Evidence Update-Safety of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in Dogs

One of the most common and effective classes of drugs for the treatment of pain are the non-steroidal anti-inflammatory drugs (NSAIDs). Like all medicines that have any benefits, they do have potential risks as well. Unfortunately, an unrealistic assessment of these risks is just as harmful as an unrealistic assessment of benefits. While many pets take these medications safely, and find relief from their pain, dramatic stories of animals who have been harmed are widely circulated, and these can generate an excessive fear in pet owners, which can lead to their denying their pets the pain relief these drugs can provide. Proponents of alternative therapies often exaggerate the risks of NSAIDs in order to frighten people into using their remedies instead, despite the fact that these are often untested and their risks and benefits not truly known.

I have previously discussed a paper reviewing the safety of NSAIDs, which concluded that while the evidence was often weak, it suggests that the risk of serious adverse effects from NSAID use is very low. This is essentially the same conclusion reached by the authors of a new, more rigorous systematic review of the literature concerning NSAIDs side effects in dogs.

Monteiro-Steagall BP, Steagall PVM, Lacelles BDX. Systematic review of nonsteroidal anti-inflammatory drug-induced adverse effects in dogs. J Vet Int Med 2013;27:1011-19.

This paper identified and critically appraised 64 studies concerning 14 different NSAIDs. The quality and quantity of the evidence was high for 3 of the drugs (carprofen, firocoxib, and meloxicam), moderate for 3 (deracoxib, robenocoxib, and ketoprofen), and low for the others drugs evaluated.

Adverse effects were reported in about ½ the studies, however aspects of the design and reporting of the studies made it impossible to determine a reliable rate of such events or the severity of them. Overall, adverse effects were reported at rates from 0% to as high as 37.5% of dogs. However, the drugs, study characteristics, and patient populations different widely, so it was not possible to directly compare particular drugs or studies.

Interestingly, when the highest quality studies were considered (randomized, placebo-controlled clinical trials), no difference in adverse effects was detected between dogs receiving NSAIDs and those on placebo. Though it is clear that such side effects do, of course, occur in some dogs on NSAIDs, and while real clinical patients are likely to respond differently than research subjects, this at least suggests that worries about common and severe harm from these medications are not justified.

A couple of interesting observations were made from these data. Adverse effects were more common in clinical trials than in research studies. This is likely associated with the fact that research subjects are usually healthy young dogs, whereas clinical trial subjects represent a variety of ages, medical conditions, and use of medications and other therapies. It is a reminder of why we cannot entirely trust research studies to predict the effects of medical treatments used in actual patients.

Gastrointestinal side effects, such as vomiting and diarrhea, were the most common in all studies, but the evidence did not allow calculation of specific rates if these symptoms.  More serious side effects, involving liver and kidney problems, were only detected very rarely, and liver problems seemed only to occur in dogs with pre-existing liver abnormalities.

Overall, this study adds to the existing evidence base to suggest that NSAID side effects are uncommon, apart from gastrointestinal symptoms, and that serious injury is rare. There is unquestionably some risk associated with these medications, and the patients they are used in have to be selected and monitored carefully and appropriately. However, they are very effective pain control drugs, and denying their benefits to our pets without a realistic assessment of the risks is a disservice to our animals.

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15 Responses to Evidence Update-Safety of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in Dogs

  1. Jennifer Robinson says:

    A blogger I sometimes read makes some strong claims that Cox-1 NSAIDs (like Ibuprofen) are not greatly different than Cox-1 NSAIDs (like Carprophen) . .. and that Rimdyl is a money gouging racket on the part of big pharma. See, eg.: http://terriermandotcom.blogspot.com/2008/05/rimadyl-relief-for-swollen-wallet.html

    a brief quote: “What’s the difference between a Cox-1 and a Cox-2 drug? In the real world, not a damn thing unless you are taking the drug daily and for a very long period of time (i.e., more than 3 weeks of daily dosing). …Cox-2 drugs, such as Rimadyl, have NOT been shown to be more effective at alleviating pain than Cox-1 drugs such as Aspirin and Ibuprofen. …So, to put a point on it, almost all Rimadyl sales by veterinarians for short-term use are a rip-off; you could be using buffered children’s Apirin or a low-dosage of Ibuprofen for a lot less money.”

