RATIONAL USE and AVOIDANCE OF ABUSE of NSAIDs – Georgina Child BVSc DACVIM (Neurology)

Non steriodal anti-inflammatory drugs or Unfortunately complaints by the public to analgesics (NSAIDs or NSAIAs) are used the Veterinary Practitioners Board frequently extensively in both human and veterinary include those regarding the treatment of pet medicine and can be very effective in animals that have had an adverse outcome, managing both acute and chronic pain including death, where NSAIDs have been in animals. However, adverse effects of administered in the course of treatment. these drugs can be life threatening and due Recurring themes in the case histories diligence by the prescribing veterinarian in of these animals are one or more of the patient selection, drug and dose selection following: a diagnosis as to the cause of and monitoring is always indicated. Advice the animal’s illness had not been made but to the owners of treated animals regarding NSAIDs given as the animal was possibly potential adverse effects and the clinical painful (clients understand and empathise signs that should prompt reassessment and with “pain relief”); a dose significantly discontinuing drug use should always be above the recommended dose of the NSAID given. was given on one or more occasions (“more is better” or “if some didn’t work more It is thought dogs and cats are more susceptible might”); NSAIDs and corticosteroids were to the adverse effects of NSAIDs than people given concurrently or within a short period of and there are species differences (humans, time (close temporal association); treatment dogs, cats, horses and ruminants) both with different NSAIDs (“switching drugs”) in the apparent effectiveness of different was given within a short period of time NSAIDs and in the adverse effects seen. and that change may have been prompted The greater range of NSAIDs available and by either lack of effect or gastrointestinal the greater tendency to prescribe these drugs signs associated with first drug; affected has the potential to increase the number patients were often old with significant risk of adverse effects reported. The increased factors (either known or not appropriately prescription rate especially in small animals investigated) that would influence drug use is multifactorial: an increased awareness or dose. and demand to treat both acute and chronic pain in animals both by veterinarians and NSAIDs have analgesic, anti-inflammatory their owners; the increased life expectancy and antipyretic actions by inhibiting of pets with associated increased incidence the production of prostaglandins (and of chronic conditions such as osteoarthritis; leukotrienes) primarily by inhibiting the and the formulation and promotion of new action of cyclo-oxygenase (COX) enzymes. NSAIDs by pharmaceutical companies. Two distinct COX isoforms (COX1 and COX2) have been identified and both NSAIDs collectively are among the most are responsible for the production of frequently prescribed medications in small prostaglandins (PGs), prostacyclin and animal practice. The availability of multiple thromoboxanes from arachidonic acid (AA) NSAIDs has also increased the likelihood that in phospholipid cell membranes. A third patients receive multiple drugs concurrently form COX3 may have a role in the CNS or in a short period of time. control of pain. COX1 converts AA to a

Boardtalk May 2013 - Insert 1 - 1 - wide variety of prostaglandins, thromboxane or selective drugs developed to reduce and prostacyclin. COX2 activity produces some of these side effects still cause a narrower spectrum of prostaglandins adverse events in people including renal specifically PGE2 and prostacyclin. failure, thromboembolic disease and Prostaglandins are important physiologically gastric ulceration. This is also true in small in vascular homeostasis, gastroprotection animals. (gastric mucosal protection from gastric acid damage), renal development and The primary indication for NSAIDs in blood flow, blood clotting, reproduction, veterinary medicine is in the management bone metabolism, wound healing and of pain. The efficacy of many NSAIDs immune responses. PGs are also involved can be better than or equal to mu agonist in pathophysiologic processes including pain opiods (such as morphine) and butorphanol and inflammation and cancer progression or buprenophine in managing postoperative and it is these processes that are targeted by pain – both orthopaedic and soft tissue. NSAIDs however “side effects” are the result NSAIDs appear to act synergistically with of interference with the important normal opioids and may allow a reduction in the physiologic mechanisms mediated by PGs. amount of opioid analgesia required in managing mild to moderate but not severe COX1 has long been considered to be most pain states (Mathews 2010). The duration involved in physiologic functions including (24 hours or longer) and efficacy makes the cytoprotective effects on gastric mucosa, them ideal for treating acute and chronic normal platelet function and maintenance pain - predominantly post operative pain and of renal perfusion. COX 2 also appears to pain associated with osteoarthritis. NSAIDs contribute to some extent to homeostasis are metabolised in the liver and excreted especially in healing damaged GIT mucosa predominantly by the kidneys in urine (some but COX2 is predominantly inducible and enterohepatic circulation with some drugs). production is significantly increased during inflammation. COX1 expression however NSAIDs were first licensed in the also has a role in the inflammatory response. treatment of osteoarthritis (OA) in dogs and cats. NSAIDs are also approved for NSAIDs may inhibit COX1 and COX2 (eg the treatment of postoperative pain (mild aspirin, phenylbutazone, flunixin, tolfenamic to moderate) with effectiveness best in acid, ketaprofen) or have a greater propensity orthopaedic and selected soft tissue surgeries, to suppress COX2 than COX1 – so called especially those associated with significant COX2 preferential or sparing NSAIDs (eg soft tissue trauma or inflammation. The carprofen, meloxicam) or have negligible administration of NSAIDs prior to surgery effect on COX 1 ( the so called COX 2 so as to achieve adequate drug levels in the selective NSAIDs eg firocoxib, deracoxib immediate postoperative period remains robenocoxib mavacoxib). COX1 inhibitors controversial primarily as untoward may result in better pain relief in some events during surgery or immediately post species eg phenylbutazone in horses. operatively that may increase the risk of adverse drug effects, such as hypotension, COX1 inhibition has been implicated in cannot be predicted preoperatively. the cause of most NSAID side effects - An approach by some surgeons is to give especially gastric ulceration and platelet NSAID 30-45 mins prior to the end of dysfunction. However COX2 preferential surgery. If given post operatively another

