TREATMENT of OA should incorporate not only treatment of pain, but an attempt to limit dysfunction for as long as possible, to limit the frustration of the patient from having its resources restricted, and to limit the guilt felt by the owners from having to limit these resources and administer medication about which they feel ambivalent. Above all, the approach must be dynamic and, where possible, proactive. Carmichael describes an approach that fits these requirements.14 The straightforward A, B, C, D, E mnemonic provides an instant checklist for practitioners in the treatment of OA: A = Analgesia; B = Bodyweight; C = Control (i.e. control of complications and of comfort, and giving the owner a sense of control. It also stands for common sense. To paraphrase Carmichael: “If the dog is running about freely and happily and the only thing it cannot do is get in the car, then the dog needs a ramp and not a hip replacement”.); D = Disease modification; E = Exercise. Carmichael and Lindley have consolidated this approach in the Pet Arthritis Counsellor Training course:
A = Analgesia
NSAIDs are the first line of approach for dogs with OA. NSAIDs, as it is well known, act partly by decreasing prostaglandin synthesis by inhibiting the enzyme cyclo-oxygenase (COX) which occurs in two forms: COX 1, the so-called constitutive COX, and COX 2 which is induced during cell injury and inflammation. The general trend in veterinary pharmaceuticals is towards preferential COX 2 inhibition since, although the story is not so clear cut as to label COX 1 “all good” and COX 2 “all bad”, there is increasing evidence that significantly more COX 2 has been found in the synovium of OA affected hips than normal joints in dogs.15,16 COX 2 is also implicated in the development of central sensitisation and inhibition of COX 2 has been shown to decrease central sensitisation.16 The administration of a COX 2 inhibiting NSAID is now taking on a further potential importance for the patient: it should specifically target the inflammatory process in affected joints and it should decrease central sensitisation, therefore having an impact on chronic pain states. From the evidence that if central sensitisation is decreased, peripheral disease and inflammation are reduced,7 it may be hypothesised that COX 2 inhibiting NSAIDs may actually help to treat the disease by treating the pain. Each NSAID has a different profile, differing pharmacokinetics and, therefore, it is not surprising that on occasion, different individuals respond differently to a variety of NSAIDs. Sometimes this varying response is in terms of side effects, and sometimes in terms of apparent efficacy. Some individuals appear to respond predictably and adversely to all NSAIDs, and some only to one. It is claimed that some patients no longer have a benefit from a given NSAID after a while (so-called “tolerance”), and a change to another NSAID may
elicit an improved response. It is possible that the patient may always have been likely to respond better to the alternative drug and that its condition was simply getting worse, such that the first no longer provided sufficient analgesia. Without reliable and consistent pain scoring, it would be impossible to say whether this effect is real or just due to the vagaries of chronic pain, individual response to NSAIDs, and/or the progression of OA. There appears to be no logical mechanism by which such “tolerance” of these drugs occurs. It is also not infrequent that the owner realises that the first NSAID was actually having an effect when the replacement NSAID appears to have no effect at all on their animal’s pain. Side effects of NSAIDs are well documented, and include gastric irritation and ulceration, kidney failure and hepatotoxicity. Whilst caution is sensible in the face of any gastrointestinal disturbance if its origin is not known, it is probably true to say that NSAIDs are withdrawn too often in response to vomiting and diarrhoea. Unless there are signs of gastric ulceration (which would obviously indicate treatment in its own right), it is probably wise to withdraw the NSAID whilst the problem is present, and then reintroduce it when the signs are resolved. One side effect from NSAIDs that is not much discussed is nausea. It is not known whether there is a connection between nausea and gastric ulceration caused by NSAIDs, or whether nausea is a risk factor for ulceration. However, nausea itself is a highly unpleasant experience, and replacing pain with nausea is not likely to improve the animal’s well-being. Signs of nausea include an increase in grass or plant eating (pica is also possible), an increase in lip licking, excessive yawning and stretching (although the latter may also indicate abdominal pain/low back pain), inappetence and general dullness of demeanour, with or without vomiting. These signs should be checked for by questioning the owner at each consultation.