    How skeptical should I be of this other skeptic?

  2. skeptvet says:

    There is a LOT of reason to be skeptical of this advice. There is no question that the safety of more COX-2 selective drugs was overhyped when they were introduced, and they have risks like any other NSAID (or any other therapy that does anything, for that matter). But there is good evidence that they are safer and more effective that COX-1 selective drugs or non-selective NSAIDS like aspirin. Here are some examples of the evidence concerning this:

    J Vet Intern Med. 1999 Sep-Oct;13(5):472-7.

    The gastroduodenal effects of buffered aspirin, carprofen, and etodolac in healthy dogs.

    Reimer ME1, Johnston SA, Leib MS, Duncan RB Jr, Reimer DC, Marini M, Gimbert K.

    Author information

    Abstract

    Twenty-four healthy mixed-breed dogs were divided into 4 groups. Group 1 received a placebo p.o. q12h, group 2 received an average of 16.5 (15.1-17.8) mg/kg buffered aspirin p.o. q12h, group 3 received an average of 2.2 (2.0-2.4) mg/kg carprofen p.o. q12h, and group 4 received an average of 12.8 (11.7-13.8) mg/kg etodolac p.o. q24h (with a placebo in the PM). All treatments continued for 28 consecutive days. Gastroduodenal endoscopy was performed on days -9, 0, 5, 14, and 28. Multiple gastric biopsies were obtained endoscopically on day -9 to determine each dog’s Helicobacter infection status. Four regions in the stomach and 1 region in the proximal duodenum were evaluated endoscopically, and each was assigned a score from 1 to 11. Scores for each region then were summed to give a total score for each endoscopic evaluation. Erosions and submucosal hemorrhages were seen in all dogs receiving aspirin. Only minor gastric lesions were observed in the carprofen, etodolac, and control groups. No adverse clinical signs were noted in any dog given any treatment. Median total score on days 0, 5, 14, and 28, respectively, were as follows: group 1: 5.0, 5.0, 5.0, 5.0; group 2: 5.0, 27.0, 26.0, 27.5; group 3: 5.0, 5.0, 6.0, 5.0, group 4: 5.0, 7.0, 5.0, 5.0. There was no significant difference among dogs receiving carprofen, etodolac, or placebo. The administration of carprofen, etodolac, or placebo to healthy dogs resulted in significantly less gastroduodenal lesion development than in dogs receiving buffered aspirin.

    Semin Arthritis Rheum. 1997 Jun;26(6 Suppl 1):21-7.

    Meloxicam: selective COX-2 inhibition in clinical practice.

    Furst DE.

    Author information

    Abstract

    Nonsteroidal antiinflammatory drugs (NSAIDs) exert their actions by inhibiting cyclooxygenase (COX). It has recently been postulated that NSAIDs’ antiinflammatory efficacy arises from inhibition of the COX-2 isoform of cyclooxygenase, whereas inhibition of the COX-1 isoform produces the troublesome and sometimes serious gastric and renal side effects of NSAIDs. A relatively selective COX-2 inhibitor, such as meloxicam, may combine antiinflammatory efficacy with improved tolerability. In volunteers, indomethacin 75 mg, but not meloxicam 7.5 mg, inhibited renal prostaglandin E2 excretion and platelet aggregation (COX-1 mediated effects). Double-blind, randomized trials in osteoarthritis and rheumatoid arthritis patients have shown equivalent antiinflammatory efficacy among meloxicam 7.5 mg or 15 mg and diclofenac 100 mg, naproxen 750 mg, and piroxicam 20 mg. In a double-blind, placebo-controlled trial, meloxicam (7.5 or 15 mg) caused less endoscopically detected gastrointestinal (GI) damage (Lanza scale) than piroxicam 20 mg. The MELISSA study, a double-blind, randomized, 28-day trial in over 9,000 patients showed that meloxicam 7.5 mg caused statistically less total GI toxicity, dyspepsia, abdominal pain, nausea and vomiting, and diarrhea than diclofenac 100 mg, despite equivalent reductions in pain on movement for each treatment. A global safety analysis of clinical trials, representing over 5,600 patients and comprising 170 and 1,100 patient-years of exposure for meloxicam 7.5 mg and 15 mg, respectively, showed that meloxicam caused less GI toxicity and fewer peptic ulcers and GI bleeds than naproxen, diclofenac, or piroxicam. The renal safety profile and incidence of liver function abnormalities with meloxicam is equivalent to other NSAIDs available for clinical use. In conclusion, relatively selective COX-2 inhibition exemplified by meloxicam may offer effective symptom relief with an improved GI tolerability profile.