- 2 - Boardtalk May 2013 - Insert 1 analgesic (opioid) may be given to provide review of the literature on NSAID drug use analgesia in the approx 45 min period to in dogs assessing the efficacy and safety of onset of action of the NSAID. In studies NSAIDs (Innes 2010) in the treatment of OA looking at adverse events associated with shows the balance of evidence supports long preoperative administration of NSAIDs term use for increased clinical effect and where intraoperative fluids were given and that long term use was not associated with patient monitoring conducted adverse events a reduction in safety. However “robust data did occur but were rare. Generally patients in on the safety of long term NSAID use was these studies were <10 years of age, in good not available in a large population of dogs”. health and undergoing elective procedures. No specific studies in geriatric dogs or those with compromised renal or hepatic function. Higher NSAID doses are recommended in the treatment of perioperative pain and the In small animals GIT and renal toxicity prescribed doses and the dosing interval are the most common adverse effects of and period of time that higher doses are NSAID use. prescribed for each drug varies from 1- 7 days. Parenteral administration of an NSAID is Both COX1 and COX2 are important recommended at a higher dose once only in maintaining renal function. PGs for the majority of drugs to be followed by normally act to increase blood flow during oral administration. The dose given should times of reduced renal perfusion. Any be tapered as pain reduces (usually within 1-3 haemodynamic compromise such as days). NSAIDs are absorbed rapidly orally dehydration; hypotension during anaesthesia and peak concentrations reached within 2-4 or haemorrhage during surgery; hypotension hours and NSAIDs should be given orally or haemodynamic instability as result of when animals are able to eat. trauma, cardiac disease or severe illness and preexisting renal disease all significantly For animals presented with painful increase the risk of ischaemic renal injury conditions such as minor soft tissue and renal failure in association with NSAID trauma, inflammation or musculoskeletal administration. This risk applies to use in pain the same recommendations are made. the short term treatment of acute pain A higher dose is advised once only and the (surgical or non surgical) and in the subsequent dose tapered depending on the longer term treatment of animals with drug used and given orally. chronic osteoarthritis especially those with concurrent disease (often cardiac Various NSAIDs are also approved for the or renal). Administration of diuretics or long term treatment of OA in dogs and some other nephrotoxic drugs may increase renal have been approved for long term use in cats toxicity of NSAIDs. (not in all countries). Recommendations are not to give above the approved dose for the Toxicity is increased in dogs and cats with particular drug and to give the lowest dose hepatic dysfunction largely due to reduced that is efficacious which may be significantly metabolism increasing the drug half life less than the recommended dose or at a and increasing drug concentration with longer dosing interval than recommended repeated dosing. Large NSAID overdosage for shorter term use - this applies especially also causes hepatotoxicity. Rare acute in cats. Guidelines on the long term use hepatotoxicity has been reported after of NSAIDs in cats are available. A recent NSAID administration at approved

