hydrotherapy are encouraged in all patients.