continuing education Nonsteroidal antiinflammatory drugs in dogs and cats what s new? Isabelle Iff Dr.med.vet. DipECVAA CertVetAc (IVAS) Veterinary Anaesthesia Services Zürcherstrasse 39 CH 8400 Winterthur Switzerland abstract Recently, several new nonsteroidal antiinflammatory (NSAID) drugs have come on the market. The mechanism of action of NSAIDs in influencing the function of cyclooxygenase (COX) enzymes and, therefore, the production of prostaglandins responsible for homeostasis as well as the inflammatory process is reviewed in this article. Side effects mainly on the renal and gastrointestinal (GI) systems are reviewed. Amongst the older established NSAIDs, carprofen, meloxicam and firocoxib seem to be of comparable efficacy and better than some of the very old NSAIDs like ketoprofen and flunixin. Three of the drugs of the coxibs which have come on the market recently (Cimicoxib, Mavacoxib, Robenacoxib) have different pharmacological characteristics resulting in a potential benefit through ease of use and possibly better adverse effect profile. Naturally, they have not been evaluated in as many scientific studies as the older products and therefore comparison is as yet still difficult. Paracetamol, which often is not classed as a typical NSAID anymore, has actions on systems other than prostaglandin production and might be a multimodal analgesic for dogs in itself. Pharmacology of NSaIDS NSAIDs reduce the production of prostaglandins (PGs) by inhibition of the enzyme cyclooxygenase (COX). Currently, two isoforms of cyclooxygenase have been identified. The discovery of a third isoform was dicussed a couple of years ago, but this cyclooxygenase3 is now classified as a splicevariant of COX1, which may have a role in the central control of pain. There are important differences between COX1 and COX2. While COX1 produces a wide range of prostaglandins and thromboxanes, COX2 only produces PGE2 and prostacycline, both important mediators in the inflammatory process. Many physiologic pathways, including vascular homeostasis, gastroprotection, renal development and blood flow, blood clotting, reproduction, bone metabolism, wound healing, nerve development and growth, and immune responses are regulated by prostaglandins mainly produced by COX1. COX1 and COX2 are expressed in several tissues to maintain physiologic functions (constitutively expressed), but also present in higher concentrations at the time of inflammation (induced). COX1 is mainly constitutive and COX2 is primarily induced during inflammation, but also with certain cancer forms like cell carcinomas, squamous cell carcinomas, mammary carcinomas and pancreatic carcinomas. COX selectivity may be beneficial in terms of side effect, where it would be preferable to block COX2 more than COX1. However, it is important to realise that there is no such thing as a good (COX1) and a bad (COX2) COX. Cyclooxygenase specificity is very much species dependent. A common measure to assess COX specificity is the half inhibitory concentration (IC 50 ) IC 50 COX1: IC 50 COX2 ratio in the whole blood assay. The half inhibitory concentration is a measure for how much drug is needed to inhibit each of the COX enzymes. For example, for the newer NSAID robenacoxib the IC 50 COX1: IC 50 COX2 of the whole blood assay is about 1:140 for the dog and 1:500 in the cat, demonstrating a clear speciesspecific difference. The agents available are often grouped according to COX selectivity, (COX1 sparing, COX2 specific/selective, COX2 preferential and coxib), but it is important to note that this classification remains without a generally agreed definition. The actual numeric value of the COX ratio depends on the method and the assay used. Comparison between different drugs remains difficult as often the actual numbers are derived from different test situations. To treat acute pain a number of NSAIDs are licensed in cats and dogs. As the wealth of drugs can get quite confusing an attempt was made to summarise licensed drugs available in Ireland in Table 1. Commonly NSAIDs are administered subcutaneously (some may also be administered intravenously) and a number of them are licensed for perioperative use although most companies will caution that in hypotensive animals (as for example during anaesthesia) as there is an increased risk of side effects. The remainder of this article will mainly focus on the chronic use of these drugs, for example to treat osteoarthritis. For the treatment of chronic (musculoskeletal) pain, several NSAID are licensed for longterm use in dogs, but only one in cats at the time of writing. There may be interindividual differences in response to any particular NSAID and in clinical studies insufficient response has been reported in up to 10% for one particular drug. As some of these unsatisfactory 506