Boardtalk May 2013 - Insert 1 - 3 - doses. In cats the potential for toxicity is 24 hours of deracoxib administration. In higher with NSAIDs due to limited ability all, 90% had either received a higher than to glucuronidate NSAIDs resulting in recommended dose and/or had received prolonged duration of the drug. For example, another NSAID or corticosteroid in close in cats carprofen has double the mean half temporal association. The first clinical signs life of that in dogs and the range is highly seen in dogs with GIT perforation were variable (9-49 hours). Daily dosing in cats vomiting and generalized pain. This study risks drug accumulation and the duration of specifically looked at dogs treated with efficacy is difficult to predict. It is approved deracoxib as information on affected dogs for use in cats once only for surgical pain. was obtained from the pharmacovigilance database of the drug company manufacturing Gastric mucosal and duodenal erosion this NSAID. The risks associated with has been reported with most NSAIDs in administration are likely not to be confined both research studies and clinical studies. to this particular COX2 selective NSAID. There may be some local gastric effects in Duodenal ulceration and perforation some animals with oral administration but has also been reported associated with the risk of adverse effects on the gastric meloxicam. and intestinal mucosa of NSAIDs is not reduced by parenteral administration. Caution is warranted with administration Stress (any cause) may increase risk of GIT of NSAIDs presurgically for oral ulceration. procedures including dentistry. COX1 inhibition reduces the formation of While COX2 preferential and selective thromboxane (important in platelet activation NSAIDs are promoted as causing less and vasoconstriction) and in combination GIT adverse effects than non selective with fibrinolytic activators in saliva and the NSAIDs all NSAIDS have the potential to oral cavity predisposes to haemorrhage. It cause GIT adverse effects. A recent case is recommended administration be delayed study (Lascelles 2005) reported 29 dogs until surgical haemorrhage is no longer a risk. with gastrointestinal perforation associated with administration of a selective COX2 Prolongation of bleeding times can occur inhibitor (deracoxib) in a 10 month period after administration of any NSAID but (2002-2003). Approximately half of the is more severe with those which bind cases were dogs being treated for chronic irreversibly to COX such as aspirin and pain associated with orthopaedic disease (all phenylbutazone as the effect persists for the but two for osteoarthritis). The remainder life of the platelet. NSAIDs should not be had been treated for acute perioperative pain given to animals with a known coagulopathy. associated with orthopaedic or soft tissue surgery. Twenty of the affected dogs died or Etodolac use has been associated with were euthanased due to gastric, pyloric or development of KCS (average duration of duodenal perforation. 55% of dogs reported administration 8-9 months). had been given the NSAID at a higher than Acute hypersensitivity may be seen rarely recommended dose and 59% had received with any NSAID and these drugs should another NSAID or a corticosteroid within not be used in animals if there is a previous history of an adverse event.

