Pharmacotherapy for chronic pain in dogs

THIS is the second part in a series of three short articles highlighting key points about chronic pain in dogs. Part I covered the recognition and quantification of chronic pain; this article will focus on the pharmacotherapy of chronic pain in dogs with a focus on non-steroidal antiinflammatory drugs (NSAIDs); the final article (next issue) will discuss the monitoring of animals receiving NSAIDs, particularly with respect to safety aspects associated with NSAID administration.

When should pharmacotherapy for chronic pain be initiated?

Decision-making about whether or not to start dogs presenting with signs of chronic pain in the consulting room on pharmacotherapy can be challenging.
Firstly, it is not uncommon for owners to be surprised when a discussion about whether their dog is in pain is raised. This is particularly the case if the dog is presented for a routine vaccination or concurrent disease problem. Some owners can be resistant to the concept of drug therapy if it is unexpected, particularly if they are not convinced that their pet is in pain. Secondly, the only class of analgesic drug licensed for the management of chronic pain in dogs, non-steroidal antiinflammatory drugs (NSAIDs), have
well-recognised side effects that can have serious adverse consequences for
the animal if they arise. Therefore, careful decision-making is required about the benefits of drug therapy, particularly NSAIDs. However, the negative welfare consequences of chronic pain and the impact that chronic pain has on the well-being of an animal must always be considered. Every effort must be made to provide analgesia, either with NSAIDs, a different class of analgesic drug or using non-pharmacological therapies such as diet supplementation, disease-modifying osteoarthritis drugs and weight reduction (if the chronic pain is caused by osteoarthritis), heat or cold therapy. Generally, non-pharmacological therapies either take some time to
become effective (e.g. weight loss, diet supplementation) or are too impractical to provide continuous analgesia when used alone (e.g. heat or cold therapy). Therefore, in most dogs that present with signs consistent with chronic pain, immediate pharmacological therapy will be indicated for the provision of analgesia. However, adjunctive medical strategies should not be ignored, particularly for the management of pain associated with osteoarthritis. Consider starting the dog on analgesic therapy while talking to the owner about other non-pharmacological strategies that can be implemented concurrently, so that an holistic approach to the management of chronic pain is adopted. For example, modifications to the home environment are simple for owners to achieve and, for animals with mobility problems, have the potential to rapidly improve quality of life. Sawaya (2007) has written a review of physical therapies in the management of arthritic patients that serves as a good starting point for further reading about nonpharmacological therapy for osteoarthritis. When reading about alternative therapies, it is important to concurrently evaluate the evidence base to support adoption of each treatment. Unfortunately, in the veterinary
literature there is a very limited evidence base to support any strategies to manage chronic pain (including, with the exception of NSAIDs, most analgesics), but some techniques are better recognised and have been more
thoroughly evaluated than others. Drug therapy for chronic pain NSAIDs should be the first-line treatment for chronic pain unless contra-indicated in an individual patient. There is a good evidence base to support the efficacy of NSAIDs in the management of chronic pain, plus there is a large amount of data to support the recommended dose and dosing interval for all licensed NSAIDs in dogs. The most significant potential side effects associated with the administration of NSAIDs for chronic pain are:

1. Gastro-intestinal effects including vomiting, diarrhoea and a degree of gastro-intestinal ulceration. Mild GI side effects occur relatively frequently in dogs starting NSAID therapy, and usually wane within the first 7-14 days of therapy. Severe GI side effects, such as ulceration and bleeding, or at worst GI perforation, are less common, but are also more likely to occur within the first two weeks of therapy. Clinical signs associated with GI ulceration and/or perforation include haematemesis, meleana and persistent vomiting. The owner should be warned about the potential for GI side effects and advised when to stop NSAID administration and seek further advice from a veterinarian.
2. The major renal side effect of NSAID therapy is reduced renal blood flow during periods of hypotension that can result in renal ischaemia and persistent renal dysfunction. Hypotension is less likely to occur in animals prescribed NSAIDs for chronic pain compared to animals given NSAIDs around the time of anaesthesia and surgery, however may still develop if the dog becomes dehydrated through reduced water intake or excessive loss (e.g. due to persistent vomiting). Warn owners about the potential for dehydration during NSAID therapy to cause renal complications, so that veterinary treatment and intravenous fluid therapy can be initiated promptly for dogs when appropriate.
3. NSAIDs are known to cause an elevation in liver enzymes (for example,ALT, ALKP); however, overt liver dysfunction following administration is very uncommon in dogs and usually attributed to an idiosyncratic reaction, or abnormal metabolism of NSAIDs in individual animals.
4. Hypertension is not uncommon in humans taking NSAIDs, particularly COX-2 selective drugs. This is attributed to the renal effects of NSAIDs resulting in sodium and therefore water retention. The incidence of hypertension in dogs receiving NSAIDs has not been documented, but it is important to be aware of this side effect, particularly in animals with known cardiovascular disease.
5. NSAIDs are known to have effects on blood clotting, via either reduced production of thromboxane A2 or prostacyclin depending on the COX 1:COX-2 selectivity of the individual NSAID. The most common effect is reduced blood clotting (manifest as a more prolonged bleeding time), although as long as the dog is not undergoing surgery this is rarely of clinical significance. In humans, some COX-2 specific NSAIDs have the potential to cause an increased risk of thrombosis, although this risk has not been investigated or quantified in dogs.