    NSAID Mechanisms of Action

    Cyclooxygenase 1 (COX-1) is constitutively expressed in many tissues and generates protective prostaglandins in the stomach, intestine, and kidney. COX-1 also generates thromboxane (TXA2), which mediates platelet aggregation. Cyclooxygenase 2 (COX-2) is induced by inflammation and generates proinflammatory prostaglandins. However, COX-2 also generates protective renal prostaglandins and is important for the healing of gastric ulcers once they occur. NSAIDs are antiinflammatory, antipyretic, and analgesic via COX-2 inhibition and have antiplatelet activity via COX-1 inhibition. For clinical decision-making, NSAIDs can be divided into three major groups: classical nonselective agents, newer COX-2 preferential drugs, and even newer COX-2 selective coxibs.

    Nonselective NSAIDs

    Aspirin
    Both COX-1 and COX-2

    Low doses selectively inhibit platelet function (0.5–1 mg/kg q 12 h)
    May be useful for prothrombotic states (hypertrophic cardiomyopathy, protein-losing nephropathy)
    GI upset and bleeding at higher dosages

    Ketoprofen
    Both COX-1 and COX-2

    Short-term analgesia
    Has been associated with bleeding and azotemia
    There are safer agents

    Piroxicam
    Both COX-1 and COX-2

    Effective to slow growth of transitional cell, nasal, and colon carcinomas in dogs and cats
    Avoid if coagulopathy present

    COX-2 preferential agents

    Carprofen (Rimadyl)
    COX-2 > COX-1

    Good pain control with minimal risk of bleeding
    Risk of renal decompensation remains
    Rare risk of idiosyncratic hepatic necrosis

    Meloxicam (Metacam)
    COX-2 > COX-1

    Good pain control with minimal risk of bleeding
    Risk of renal decompensation remains
    Acute renal failure with chronic dosing at label dose in cats

    Etodolac (EtoGesic)
    COX-2 > COX-1

    Excessive bleeding in dogs during experimental surgery (EtoGesic label)
    Fall in serum T4 in dogs with orthopedic disease, sometimes into the hypothyroid range (Ness 2003)

    COX-2 selective agents

    Deracoxib (Deramaxx)
    Firocoxib (Previcox)
    COX-2 >>> COX-1

    Apparent low risk of new GI ulceration
    Can impair healing of preexisting ulcers
    Minimal risk of bleeding
    Risk of renal decompensation remains

    Other NSAIDs

    Tepoxalin (Zubrin)
    Both COX-1 and COX-2

    Safer than coxibs for dogs with preexisting ulcers? Also inhibits 5-lipoxygenase
    Unfortunately, manufacture has been stopped

    Acetaminophen
    Weak, reversible COX inhibition

    No significant antiinflammatory effects
    Antipyretic or analgesic in dogs intolerant of NSAIDs (acetaminophen 10-15 mg/kg q 8 h)

    GI Toxicity of Available NSAIDs

    Vomiting and diarrhea are common early side effects, due to direct gastric and duodenal irritation. NSAIDs directly alter phospholipids in the mucus gel layer overlying the gastric mucosa and can damage this hydrophobic barrier (this is the rationale for enteric-coated aspirin). Gastric ulceration, which is more serious, results from inhibition of PGE2 generation. PGE2 is important for maintenance of healthy gastric mucosa (epithelial turnover, mucus and bicarbonate secretion).