- 4 - Boardtalk May 2013 - Insert 1 Recommendations for use if neurologic deterioration occurs. Animals of NSAIDS with acute spinal cord injury (including IV disc extrusion) have a known increased risk 1. Appropriate Indication for use of GIT ulceration that may be independent The indications for use of NSAIDs are relief of any NSAID or corticosteroid use. of mild to moderate pain associated with Analgesics other than NSAIDs are indicated osteoarthritis and other musculoskeletal in animals where a most probable or definitive disease, soft tissue inflammation or injury and diagnosis has not been made. post operatively after orthopaedic and some soft tissue surgeries eg ovariohysterectomy. Analgesics other than NSAIDs are indicated NSAIDs may also be of benefit in the in animals with severe pain. treatment of pain associated with some cancers. 2. Patient selection NSAIDs should not be used in those For use in non surgical conditions it animals that are haemodynamically is important that a cause of pain be unstable (ie any cause of hypotension). established and NSAIDs determined to be This includes all major trauma cases (these the most appropriate drug indicated. Not animals may also have high levels of all animals that are unwell are painful. endogenous corticosteroids), brain trauma, NSAIDs should not be used as a generic acute haemorrhage of any origin, major “anti-inflammatory” or as an antipyretic surgical cases, animals that are dehydrated without a diagnosis as to the cause. NSAID or have evidence of systemic illness (eg use may compromise and delay treatment pancreatitis, sepsis, disseminated neoplasia, that is appropriate (including antibiotics, DIC). corticosteroids, exercise restriction or surgery). Diseases that are immune mediated Use in surgical patients (including for example polyarthritis, corticosteroid dentistry) generally should be restricted responsive meningitis, granulomatous to patients < 10 years of age that have meningoencephalomyelitis require treatment been in good health and are having with corticosteroids. Pyrexia may be seen in elective procedures (not emergency). For animals with infection, immune mediated treatment of non surgical pain the same disease and neoplasia and the underlying general criteria apply (<10 years of age cause should be treated rather than the fever. and in good health otherwise). NSAIDs should not be used in animals with NSAIDs should not be used in any animals acute renal insufficiency or hepatic disease, with any neurologic signs (cerebral, spinal suspected coagulopathy or cardiac failure or peripheral nerve) until a most probable (low “effective circulating volume”). or definitive diagnosis has been made as treatment with corticosteroids may be In older animals with chronic pain associated indicated or surgical treatment may be with osteoarthritis where NSAIDs are required. NSAIDs may be indicated in indicated doses should be reduced and/or animals with spinal pain without neurologic dosing intervals increased in animals with abnormalities where IV disc extrusion/ preexisting renal, hepatic, or cardiac disease. protrusion is the most likely cause but cage confinement/exercise restriction is more NSAIDs should not be used in animals important and use may compromise treatment with gastrointestinal disease or those that are inappetant. Boardtalk May 2013 - Insert 1 - 5 - Assessment of patients by CBC, biochemistry with a higher incidence of adverse side profile and urinalysis prior to administration effects. Higher doses should be given for the of NSAIDs is recommended in all surgical minimum time as clinically indicated and/or patients. Assessment should also be extended approved. to any non surgical patients treated for any length of time that are > 5 years of age, or at There is no indication for doses higher any age if there are any significant historical than approved doses. Use NSAIDs at or clinical findings (including variation in the doses and for a time period that does behaviour, exercise tolerance, water or food not exceed those labeled or referenced in intake, body condition, body temperature, veterinary texts for both the management of HR, respiratory disease etc). acute pain and in the treatment of chronic pain associate with OA. Approved doses NSAIDs should not be used in animals for various drugs are different and should with known or suspected cortisol excess be heeded. Most injectable NSAIDS are (hyperadrenocorticism, stress). labeled for use once. Repeated parenteral administration should not be given if For anaesthetised animals (for any reason) animals are inappetant. Most NSAIDs animals should be well hydrated and have should ideally be administered with food (to no condition that affects gut, renal or hepatic ensure animal is eating) however robenacoxib blood flow. Intravenous fluids should be is labeled to be given on an empty stomach administered to maintain adequate blood or with a small amount of food. All orally pressure and ensure adequate renal blood administered NSAIDs should be withheld flow. If this cannot be guaranteed, NSAIDs if animals are inappetant. should not be given until the postoperative period when these criteria have been met. Lack of response to therapy should prompt investigation of the cause of pain NSAIDs should not be given to neonates (further diagnostics) and instituting (<6 weeks of age) and some drugs may other treatment depending on the cause not be approved for very young animals - for example surgery, appropriate medical (firocoxib labeled for use in dogs over 10 therapy or adjunctive treatments for OA weeks of age). NSAIDs may have an adverse including weight control, exercise restriction effect on ovulation, implantation, the female physiotherapy etc. reproductive tract and fetal circulation and should be avoided in bitches during oestrus, For both acute and chronic use of NSAIDs post mating, pregnancy and lactation. reduction of the given dose should be made based on clinical response. The dose 3. Dosage required may be significantly less than the The dose of any NSAID given should recommended dose or at a longer dosing be as approved for the individual drug interval. In older animals and cats doses that for the clinical indication Higher doses are effective can be very much lower than are recommended for post operative the labeled dose and every other day dosing pain than other indications. Higher than may be adequate to maintain adequate drug recommended doses or administration levels due to reduced metabolism and drug for longer periods of time than approved excretion which may result in accumulation for any indication should not be given as of the drug and much longer duration of higher doses are known to be associated action (see referenced guidelines treated long term for osteoarthritis in cats). - 6 - Boardtalk May 2013 - Insert 1 Dosage should be made on ideal body There is potential for a significant increase weight as overdosage can occur in obese in GIT pathology when an “intolerance” animals. (vomiting or inappetance) is a reason prompting a change in drug therapy (rather 4. Use of multiple NSAIDs and /or than efficacy) as GIT clinical signs may Corticosteriods reflect existing GIT pathology and GIT The incidence of adverse effects is increased ulceration is likely to continue if the patient in animals that have received multiple is switched to another drug. NSAIDs within a short period of time or have received corticosteroids either Corticosteriods are known to increase concurrently or within a short period of gastric erosion in dogs receiving NSAIDs time of a NSAID. and no information is available on the preferred or safe wash out period between The half life of NSAIDs varies between drugs corticosteroids and NSAIDs. NSAIDs are and in individual animals and concurrent heavily protein bound and may displace other use of different drugs increases possible protein bound drugs including corticosteroids adverse effects. A safe “wash out” period and potentiate their effects. Concurrent has not been determined for any NSAID. or close temporal administration with It has been recommended that switching corticosteroids increases the risk of gastric between NSAIDs be done cautiously and pathology. At least 2 days “washout” in the cumulative effects of all NSAIDs being dogs has been recommended between administered should be considered. In one the use of NSAIDs and corticosteroids study a change to a second NSAID was however this is arbitrary – it may not not associated with a significant increase be long enough and adverse cumulative in adverse effects when an interval of effects may be dependent on the time 1-7 days (majority > 2days) was allowed animals have been treated, individual between treatments. A period of 24 hours is drugs, the doses given and other factors a minimum and dependent on drug or drugs including the underlying disease, stress used. etc.