Multimodal analgesia
Pain is modulated at various sites in the nervous system and, at its simplest, multimodal analgesia exploits the different actions of different analgesics to maximise the effect on pain, and minimise the overall amount of each analgesic. Whether an animal needs analgesia additional to NSAIDs will depend on the assessment of its suffering. It is not a given that all animals need multiple analgesics, nor that all patients with OA will need analgesics all of the time, hence the need for frequent reevaluation and adaptation of the individual approach. There are many unlicensed analgesics in common use for pain in small animals. On one hand, it is reassuring to know that there is recognition that NSAIDs are not always enough and that many animals may be suffering, on the other, there is a risk that the norm simply shifts to a new protocol. Where it used to be long-term NSAIDs and glucosamine/chondroitin (or prednoleucotropin, or glucocorticoids, where NSAIDs did not work) the new “formula” may become NSAIDs, plus tramadol plus gabapentin. Although there is no proof of the efficacy of these for the treatment of pain and suffering in dogs with OA, the impression is that they have had a significant effect on the welfare of patients suffering from pain arising from a variety of sources. However, that does not mean that no circumspection is required in their use; excessive use of these medications will result in owners perceiving that their pets are being “doped up” and, of course, the more sedating drugs used, the more likely it will be that an individual will be sedated. Dullness and sedation will complicate continued assessment of the pain and suffering.
Analgesics employed in multimodal analgesia
Tramadol hydrochloride
This is often thought of as an opiate, but has only weak opiate activity, binding at μ-receptors, and also interacting with both noradrenergic and serotonergic systems, as well as having other central effects. Serotonin and noradrenaline are neurotransmitters involved in two of the descending inhibitory pain pathways that are essential in controlling and inhibiting the response to painful stimuli. It is important to remember that tramadol is not classed as an intiinflammatory and, if one suspects that active inflammation is present, then an anti-inflammatory should be used, except when contraindicated. However, there is some evidence that central inhibition of pro-inflammatory cytokines may occur with the use of tramadol, and, with increasing evidence that the inhibition of central sensitisation leads to a reduction in peripheral disease, this view may change. Tramadol is best used where the patient is suffering (this distinction was made in part 2); in short, where the pain affects its mood and demeanour. Although tramadol may have an effect on lameness, it is not unusual to see that the dog just limps more happily, i.e. one may use a different outcome measure when treating with tramadol. Since the drug is not licensed for use in animals, a comprehensive list of side effects and contraindications is not available. Side effects seen include sedation, dullness, vomiting, nausea, diarrhoea and, specifically, dysphoria. It is associated with lowering seizure threshold in man, but this does not appear to be a problem in dogs, whereas seizures have been reported in cats. The dose commonly used is 2-5mg/kg bid-tid, although starting at the lower dose range often has an effect and will limit side effects. The drug appears to be highly stable and can be used in its powder form or dispensed into gel capsules for dosing smaller dogs. Additionally, it appears to be safe to use with NSAIDs. It would be wise to keep the doses to a minimum in either renal or hepatic dysfunction. Tramadol should not be used with other serotonergic drugs such as clomipramine, amitryptline or monoamine oxidase inhibitors, because of the potential danger of causing serotonin syndrome.
Gabapentin
This is classed as an anti-convulsant and was first licensed for neuropathic pain in humans. Neuropathic pain involves the nervous tissue directly, such as nerve root irritation, foraminal stensois, or cord compression, but is also used to mean the effects of central
sensitisation and central disinhibition, where the patient experiences widespread pain, not necessarily attributable to any pathology or correlated with its severity. The latter can be relevant in OA pain and should be picked up during examination and initial assessment (or of course may occur as the disease progresses). Gabapentin is therefore indicated when allodynia and hyperalgesia are present or where the pain and suffering are not being controlled by other means. There are various theories as to how this drug works; the most commonly quoted is that it blocks calcium channels, thereby decreasing the excitability of nerve cells, slowing transmission, but there may also be some noradrenergic effects via descending inhibition. Side effects reported include sedation, vomiting and diarrhoea, excessive drinking (short lived), itch (at higher doses), but specifically, ataxia with stumbling and tripping, assumed to be associated with feelings of dizziness reported by human patients. Gabapentin is partially metabolised by the liver and eliminated by the kidneys in the dog, so minimal dosing is wise where there is renal or hepatic
dysfunction. The recommended dosages are 5-10mg/kg bid, starting low and increasing if necessary. It appears to be safe to use alongside tramadol and NSAIDs.
Paracetamol
An NSAID, with no gastric activity, paracetamol can be safely used when there is gastric ulceration, and alongside other NSAIDs and
glucocorticoids. The disadvantage of this drug is that it is not a very potent analgesic when used on its own. In humans, it is reported to be more potent in combination with other analgesics than when used alone. Its licensed combination contains codeine
and, for that reason, should really be avoided with tramadol, in case the patient is particularly sensitive to the opiate activity of both. It is contraindicated in liver dysfunction. The recommended dose is 10mg/kg bid.