    It is difficult to directly compare the relative GI toxicity of veterinary NSAIDs; most published studies using the gold standard (endoscopy) enrol relatively few dogs, and they are usually young and healthy. This may not translate to GI risk in geriatric or critically ill patients. We do know that there is a lower risk of GI upset and ulceration with COX-2 preferential compared to nonselective agents. For example, carprofen and etodolac lead to less GI ulceration than aspirin in dogs (Reimer 1999), and carprofen is associated with fewer and milder gastric lesions compared to ketoprofen in dogs (Forsyth 1998).
    Renal Decompensation

    Any NSAID can adversely affect renal function. Prostaglandins increase renal arterial blood flow in response to a drop in renal perfusion, and stimulate renin release. Both COX-1 and COX-2 generate protective renal prostaglandins, and COX-2 selective agents can drop glomerular filtration to the same extent as classical NSAIDs. The risk of renal decompensation from NSAIDs is greatest with preexisting renal disease, hypovolemia or dehydration, congestive heart failure, sodium restriction, or cirrhosis.

    Most studies of renal function with NSAIDs have been done in healthy animals undergoing elective procedures. Carprofen at the label dose showed no adverse effect on glomerular filtration rate (GFR) in one study; however, in another study, carprofen and ketoprofen both led to a decrease in GFR in dogs undergoing castration (Forsyth 2000). In addition, ketoprofen has been associated with transient azotemia, even in healthy dogs being spayed (Lobetti 2000).

    Meloxicam has no adverse effects on GFR in healthy euvolemic cats (Goodman 2009), and, unlike other NSAIDs, clearance of meloxicam in cats is not slower than in dogs. However, meloxicam has been associated with acute renal failure and death in client-owned cats given the label dose (0.3 mg/kg SC) chronically. Lower daily dosages (0.01–0.03 mg/kg daily) were well tolerated in 46 geriatric cats with osteoarthritis, but renal function was not consistently monitored (Gunew 2008). Older cats with IRIS stage 1–2 renal disease, treated with meloxicam at a median dose of 0.02 mg/kg/day, did not show clinical evidence of renal decompensation when followed for at least 6 months (Gowan 2011).
    Platelet Dysfunction and Bleeding

    Classical NSAIDs (aspirin, ketoprofen, piroxicam) inhibit platelet function most readily, via inhibition of COX-1 mediated TXA2 generation. Prolonged bleeding times were reported with ketoprofen in dogs undergoing elective orthopedic surgery (Grisneaux 1999); one ketoprofen-treated dog developed a hematoma at the surgical site. COX-2 preferential agents have less platelet inhibitory effects; while carprofen leads to mild subclinical decreases in platelet aggregation, neither carprofen nor meloxicam prolong buccal mucosal bleeding times in healthy dogs. However, etodolac has been associated with excessive bleeding in dogs during experimental surgery (Etodolac label). COX-2 selective coxibs do not affect buccal mucosal bleeding time in dogs (Deramaxx label; Steagall 2007), and coxibs are probably the safest NSAIDs in dogs with preexisting coagulopathies (e.g., von Willebrand’s disease).

    Coxibs and Hypercoagulable Patients

    Conversely, coxibs may be a poor choice in hypercoagulable patients (protein-losing nephropathy, immune-mediated hemolytic anemia, vasculitis, Cushing’s). Unopposed activity of COX-1 may lead to platelet overreactivity and impaired small vessel dilatation, resulting in thrombosis in at-risk patients. I would avoid coxibs in these patients until more is known.

