Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely to relieve pain, with or without

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1 May 2013 Contents About NSAIDs What about COXselectivity? How effective are NSAIDs? Adverse effects of NSAIDs How frequent are the adverse effects of NSAIDs? General prescribing guidelines for NSAIDs What to tell the client Conclusion Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely to relieve pain, with or without inflammation, in dogs with acute and chronic musculoskeletal problems. In the UK, ten NSAIDs (in over 30 different brands) are available for use in dogs with acute or chronic musculoskeletal pain. They are carprofen, cinchophen (in combination with prednisolone), cimicoxib, firocoxib, ketoprofen, mavacoxib, meloxicam, phenylbutazone, robenacoxib and tolfenamic acid. Most are available as tablets or oral suspension; a few are available as injections and one as an oral spray. Subscribe to Veterinary Prescriber

2 About NSAIDs All NSAIDs inhibit the enzyme cyclo-oxygenase (COX). Cells use COX in the synthesis of prostaglandins, some of which have physiological functions and some of which are synthesised in conditions where they contribute to pain and inflammation. After absorption, NSAIDs circulate bound to plasma proteins. Most NSAIDs are metabolised in the liver, and the metabolites are excreted in varying proportions in the urine, bile and faeces. What about COX-selectivity? COX exists in at least two isoforms: COX-1 and COX-2. COX-1 is generally considered to be the enzyme associated with normal body functions (e.g. involved in producing prostaglandins in the gastrointestinal tract and the kidneys), while COX-2 is induced in the presence of inflammation. Consequently, the analgesic and anti-inflammatory actions of NSAIDs are believed to depend mainly on their inhibition of COX-2, and the well-known unwanted gastrointestinal effects of NSAIDs on their inhibition of COX-1. It follows, in theory, that a drug that inhibits COX-2 at a lower concentration than is needed to inhibit COX-1 might be safer, and NSAIDs that are more selective for COX-2 have been developed with the aim of minimising gastrointestinal toxicity. However, the concept of COX-1 as good and COX-2 as bad is an oversimplification. 1 Also, COX-selectivity information on specific NSAIDs has limitations: selectivity can depend on the dose of the drug and the animal species, and different methods for testing and calculating selectivity can give inconsistent values for any given NSAID. 2 Evidence on the relative efficacy and safety of NSAIDs therefore needs to come from clinical trials. 1. Innes J et al. Use of nonsteroidal anti-inflammatory drugs for the treatment of canine osteoarthritis. In Practice 2010; 32: KuKanich et al. Clinical pharmacology of nonsteroidal anti-inflammatory drugs in dogs. Vet Anaesth Analg 2012; 39:

3 How effective are NSAIDs? The authors of a systematic review aimed to assess the efficacy of long-term NSAID therapy (at least 28 days) in dogs. 3 They included 15 published trials (8 randomised controlled trials and 7 non-randomised controlled trials; involving a total of 1,595 dogs) but were unable to estimate the efficacy of long-term NSAID therapy, because of a lack of data. However, in one short-term trial (lasting 14 days) it was possible to calculate that 5 dogs (95% confidence interval 2 7) would need to be treated with carprofen (the number needed to treat [NNT]*) instead of placebo to see a positive response on force-plate evaluation in one dog. It is widely believed that there are inter-individual differences in how dogs respond to NSAIDs and it may be worth trying a different NSAID if one is not effective. *Numbers needed to treat (NNTs) (the inverse of the absolute risk difference) are considered to offer a clinically useful measure of the relative benefit of an active treatment over a control. In human medicine, NNTs for effective treatments are usually expected to be in the range of Innes JF et al. Review of the safety and efficacy of long-term NSAID use in the treatment of canine osteoarthritis. Vet Record 2010; 20: Aragon CL et al. Systematic review of clinical trials of treatments for osteoarthritis in dogs. JAVMA 2007; 230: Sanderson RO et al. Systematic review of the management of canine osteoarthritis. Vet Rec 2009; 164: It is unclear from published trials whether any one NSAID is more effective than any other in relieving pain. 3 5 Carprofen, firoxocib and meloxicam are the NSAIDs for which there is the most high-quality published evidence on their use in the treatment of osteoarthritis in dogs. 3 5