The major reported adverse effects of Three to five days between drug treatments NSAIDs are gastrointestinal with vomiting has been recommended in cats and >7 days and inappetance the predominant clinical if aspirin has been used. signs. Vomiting and inappetance should not be ignored. Local gastric irritation NSAIDs may also affect the efficacy and may be a cause of GIT signs but this is concentration of other drugs given that are indistinguishable from a more sinister cause protein bound including ACE inhibitors. such as ulceration, GIT perforation, renal failure or hepatotoxicity. Any “switch” to 5. Monitoring another NSAID should only be made after Advice re the potential adverse effects of an appropriate time for clearance of the NSAIDs should be given to the owners of initial NSAID and it has been determined all animals receiving NSAIDs. Any clinical that the animal is eating and in good signs of unwellness including inappetance, health. vomiting, diarrhoea, melaena and/or pain should prompt reassessment of both the original diagnosis and possible adverse drug

Boardtalk May 2013 - Insert 1 - 7 - effect in both outpatient and post surgical Other recommendations patients. • Doses should be prescribed and measured accurately. As a group NSAIDs are not reversible • Large animal preparations should and it is imperative that general health be not be used for small animals as considered prior to prescribing NSAIDs small variations in dose may result – this may include baseline CBC, biochem in a relatively large overdosage. and UA in animals, especially older animals, Similarly appropriate preparations where longer term therapy is instituted and should be used for cats and small where long acting NSAIDs (mavacoxib) are dogs. given. A concern with the administration of • Flavoured chewable tablets are a long acting NSAID is that alteration of PG attractive to animals and small activity may be seen for up to 2 months after children and must be dispensed in a single tablet and treatment may complicate child proof containers and owners other treatment or health in unforeseen advised to store securely to pre- situations (trauma, illness). vent accidental poisoning.

Adverse effects associated with any NSAID use can be seen in both therapeutic and overdose. All animals receiving NSAIDs chronically should be monitored for gastrointestinal abnormality including melaena. Physical examination, PCV, hepatic and renal function References should be monitored periodically in animals Mathews KA, Non steroidal anti- on long term NSAID therapy. inflammatory Analgesics Chap 158 Ongoing monitoring for early signs of Therapeutics Considerations in Medicine and toxicity is imperative as adverse drug Disease in Textbook of Veterinary Internal effects are typically treatable if recognised Medicine, Ettinger and Feldman 7th edition early, the NSAID is discontinued and 2010 pp 608-615. appropriate supportive treatment is given. Sparkes AH et al., ISFM and AAFP Consensus guidelines on long term use of NSAIDs in cats JFMS 12: 521-538, 2010. Lascelles BD et al, Gastrointestinal perforation in dogs treated with a selective coclooxygenase-2 inhibitor: 29 cases (2002- 2003) JAVMA 227 :1112-1117, 2005. Innes JF et al., Review of the safety and efficacy of long-term NSAID use in the treatment of canine Osteoarthritis Vet Record 166 226-230, 2010.

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