DOGS name DOSE/KG route FrEqUEnCy length OF TiME OThEr COMMEnTS injectable PEriOPErATiVE injection FOllOWED By carprofen 4 mg/kg iv/sc SiD 5 days yes yes up to 5 days ketoprofen 2 mg/kg iv/im/sc SiD up to 3 days yes up to 5 days (total) meloxicam 0.2 mg/kg SC once yes yes metamizole 50 mg/kg iv/im once combination with butylscopolamine robenacoxib 2 mg/kg SC once yes tolfenamic acid 4 mg/kg im/sc q 48 h two injections yes yes up to 3 days carprofen 2 mg/kg PO BiD or 4 mg/kg SiD use lowest cimicoxib 2 mg/kg PO SiD chronic use yes firocoxib 5 mg/kg PO SiD 90 days ketoprofen 0.25 mg/kg PO SiD 30 days acute use 1 mg/ kg up to 5 days mavacoxib 2 mg/kg PO once monthly 6.5 months meloxicam 0.1 mg/kg PO SiD chronic use use lowest paracetamol 15 mg/kg PO TiD 5 days robenacoxib 1 mg/kg PO SiD chronic use tepoxalin 10 mg/kg PO SiD dual inhibitor tolfenamic acid 4 mg/kg PO SiD 3 days 3 days on, 4 days off CATS name DOSE/KG route FrEqUEnCy length OF TiME OThEr COMMEnTS injectable PEriOPErATiVE carprofen 4 mg/kg SC, iv once yes no injection FOllOWED By ketoprofen 2 mg/kg SC SiD up to 3 days yes up to 5 days meloxicam 0.2 0.3 mg/kg SC once yes yes up to 4 days robenacoxib 2 mg/kg SC once yes tolfenamic acid 4 mg/kg SC SiD 2 days preferably not yes up to 3 days ketoprofen 1 mg/kg PO SiD up to 5 days meloxicam 0.05 mg/kg PO SiD chronic use use lowest robenacoxib 1 mg/kg PO SiD up to 6 days tolfenamic acid 4 mg/kg PO SiD up to 3 days licensed and available in UK/Europe CoNTINUING EDUCATIoN 507
CoNTINUING EDUCATIoN responses may be an individual treatment response, switching NSAID is warranted in most cases as a firstline approach. An unblinded canine study has shown that switching NSAID resulted in improved clinical signs in a proportion of animals, even though in these severely affected animals complete resolution was not achieved. Many authors anecdotally report the necessity of a washout period (commonly 48 hours). In cats, a washout period of sevento10 days has been recommended when switching from aspirin to another NSAID and threetofive days when switching between NSAIDs of the newer generation. However, this is controversial and other than for aspirin there is currently no scientific evidence to support a wash out period. Most companies recommend a washout period of at least 24 hours or as long as pharmacology of the previous agent dictates. The main clinical side effects observed are related to the gastrointestinal (GI) and renal systems in acute and chronic use of NSAIDs. The most commonly adverse effects are observed on the GI tract and affect between 07% of treated animals in the clinical setting. Prostaglandin E, which is produced by COX1 is important in maintaining gastric mucosal blood flow, is important for repair of mucosal cells and the release of bicarbonate neutralising gastric acid. COX1 is therefore important for the integrity of the gastric mucosal cell and mucus layer. Recent studies have shown that COX2 has a role in GI function, mainly related to gastric and duodenal ulceration healing. At the level of renal physiology, both COX1 and COX2 and their respective prostanoid products maintain renal blood flow as well as ion transport. This is especially important in old patients suffering from other disease, dehydrated or hypovolaemic animals and animals under therapy with drugs influencing the renal system. Longterm NSAID use is common in older and geriatric patients, as this population commonly suffers from chronic locomotor disease and illness leading to chronic pain. This patient group may be more prone to side effects due to reduced drug metabolism and excretion, lower levels of plasma proteins and changes in the volume of distribution. Generally, NSAIDs should not be administered to hypovolaemic, dehydrated or hypotensive animals and the use in pets with cardiac, renal, hepatic, GI and haemostatic dysfunction should be carefully considered. Animals on longterm medication should undergo regular veterinary examinations. For dogs no clear guidelines about the frequency and nature (clinical examinations and/ or blood test) of these have been established. Generally, the approach seems to vary between geographical locations. Suggestions for dogs are reevaluation and reexamination every threetosix months. A paper published recently established guidelines for the use of NSAIDs in cats based on the opinion of an expert panel (Sparkes et al. 2010). The suggestions for longterm use are thorough history and clinical examination Old dogs commonly suffer from chronic pain and require treatment with nsaids. before the NSAID is started. Specific blood values (PCV, renal and hepatic biochemistry parameters) and urine parameters should be monitored before the start