Amantadine
Amantadine is an NMDA receptor antagonist that is reportedly useful for controlling canine OA pain. However, it appears to be most useful in this regard alongside an NSAID or opiate, although there are anecdotal reports of success in its treatment of neuropathic pain as a sole agent. It would be indicated in uncontrolled OA pain, where there is evidence of central sensitisation, and where gabapentin/tramadol is not tolerated or not working. Side effects are sedation and vomiting/diarrhoea.
Recommended doses are 2-4mg/kg sid.
Amitryptline
Amitryptline is a tricyclic antidepressant (TCA) which is an effective analgesic for both neuropathic and nocioceptive pain in humans, when used at lower doses than for emotional disorders. However, it has not been assessed in canine OA. It has been dubbed a multimodal analgesic on its own because of its widespread actions via descending inhibitory pain control, regulation of sleep, anxiolysis, and antihistamine effects. It has more noradrenergic activity than other TCAs and therefore is considered superior to them for pain relief in humans. The SSRIs (specific serotonin reuptake inhibitors such as fluoxetine) have not been found at all useful for analgesia. Amitryptline requires competent hepatic and renal function for elimination. In humans it causes drying of the mucous membranes and therefore should perhaps be used with caution in KCS. It is dysrhythmogenic in overdose and should be used with extreme caution in patients with dysrhythmias. Because of these cautions, it tends to be used less frequently than tramadol and gabapentin, although time and experience may also inhibit the use of these in certain circumstances. Side effects of amitryptline include transient vomiting and diarrhoea, sedation, and occasionally, changes in behaviour (disinhibition).
Acupuncture
Acupuncture is being used increasingly in the treatment of OA pain in humans and animals (Figure 6). There are now systematic reviews to support the use of acupuncture in OA of the human knee, but there are few useful studies in the canine field. Currently, acupuncture should be thought of as primarily providing pain relief, rather than an anti-inflammatory action, although there is an emerging suggestion that the treatment of pain may modify disease. Until this is more firmly grounded, it is sensible to use acupuncture as an adjunct to treat OA, rather than a sole treatment if an active inflammatory process is suspected. Acupuncture triggers and enhances potent analgesic pathways in the body via the stimulation of (primarily) A delta (or Type II and III) fibres in skin and muscle. This stimulation causes inhibition of C fibre pain in the dorsal horn and release of beta-endorphins,
noradrenaline and serotonin, amongst other neurotransmitters,
from the brain.17
Physiotherapy
Physiotherapy is increasingly used in small animals for a wide range of problems. Like acupuncture it is an emerging field in veterinary medicine, with limited research to demonstrate efficacy in the
veterinary species. However, it should be remembered that lack
of evidence of efficacy is not evidence of lack of efficacy. Additionally, there are complex reasons regarding the assessment of any physical therapy (including acupuncture), that are outside the remit of this article, as well as simpler reasons regarding funding, that are limiting progress in these fields. Meanwhile, combinations of therapies including cryotherapy (for acute inflammation) and the application of heat (when acute inflammation has resolved); range of motion exercises; hydrotherapies, including swimming and underwater treadmill walking (Figure 7); electrical nerve stimulation, and active exercise, appear to be the most helpful in rehabilitating, or palliating, patients with OA. Exercises include sit-to-stands (Figures 8a, b,c), “dancing”, shaking hands, step climbing and lead walking.
Such exercises may be best designed and demonstrated by a qualified physiotherapist, although the simpler strategies can be easily learned and demonstrated. Beware of forcing or encouraging
animals with severe pain to engage in such activities without the benefit of sufficient analgesia.
14. Carmichael, S. (2005) Putting theory into practice – best practice management for osteoarthritis. 9th Annual Symposium, Geneva. 15. Lascelles, B. D., King, S., Roe, S. et al (2009) Expression and activity of COX-1 and 2 and 5-LOX in joint tissues from dogs with naturally occurring coxofemoral joint osteoarthritis. The Journal of Orthopaedic Research 27 (9): 1,204-1,208. 16. Veiga, A. P., Duarte. I. D. G., Marcelo, N. A. et al (2004) Prevention by celecoxib of secondary hyperalgesia induced by formalin in rats. Life Sciences 75: 2,807-2,817. 17. Bowsher, D. (1998) Mechanisms of acupuncture. In: Filshie J, White A, editors. Medical Acupuncture: A Western scientific approach. Churchill Livingstone, Edinburgh: pp69-82.