  3. Nicole says:

    Thank you for this. I have a young Staffordshire mix who had CCL surgery last year and, while X-rays after the surgery showed it healed well, recently she’s had increased stiffness and on-again, off-again lameness in the knee that was operated on. I’ve asked my vet about long-term NSAIDs, as I think my pooch is developing arthritis in the knee (she’s not overweight, FWIW), but the vet objects because the dog is young and keeps suggesting glucosamine. I argued that there isn’t good proof glucosamine does anything (thanks to this site), and she agreed, but said at least it has no side effects. Sigh. So I think she’s reluctant because she thinks there’s a high risk of liver or renal damage with long-term usage. I will likely send her a link to this entry next time I make my plea.

  4. Mag says:

    Nicole,
    I am reading this because, at 13, my lab/chow mix finally has begun needing to take Rimadyl. This “athlete” dog has had both CCL repaired (one at 2 1/2, one at 8) and has torn his right Achilles. Until a few months ago, he did extremely well on glucosamine chondroitin, 12oo mg of fish oil and 1/8 tsp of MSM daily. It is well worth trying for your dog. Fish oil at high doses is an anti inflammatory. It is well studied in humans and I upped my and my dogs dose after a talk by a Graves Disease researcher recommended that and I was able to stop taking Celebrex myself.
    My beagle has ankle issues that also resolved with these supplements. When other issues prevented him from taking them, he began limping again a
    nd it went away when he resumed. Study with N=1, but again, worth a try.
    I am not against using prescription meds (my beagle is doing very well on oral chemo for a lymphoma) but if you can postpone the NSAIDs, do.

  5. skeptvet says:

    I would make the case in the opposite direction. There is some evidence to support fish oil, though glucosamine almost certainly does nothing, but I am not against using these supplements, however there is no reason to postpone NSAIDs. Doing so only subjects pets to unnecessary discomfort.

  6. R says:

    What is your opinion on tramadol (prn) for pain, my 15 year old small breed is cranky, irritable and has some spinal degenerative issues. The tramadol, in low doses, especially at bedtime (he sleeps through the night) seems to work.
    I want to keep him comfortable. TIA

  7. skeptvet says:

    The clinical literature is mixed, but generally tramadol doesn’t seem like the best pain reliever. My clinical experience with it, for what that’s worth, has also not been impressive. I haven’t seen many significant side effects, and it appears to be pretty safe, but I think it’s pretty clear NSAIDs work better if there is sufficient need.

    Here are a few studies on the subject:

    Clinical efficacy of hydrocodone-acetaminophen and tramadol for control of postoperative pain in dogs following tibial plateau leveling osteotomy.
    The effects of preoperative oral administration of carprofen or tramadol on postoperative analgesia in dogs undergoing cutaneous tumor removal.
    Comparison of carprofen and tramadol for postoperative analgesia in dogs undergoing enucleation.
    Cardiorespiratory, sedative and antinociceptive effects of dexmedetomidine alone or in combination with methadone, morphine or tramadol in dogs.

  8. R says:

    He is just old, I took him in for a geriatric workup and his lab work is better than mine, lol. In his case it seems to be effective. Thanks for your response.

    PS: Most vets won’t prescribe anything stronger (outpatient setting), I found that out with my dog that had terminal cancer.

  9. Ron says:

    “The clinical literature is mixed, but generally tramadol doesn’t seem like the best pain reliever.”

    I would have to concur, my dog was put on tramadol prescribed by a MS Vet. surgeon.
    I was not impressed, he was also Gabapentin, it may have helped some, but not enough.

  10. Ron says:

    I have read that quite a few Vets. strongly recommend blood work before starting on these meds. I don’t see that you recommend that in your writings, unless I missed it.
    I think you mentioned above that it can only effect liver values if there are pre-existing problems. There seems to be some studies that it can, I believe it even states that on the FDA website, if I am not mistaken. Also there seems to be some evidence if you aware that in Labradors , the often prescribed drug Rimadyl , may be a problem.