of NSAID and on regular basis, if possible. Actual time intervals for screening in cats suggested, are an initial reassessment after fivetoseven days, twotofour weeks and thereafter every six months for lower risk patients and every twotosix months for higher risk patients. update on older NsAids Several recent reviews contain updates on new and old NSAIDs, as well as dual COX and LOX inhibitors in cats and dogs. Recently a systematic review (Sanderson et al, 2009) looking at efficacy of NSAID to treat osteoarthritis in dogs has shown strong evidence for efficacy for long term pain treatment for carprofen, firocoxib and meloxicam. Celecoxib, deracoxib, etodolac, ketoprofen, and lowdose prednisolone were less efficient. The use of carprofen was supported by the largest number of studies followed by meloxicam and firocoxib. Most of the newer NSAIDs are compared to either one of these three agents to show efficacy. the New AgeNts There are several new agents on the market and the aim is to give a brief overview on their use; for details please refer to the data sheets. As most of these are relatively new molecules the body of clinical evidence at this time is smaller than for some of the older agents. The three agents discussed in alphabetical order are all of the class of the coxibs, which have a higher efficacy in blocking COX2 in vitro than COX1. It is important to note that reporting of adverse events for drug licensing has changed to a more standardised manner and this has been used to describe the side effects in these new agents. The 508
following terms are now commonly used in relation to the incidence of adverse events: Very common (incidence 1: 10), common (< 1:10 but 1: 100), uncommon(< 1: 100, but 1: 1000), rare (< 1: 1000, but 1: 10 000) and very rare (< 1: 10 000). cimicoxib (cimalgex) Cimicoxib has very recently been launched in mainland Europe for use in dogs only. At the time of writing this review, clinical scientific data have not been published in the veterinary literature and only data provided by the company are available. It is available as an oral preparation licensed for dogs with once daily administration. Clinically it is licensed for the control of postoperative pain and the use of chronic musculoskeletal disorders. It has been used chronically up to 90 days with an efficacy similar to firocoxib. It is mainly eliminated via the bilary system. Mild GI signs have been reported as common (0.11%) in the clinical setting. Changes in renal biochemistry values have been reported as very rare. The side effects observed have not been different from treatment with firocoxib. It has been studied in dogs with a reduced glomerular filtration rate. The pharmacokinetic profile of the drug remains unchanged in this population and the renal biochemistry parameters remained stable. Safety has not been established in dogs less than 10 weeks of age. MAVAcoxiB (trocoxil) Mavacoxib, a long acting coxib, is only licensed for dogs. Mavacoxib is available as chewable tablets and has a very slow clearance. Bioavailability is enhanced when given with food. It exhibits an extended plasma half life due to its low rate of elimination and has a duration of effect of one month after reaching steady state conditions (after second dose). In about 5% of dogs prolonged clearance (80 days) is observed and therefore the recommended treatment period is 6.5 months. As mavacoxib is excreted via the bile it should not be give to dogs with hepatic disorders. Clinically mavacoxib is comparable with carprofen in the treatment of osteoarthritis in dogs (6.5 months treatment). Clinically mild GI signs have been reported as common and changes in renal biochemistry values as uncommon. The adverse events are similar to the ones observed with daily administration of carprofen. According to the manufacturer, gastrointestinal side effects (treated symptomatically) do not last longer than with daily administration of NSAIDs. Safety has not been established in dogs less than one year old or under 5kg bodyweight. robenacoxib (onsior) Robenacoxib is licensed for dogs and cats. The flavoured tables have been shown to be very palatable in dogs and especially so in cats. Robenacoxib has an elimination half life of only two hours, but persists in inflamed tissue. This has been termed tissue selective and makes oncedaily Adequate pain relief in cats is very important and nsaids are an important management strategy for feline pain. dosing sufficient despite rapidly falling plasma levels. This has been discussed as one of the reasons for a low incidence of side effects with maintained treatment effect. It has been licensed for acute pain in cats and dogs and chronic use in dogs. The tablets were studied over six days in cats with acute