4 Adverse effects of NSAIDs Prostaglandins have a physiological role in protecting the gastric mucosa and they also play a significant role in maintaining renal function. Inhibition of prostaglandin synthesis by NSAIDs can therefore result in adverse gastrointestinal and renal effects. The summaries of product characteristics (SPCs) for NSAIDs contraindicate use of the drugs in animals with pre-existing gastrointestinal damage (such as those with ulceration) and in animals with haemorrhagic disorders or blood dyscrasias. The SPCs for most NSAIDs also contraindicate their use in animals with impaired cardiac, hepatic or renal function; in contrast, the SPCs for cimicoxib and firocoxib advise that there may be additional risk in animals with suspected or confirmed cardiac, hepatic or renal function and recommend careful monitoring if used. The authors of a recent systematic review set out to learn more about the adverse effects of NSAIDs in dogs. 6 They searched for all prospective trials in English that assessed the safety of acute or chronic administration of NSAIDs in dogs and found 64 studies, evaluating 14 different NSAIDS (in a total of 3,456 dogs). The strength of evidence was highly variable for the different drugs. For carprofen, firocoxib and meloxicam, there was a high strength of evidence (defined as relevant studies of high quality, including sufficient animals and giving results relevant to the target population); for ketoprofen and robenacoxib, there was a moderate level of evidence (relevant studies of high-to-moderate quality, including sufficient animals and giving results that could be extrapolated to the target population with some confidence); and for rofecoxib and tolfenamic acid, there was an extremely low level of evidence (few high quality studies involving few animals). 6. Monteiro-Steagall BP et al. Systematic review of nonsteroidal antiinflammatory drug-induced adverse effects in dogs. J Vet Intern Med 2013; 27:

5 How frequent are the adverse effects of NSAIDs? The most common outwardly detectable effects reported The review s authors also looked at the trial results on in the clinical trials in the systematic review were: vomiting, diarrhoea, anorexia, lethargy and melaena. 6 Also re- liver enzyme activity during or after long-term (at least 28 pathology monitoring. There were no significant changes in ported were: faecal blood, bleeding, colitis, abdominal pain, days) administration of NSAIDs. There were no differences aggressiveness or behaviour change, hypersalivation, polydipsia, polyuria, adipsia, constipation, icterus, skin reactions ous NSAIDs or between treated and control groups. Renal in the incidence of renal adverse effects between the vari- and weight loss. Out of all the studies, two gastrointestinal function tests failed to detect renal adverse effects in dogs perforations were recorded: one in a dog that accidentally undergoing general anaesthesia and submitted to hypovolaemic and/or hypotensive stress. Outwardly detectable received a double dose of firocoxib; the other in a dog that received an NSAID concurrently with a topical corticosteroid. When NSAIDs were compared with placebo effects were seen in 4 studies and included polyuria, poly- adverse effects that could have been attributable to renal (in a subgroup of 25 randomised blinded trials), there was dipsia and adipsia although it cannot be certain that these a statistically significant difference between NSAID and were due to NSAID use. They comment that adverse effects placebo groups (in 5 out of the 25 trials) for the following on the liver associated with NSAID use appear more likely objective outcome measures: scores for gastrointestinal to be idiosyncratic, in contrast to kidney injury and gastrointestinal effects, which can be dose-dependent. lesions (which were higher with NSAIDs), and platelet aggregation, food consumption and body weight (which were A problem with this evidence is that most of the trials all reduced compared with placebo). (55%) were in research dogs, which are usually young and free of naturally-occurring disease; only 45% of the studies It was not possible from the data provided in the trials to were clinical (i.e. involved dogs likely to be representative of estimate the true incidence of any of the adverse effects in dogs treated in practice). The results therefore have limited dogs. relevance to the use of NSAIDs in practice. 6. Monteiro-Steagall BP et al. Systematic review of nonsteroidal antiinflammatory drug-induced adverse effects in dogs. J Vet Intern Med 2013; 27:

