One Cox does not fit all: Choosing the right NSAID Stephen Cital RVT, SRA, RLAT, VCC, CVPP, VTS-LAM Veterinary Cannabinoid Academy, Veterinary Anesthesia Nerds, Stanford University www.stephencital.com The importance of NSAIDS is more critical than ever. In general, all NSAIDs have about the same analgesic capacity. With constant drug shortages NSAIDS play a critical role in a robust and effective pain control protocol for animals that can tolerate them. In fact, in human studies where NSAIDS are used at appropriate dosages and intervals, pain scores in comparison to those patients on opioids are the same if not better. Non NSAID medications with anti-inflammatory properties Lidocaine- This common and very effective analgesic is not only free radical scavenging but also has some notable anti-inflammatory effects described by Caracas et al. The studies do not support relying on lidocaine as an anti-inflammatory but it is a benefit to consider. Buprenorphine- Known for its effects at opioid receptors the information coming out on buprenorphine is exciting. Not only can this drug be used safely at higher doses in companion animals for equipotent effects as full mu-opioid drugs, it also has very mild anti-inflammatory properties in induced arthritic animal models. Cannabinoids- These diverse molecules not only delay or prevent the formation of arachidonic acid but also can have COX inhibiting effects. Acetaminophen aka Paracetamol (Tylenol)- This drug is NOT an NSAID but works in conjunction with NSAIDS. It should never be given to cats. Maropitant (Cerenia)- Is not an NSAID but some research has suggested its use as an analgesic. However, the evidence is still very weak for this theory and it is not recommended to rely on this drug as a stand alone analgesic. Instead it should be considered in conjunction with traditional protocols. The mechanism of action for an “anti-inflammatory” response is dynamic and will depend on the medication being used. When it comes to traditional NSAIDS we see the following. NSAIDS are an ever- evolving group with medications that have varying effects acting through inhibition of prostaglandin synthesis secondary to their inhibition of the enzyme cyclooxygenase (COX). This results in suppression of inflammation, and thus analgesia. Most NSAIDs not only inhibit prostaglandins at sites of inflammation, but systemically. Prostaglandins serve important functions in other parts of the body (kidneys and GI), a factor that accounts for some of the toxicity of these agents. The most frequent complications associated with NSAID usage are those involving the gastrointestinal tract and the creation of ulcers after administration. Studies on NSAIDS use the negative side effects on the gastrointestinal track as standard in safety testing. The evolution of NSAIDS has developed more specific (COX1, COX2) acting medications with improved safety and anti-inflammatory effects. NSAIDs that inhibit COX1, with increases up to 3 times with tissue injury were the first generation with more detrimental side effects on GI tissue. COX2 NSAIDS are more pain relieving by way of inhibiting the isoform synthesized by macrophages and inflammatory cells with tissue injury, which is the more pain stimulating concern able to produce severe inflammation and hyperalgesia. NSAIDS do have positive synergy with other analgesics, such as opioids, and can actually help reduce the dose of opioids to achieve the same level of pain without the NSAID synergistic effect. Some studies suggest one can anticipate cutting the opioid dose by 40%. More and more evidence is supporting the use of certain NSAIDS pre-operatively, affectively alleviating the inflammation process BEFORE it starts for hydrated, elective and healthy patients over 8 weeks of age. It is critical renal infarct is avoided to reduce potential negative side effects. Grapiprant (Galliprant) is a member of a new piprant chemical class developed by Arantana that works through a specific targeted mechanism. Specificity at the EP4 prostaglandin receptor. Instead of inhibiting the cyclooxygenase enzymes, grapiprant has a specific target, at the EP4 prostaglandin receptor. What is particularly unique about this mechanism is grapiprant does not affect the function of the other prostaglandin pathways that are necessary to support normal kidney function, platelet function and other important physiological processes. In the classic definition of an NSAID, Galliprant is not an NSAID. Non-Selective NSAIDS COX2 selective COX2 preferred Phenylbutazone Firocoxib Carprofen (Non-selective in Ketoprofen Deracoxib people) Flunixin Celecoxib Meloxicam Piroxicam (Great for birds?) Mavacoxib (long lasting, only Aspirin approved in UK) Cimicoxib Robenacoxin My patient doesn’t seem to be responding to the NSAID anymore • This rare occurrence can be telling about the patient. It could suggest GI changes and absorption concerns or an increase inflammatory response/ hypersensitive nociceptor. To calm this effect amantadine can be administered to animals suffering from decreased responsiveness to NSAID therapy. Generally, benefits from the co-administration of amantadine are expected after or before a 21 day course of amantadine. • Amantadine appears to be helpful in maintaining comfort in dogs with musculoskeletal pain or osteosarcoma. • The dosage of both drugs for dogs and cats is approximately 3 to 5 mg/kg orally (PO) once daily. • Some clinicians prefer to switch NSAIDS, which usually includes a washout period between differing NSAID options. This should be avoided unless absolutely necessary. This washout period allows for inflammatory molecules to surge, leaving the pet in pain and us having to play catchup. • Instead, one can consider amantadine as described above or trying Galliprant or CBD. Long term use and use with chronic kidney disease NSAIDS are often used off label. More recent literature supports notorious NSAIDS like meloxicam are in fact safe for use in cats- as practiced by many foreign practitioners and can be used longer term. Robenacoxib (Onsior) can also be given longer term despite box labeling. It is in the patient’s best interest if maintaining on a chronic NSAID to have regular blood work done to ensure patient safety, such a q6 month liver and kidney function. Well maintained chronic kidney patients can tolerate NSAIDS despite long held fears and miseducation. However, there are some critical points to consider. • Acute renal azotemia would be a contraindication. • Pre-renal azotemia may be a different story. (A risk-benefit analysis of NSAID administration may suggest that it can be done with the owner’s informed consent.) • The animals should be eating and drinking normally. Safety Concerns There is a thought that adding a PPI such as omeprazole may be beneficial in reducing GI related concerns. A study released in 2020 by Jones et al. found that adding omeprazole was in fact not beneficial and could create more concern than alleviate. “Omeprazole prophylaxis induces fecal dysbiosis and increases intestinal inflammatory markers when coadministered with carprofen to otherwise healthy dogs with no other risk factors for GI bleeding.” Instead, misoprostol can be considered as a synthetic PGE producer to replace the PGE’s knocked out by NSAIDS. Addisonian patients receiving physiological doses of prednisone? Because they are only getting a physiological dose there should be minimal concern of co-administration. The author prefers to start with half the recommended dose to gauge efficacy and will increase from there. Human data affirms patients taking NSAIDs undergoing R/A have a higher rate of leakage from the anastamotic site; this might be especially true for the more highly selective COX2 NSAIDs (this is because PGE2 is also a factor in promoting tissue repair). Lactation- Only 1% of NSAID dose enters milk. Short term (<3-5 days) use for damns or bitches that are nursing raises little concern for the neonates. Wash out 5x half-life = 97% of drug elimination 10x half-life = 99% of drug elimination Half-life of common NSAIDS: Carprofen 8 hours Meloxicam 12-36 hours Robenacoxib 1 hour Deracoxib 3 hours References available upon request. .