musculoskeletal disorders, for six weeks in toxicity studies in cats and for up to one year in aged dogs with osteoarthritis. It is licensed for up six days in cats and infinitive use in dogs. In dogs the tablets should be administered without food to improve bioavailability; in cats they can be given with a small amount of food. The clinical efficacy and the side effect profile were comparable to chronically administered carprofen. The main side effects reported were gastrointestinal side effects occurring very commonly to commonly depending on the actual symptom. In dogs an increase in liver enzymes during longterm treatment was common, and it has been recommended to monitor these in such cases. The safety of robenacoxib has not been established in dogs under three months of age or weighing less than 2.5kg. paracetamol Paracetamol is often no longer classified as an NSAID. Besides the eicosanoid (prostaglandins) system, paracetamol influences the opioidenergic, serotoninergic and possibly the cannabinoid systems in the preclinical setting. Pharmacokinetic data are available for several species and its efficacy has been evaluated in acute pain and inflammation in dogs. Paracetamol is the first treatment of choice for osteoarthritis in people. Paracetamol is licensed in combination with codeine for dogs in the UK for five days. Paracetamol has anecdotally been reported to have a good safety profile and has clinically been used as an analgesic in dogs receiving steroids. However, scientific data regarding its chronic use is literally nonexistent. The cat has poor ability to metabolise paracetamol and it should not be administered to cats. CoNTINUING EDUCATIoN 509
CoNTINUING EDUCATIoN AckNowledgeMeNt The author would like to acknowledge the contribution of M. Mosing, Zürich Switzerland for the helpful correction of the manuscript. further reading An update on nonsteroidal antiinflammatory drugs (NSAIDs) in small animals. Papich MG. Vet Clin North Am Small Anim Pract 2008; 38(6): 124366. Use of nonsteroidal antiinflammatory drugs for the treatment of canine osteoarthritis. Innes J, O Neill T, Lascelles D. In Practice 2010; 32: 126137 Review of the safety and efficacy of longterm NSAID use in the treatment of canine osteoarthritis. Innes JF, Clayton J, Lascelles BD. Vet Rec 2010; 166(8): 226 230. Systematic review of the management of canine osteoarthritis. Sanderson RO, Beata C, Flipo RM, Genevois JP, Macias C, Tacke S, Vezzoni A, Innes JF. Vet Rec 2009; 164(14): 418424. Systematic review of clinical trials of treatments for osteoarthritis in dogs. Aragon CL, Hofmeister EH, Budsberg SC. J Am Vet Med Assoc 2007; 230(4): 514 521. ISFM and AAFP consensus guidelines: long term use of NSAIDs in cats. Sparkes AH, Heiene R, Lascelles BD, Malik R, Sampietro LR, Robertson S, Scherk M, Taylor P; ISFM and AAFP. J Feline Med Surg 2010; 12(7): 521538. Long term pain in cats: how much do we know about this important welfare issue? Roberstons SA, Lascelles BD. J Feline Med Surg 2010; 12(3): 188199. Amantadine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs. Lascelles BD, Gaynor JS, Smith ES, Roe SC, Marcellin Little DJ, Davidson G, Boland E, Carr J. J Vet Intern Med 2008; 22(1): 5359. Potential analgesic mechanisms of acetaminophen. Smith HS. Pain Physician 2009; 12(1): 26980. continuing education: reader Questions and answers AD b) COX2 has absolutely no function in the GI tract. Which of the following statement regarding cyclooxygenase (cox) is true? a) cox1 is the good enzyme responsible for homeostasis, cox2 is the bad enzyme responsible for inflammation. c) cox1 and cox2 are both constitutively expressed in the kidney and are responsible for renal homeostasis. d) COX 3 only exists in cats. Which of the following new nsaids is more effective in treating chronic pain than carprofen, firocoxib or meloxicam? a) robenacoxib b) mavacoxib c) none d) cimicoxib e) all false regarding mavacoxib? a) Undergoes bilary excretion. b) has the same pharmacokinetic halflife in every animal. c) Is available as an oral preparation. d) Should not be given to dogs with hypovolaemia. false regarding cimicoxib? a) It is licensed in cats. b) Is a coxib with oncedaily administration. c) has stable pharmacokinetics in renally impaired dogs. d) Is only available in the oral form. regarding the mechanisms of action of paracetamol Which receptors have not been shown to be involved? true regarding robenacoxib? a) Is licensed for long term use in cats. b) Is only available as an oral preparation. c) monitoring liver enzymes is recommended for long term use in dogs. d) shows better oral bioavailability when given with food in dogs. a) opioid receptors b) gaba receptors c) serotonin receptors d) canabinoid receptors answers: c, c, c, d, a, b 510