    Now here is a Vet, you might consider him a quack also, but I have never had a Vet in all the years, admit this. All the conventional Vets I have experience with never have, to this point. Most want you to think its as safe as taking a lifesaver.
    https://www.vetinfo.com/drimdyl.html
    “Almost every medication that is used in veterinary medicine has the potential to cause side effects. Many of them have the potential to cause death as a side effect. The list of these medications is very long. Antibiotics often have the potential to cause injury or death. Vaccinations occasionally cause sickness or death. Anesthesia will occasionally cause serious problems, including death. Non-steroidal anti-inflammatory medications can also have detrimental effects. I have treated animals dying from the effects of herbal medications administered at home and have heard unconfirmed reports, similar to much of the information on the Senior Dog site, of problems associated with the use of injectable polyglycosamines, and it seems very likely based on the injection schedule provide that Cartrophen is a polyglycosamine product — although I must emphasize that is just a guess. ” Mike Richards, DVM

  11. skeptvet says:

    1. Bloodwork- Yes, it is prudent to run bloodwork before beginning chronic use of any NSAID, and then to followup regularly. In dogs, I typically recommend testing before beginning use and then at 2-4 weeks and annually thereafter, though as always every individual is different and treatment and monitoring have to be adjusted to individual needs and circumstances. Cats and NSAIDs are an entirely different subject.

    2. Idiosyncratic reactions to medications, including NSAIDs (not just Rimadyl but any NSAID) are inherently unpredictable, and pre-use bloodwork does not indicate whether or not such a reaction will occur. Fortunately, these reactions are incredibly rare.

    2. Dr. Richards is quite correct that all medical treatment is about balancing risks and benefits. Any drug can cause unwanted effects and, as I’ve said many times, if it has no possible side effects it isn’t doing anything. I think the paragraph you quote overstates the cae a bit (e.g. antibiotics do not cause serious injury or death “often” but in fact incredibly rarely), but the possibility is there.

    3. You’ve either read only limited parts of my blog or you’ve read it quite selectively. Almost every article about any treatment includes a discussion of the improtance of balancing risks and benefits in the context of the individual case. And I’ve actually gone so far as to coin “McKenzie’s Law, in order to emphasize that any treatment claiming it has no risks is either inert or the proponents are misleading you.

  12. Mariah says:

    I recently started my 15 yr old border collie on galaprant for arthritis causing pain in her left leg. She is 46 lb otherwise excellent health. I only give her 30 mil she is picky on her food now but will eat hamburgers or chicken if I offer it & seems to rest more deeply but not lethargic up for walks & play. But her leg seems weak she will fall sometimes also still in some pain would you suggest upping her dosage. My vet prescribed 60 but the pharmacist questioned that much I am confused what to do? Reading some dogs experiencing Gi symptoms with galaprant. I also give her tumeric in food have for years & kale.

  13. skeptvet says:

    Every individual is unique, and it is important to look at all the relevant aspects of your dog’s health an circumstances, so I can’t really give dosing advice online. I would try having a detailed discussion with your vet about your concerns an options, or consider a second opinion from another vet in your area.

    Good luck!

  14. Kathy says:

    My 13 year old ShihTzu has suddenly developed arthritis and can hardly walk. Back legs weak and give out. It ha affected front legs also. She was started on Galliprant 2 days ago. No significant change yet. Having a bad night. I was wondering how long it usually takes to show improvement and is it safe for dogs with a congestive heart failure history. She is on Vetmedin, Lasix and enalapril. She has been on these meds for 2.5 years and has been stable other than a cough. She is in pain and I am not sure what to do and what is safe for her. I have a prescription for Hycodan for her cough and was going to try that tonight. It is a narcotic pain med. Any suggestions.

  15. Jana Cryan says:

    My Vizsla was just started on Galliprant also. Recently diagnosed with hip dysplasia and severe osteoarthritis. She’s 11 1/2 and very fit. Has never been overweight. Her legs are very weak when she squats to potty. I’m not sure how to tell if she’s better from the medication. She was initially started on Tramadol and Gabapentin then X-rays were done since we saw no change in her. She is able to walk and trot some. She still enjoys a walk. She is slow getting up and it’s clear the squatting is difficult for her. She does not cry or whine. She is tender when her hips are palpated. Our vet is going to review her x-rays with an Orthopedic specialist next week to see if they have any other recommendations.

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