How do these side effects modulate decision making about NSAID therapy?

Animals with chronic pain commonly have concurrent disease and/or are clinically geriatric, which may modify the pharmacokinetics of some NSAIDs. However, although no precise data on the incidence of side effects following NSAID treatment relative to the number of dogs receiving therapy are available, it must be considered that, for many dogs, NSAIDs are a very safe and effective class of analgesic agent. The difficulty lies in identifying dogs that may be at a higher than normal risk of side effects, or animals for which administration of NSAIDs is contraindicated. Decision making about whether to withhold NSAID therapy must be carried out following a careful riskbenefit analysis in conjunction with the owner for each individual patient. For example, if analgesia is necessary as part of palliative care, it is probable that an increased risk of NSAID side effects will be tolerated due to the requirement for efficacious analgesia in the home environment. The likelihood of side effects should also be used to determine the requirement for blood sampling and biochemical and haematological investigation before starting NSAID therapy. However, these are only worthwhile if they will influence decision-making about therapy. Due to the high incidence of concurrent disease in animals with chronic pain, blood sampling and testing is recommended before starting therapy in this patient group, but if the owner cannot afford to pay for these investigations, NSAID therapy should still be considered. Case studies show that the greatest risk factor for NSAID side effects is inappropriate administration: for example, administering too high a dose, giving two different NSAIDs at the same time, or combining NSAID and steroid therapy (Lascelles et al, 2005). Other concurrent disease conditions that affect decision making about NSAID therapy include:

1. GI disease. Animals with a history of GI ulceration or presenting with GI ulceration are more likely to develop ulceration as a result of NSAID therapy. Administration of gastric protectants, antacids and proton-pump inhibitors (omeprazole) have not been shown to reduce the risk of NSAID-related ulceration. Consider other analgesic drugs, e.g. opioids, amantadine, tramadol, gabapentin in these animals. If NSAID therapy is initiated, monitor animals carefully for signs of GI complications and warn owners about risks and inform them of the clinical signs associated with GI-related complications.
2. Renal disease. Reduced renal function is not necessarily a contra-indication to NSAID administration in dogs because renal side effects predominantly occur during periods of reduced renal blood flow. The progression of renal disease must be monitored carefully and frequently and owners must be warned about the risks associated with NSAIDs and renal function. It is imperative that owners stop NSAID administration if their dog stops eating or drinking, becomes dehydrated or develops GI disease. Water must be freely available to dogs during the day to allow regulation of adequate water intake.
3. Liver disease. Dogs with reduced liver function may have altered pharmacokinetics of some NSAIDs, depending on the metabolic pathway of each individual drug. Reduced liver function is most likely to cause a reduced rate of NSAID metabolism, risk of drug accumulation and therefore side effects. It is possible to reduce the dose or frequency of NSAID dosing in animals with liver dysfunction, although this can only be done empirically and the dose must be sufficient to provide analgesia.
4. Cardiac disease. There is the potential for NSAIDs to exacerbate volume overload, pre-existing hypertension and the risk of thrombo-embolic disease, although these risks have not been quantified. Consider these risks in animals with cardiac disease and, if NSAIDs are administered, monitor this patient group carefully, including regular blood pressure measurement. The risk of reduced renal blood flow is greater in animals receiving diuretics or ACE inhibitors, therefore owners must be warned about maintenance of adequate water intake.
5. Hypoproteinaemia. Most NSAIDs are highly protein bound, therefore severe hypoproteinaemia has the potential to increase the free fraction of any given NSAID dose, elevating the risk of side effects.

Conclusions

A full review of pharmacological therapy for chronic pain is beyond the scope of this article, hence the focus on NSAID therapy, the only licensed class of analgesic drug for the management of chronic pain in dogs. Some review articles about pharmacotherapy are listed below. Decision making about NSAID administration to individual animals should always be carried out as a risk:benefit analysis and the owner should be fully informed about potential side effects. Monitoring of animals receiving NSAID therapy should also be tailored to the risk of side effects in individual patients and this will be covered in article three.

References and further reading

Lascelles, B. D., Blikslager, A. T., Fox, S. M. and Reece, D. (2005) Gastrointestinal tract perforation in dogs treated with a selective cyclooxygenase-2 inhibitor: 29 cases (2002-2003). J Am Vet Med Assoc
227: 1,112-1,117. Grubb, T. (2010) Where do we go from here? Future treatment strategies for chronic pain. Top Companion Anim Med 25: 59-63.
Grubb, T. (2010) Chronic neuropathic pain in veterinary patients. Top Companion Anim Med 25: 45-52. Looney, A. (2010) Oncology pain in veterinary patients. Top Companion Anim Med 25: 32-44. Sawaya, S. (2007) Physical and alternative therapies in the management of arthritic patients. Veterinary Focus 17: 37-42.