6 General prescribing guidelines for NSAIDs The potential benefits of treatment with an NSAID must be weighed against the risks. An NSAID should be used in the lowest effective dose, without prescribing more than the maximum recommended dose. Most NSAIDs are recommended for once daily administration daily; some are given twice daily, or on alternate days (check the product SPC for dosage and administration information). An exception is mavacoxib, which, because of its long half life (around days) is given once a month. If one NSAID is ineffective, a different one may be considered; it is logical for a vet to acquire experience with a few from the many NSAIDs available. The risk of renal adverse effects might be increased if NSAIDs are used concurrently with other drugs that affect renal function (e.g. aminoglycosides, diuretics). Renal function should be monitored in dogs with pre-existing renal disease. Some products SPCs advise against use in dogs with renal dysfunction. Using a high dose of NSAID, or using an NSAID concurrently with a corticosteroid, or using two NSAIDs together appear more likely to cause adverse gastrointestinal effects. 2 The risk of adverse effects can be reduced by checking the animal s record for co-existing disease (e.g. renal dysfunction) and current drug treatments (particularly corticosteroids) before prescribing. 7. Lascelles BD et al. Gastrointestinal tract perforation in dogs treated with a selective cyclooxygenase-2 inhibitor: 29 cases ( ). Vet Med Assoc 2005; 227: KuKanich et al. Clinical pharmacology of nonsteroidal anti-inflammatory drugs in dogs. Vet Anaesth Analg 2012; 39: When switching a patient from one NSAID to another (when no adverse effects have been seen), some guidelines recommend a washout period of 5 to 7 days to reduce the likelihood of drug interactions. 2 ) However, there seems to be no rational basis for this and for most NSAIDs the replacement NSAID could be started 24 hours after stopping the previous one. An exception is mavacoxib (which has a very long half life) for which the SPC recommends waiting 1 month before starting another NSAID. Clinical signs that suggest ulceration include depression, anorexia, reduced appetite, vomiting, diarrhoea and hematochezia or melaena. But ulceration can occur without overt clinical signs and, conversely, symptoms such as vomiting, anorexia and diarrhoea can occur independently of gastrointestinal damage or ulceration. 2

7 What to tell the client Informing clients of the potential adverse effects of NSAID therapy and signs of toxicity is likely to promote safer use of this class of drugs. Typical adverse effects of NSAIDs such as loss of appetite, vomiting, diarrhoea, faecal occult blood and apathy generally occur within the first 2 weeks of therapy to ensure the dog has easy access to plenty of water at all times; and are in most cases transient and disappear after stopping the treatment. Advise on the need for re-examination and/or regular laboratory tests where appropriate. Clients should be also advised: not to increase the dose if the dog seems to be in greater pain (e.g. after a long walk); to stop administering the drug and contact the vet if the dog becomes unwell (e.g. with vomiting or diarrhoea); to know the dosage frequency; not to give human NSAIDs to dogs; to keep the medicine out of the reach of animals; flavoured tablets if found and eaten in bulk by the animal could lead to toxicity.

8 Conclusion Overall, published clinical trial evidence does not show any one NSAID to be more effective or safer than any other in the management of musculoskeletal problems. Carprofen, firoxocib and meloxicam are the NSAIDs with the best published evidence on efficacy and safety (i.e. the ones about which there can be greater certainty of their effects). The safety of NSAIDs has been poorly studied and the true incidence of adverse effects from NSAIDs in dogs is not known. Contact Veterinary Prescriber to give feedback on this article or get involved as a writer, commentator or editorial consultant. Use the mail link below to get in touch. Subscribe to Veterinary Prescriber Veterinary Prescriber is an essential resource for veterinary professionals who want impartial, evaluated and practical information on veterinary medicines. The succinct articles are clearly referenced, make a distinction between evidence and opinion, and are easy to read on computer, tablet or smartphone. The practical what to say to clients advice in the articles, and unique product guides, help you to give better advice to clients. We aim to make the information easy-to-read and convenient. Use the contents list on the first page to get to the parts of the article you want to read; use the forward and back arrows to move from page to page; and click the Veterinary Prescriber logo in the top left hand corner to get back to the first page. We d like to hear from you Click the Veterinary Prescriber logo below to go to the website and fill in the contact form: to find out about how to subscribe to Veterinary Prescriber, to send us feedback on the articles and/ or the website, to suggest topics for articles, or to tell us if you would like to write or comment on articles. And don t forget to follow on Facebook and Twitter for the latest updates in independent veterinary medicines information. copyright 2013 Mixolydian Publications ltd. All rights reserved.