Non-steroidal anti-inflammatory analgesics: a review of current practice
Karol A. Mathews, DVM, DVSc, University of Guelph, Ontario Veterinary College, Department of Clinical Studies, Guelph, Ontario, Canada N1G 2W1E-mail: firstname.lastname@example.org
Objective: This review is intended to update the reader on the clinical aspects of the non-steroidal anti-inflammatory analgesics (NSAIAs) currently used in veterinary practice. Most NSAIAs act by selectively, or preferentially, inhibiting the synthesis of cyclooxygenase (COX)-1 or COX-2, or both COX-1 and COX-2 enzymes which oxidize arachadonic acid to a series of prostenoids. The prostenoids are precursors of various prostaglandins required for many homeostatic functions throughout the body. The COX-1 and COX-2 enzymes are constitutive, however the COX-2 enzyme is also induced following injury or inflammation facilitating the transmission of pain. As the newer NSAIAs focus on the inhibition of COX-2, this review offers a more detailed discussion of this enzyme.
Data synthesis: This data was obtained from recent review articles and original published reports in both the veterinary and human literature. A CAB and Medline search was also used.
Conclusions: The NSAIAs are effective analgesics for managing moderate to severe pain in many species of animals; however, potential adverse effects may occur if used inappropriately. Guidelines, including indications, contraindications and dosing regimens for the commonly available NSAIAs are included.
Non-steroidal anti-inflammatory analgesics (NSAIAs) relieve moderate to severe pain. The efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) is comparable to the pure opioids in managing soft tissue and orthopedic pain. NSAIDs appear to confer synergism when used in combination with opioids and may demonstrate an opioid-sparing effect should lower dosages of opioid be required. The duration (12–24 hours) and efficacy of the NSAIAs make them ideal for treating acute and chronic pain in veterinary patients however patient and NSAIA selection must be considered prior to administration due to their potential for adverse effects.
Non-steroidal anti-inflammatory analgesics are inhibitors of cyclooxygenase (COX) enzyme-1 (COX-1) and COX-2. COX-1 is a constitutive, or “housekeeping” enzyme, present in tissues, that ultimately converts arachidonic acid into prostanoids (thromboxanes, prostacycline and prostaglandins ([PG]E2, F2 and D2).1 In the context of NSAIA activity, these prostanoids may be reduced and consequently affect primary plug formation of platelets, modulation of vascular tone of the kidney and inhibit cytoprotective functions on the gastric mucosa.1
COX-1 is increased approximately 2 to 3 fold in tissue injury and, therefore, is involved in pain transmission but to a lesser degree than COX-2. COX-2 is the inducible isoform, synthesized by macrophages and inflammatory cells in the presence of tissue injury and inflammation, potentially increasing by 20-fold over baseline.2 The increased cyclooxygenase levels increase prostanoid production where these compounds serve as amplifiers of nociceptive input and transmission in both the peripheral and central nervous systems.2 By this mechanism, COX-2 is responsible for most of the pain and hyperalgesia experienced after tissue injury.
COX-2 also has important constitutive functions. Recent experimental studies indicate there may be a protective role for COX-2 in maintenance of gastrointestinal integrity,3 ulcer healing4 and in experimental colitis in rats.5 In addition, the COX-2 enzyme appears to have constitutive functions associated with nerve, brain, ovarian and uterine function and bone metabolism, therefore, the potential for NSAIA-associated side effects with these systems are of concern.3 COX-2 has constitutive functions in the kidney that differ from those of COX-1. For example, COX-2 is important in nephron maturation.6 The canine kidney is not fully mature until 3 weeks after birth; administration of a NSAIA during this time, or to the bitch prior to birth, may cause a permanent nephropathy.
COX metabolites have also been implicated in functional and structural alterations in glomerular and tubulointerstitial inflammatory disease. Administration of COX-2 selective inhibitors decreases proteinuria and inhibits development of glomerular sclerosis in rats with reduced functioning renal mass.6 Because COX-2 expression is also increased in glomerulonephritides (such as lupus nephritis), it is possible that COX-2 inhibitors may also alter the natural history of glomerular inflammatory lesions.6 The COX-2 derived metabolite production is regulated and localized to the structures in the kidney that play an essential role in renal blood flow (i.e. renin activity) and fluid-electrolyte homeostasis. This topic is beyond the scope of this article. The reader is encouraged to review this fascinating area.7
Cyclooxygenase-2 is glucocorticoid sensitive in that it is reduced following administration of glucocorticoids, which may partially explain the anti-inflammatory and analgesic effects of this class of medications. Of interest, in addition to the COX-2 role in inflammation, aberrantly upregulated COX-2 expression is increasingly implicated in the pathogenesis of a number of epithelial cell carcinomas, including colon, esophagus, breast and skin, and in Alzheimer's disease and other neurological conditions.8–10 The COX-2 inhibitors are being researched as potential anti-carcinogenic agents.
A significant part of the NSAIAs' anti-nociceptive effects is exerted at the spinal cord and supraspinal levels.2,11–13 This action, in addition to pain relief, may account for the observed overall well-being and improved appetite of patients receiving injectable NSAIAs for relief of acute pain (personal observations). The prostaglandins are ubiquitous throughout the body and serve to facilitate many normal physiological functions during health and illness. Associated with the use of NSAIAs is the risk of perturbation of these functions resulting in potential severe organ dysfunction. However, “not all NSAIAs are created equal” in this regard. Some NSAIAs have both COX-1 and COX-2 inhibitory effects (e.g. aspirin, ketoprofena, ketorolacb) while others preferentially inhibit COX-2 or are COX-1 sparing to varying degrees (e.g. meloxicamc, carprofend, etodolace, tolfenamic acidf). As the COX-2 appears to play a significant role in nociceptive transmission, drugs that prevent COX-2 activity and spare COX-1 should be efficient, with potentially fewer adverse effects, in the management of pain.
The general health of the patient greatly influences the decision to use NSAIAs. Cats and dogs are more susceptible than humans to the adverse effects of NSAIAs; therefore, the reported safety of any one non-steroidal analgesic in the human patient should not be assumed to be the same in the veterinary patient. Most NSAIAs have a narrow safety margin; therefore, accurate dosing is absolutely necessary.
At the present time, the administration of NSAIAs for peri-operative pain management should be restricted to animals older than 6 weeks of age that are well-hydrated and normotensive. Patients should have normal renal and hepatic function, normal hemostatic function, no evidence or concern for gastric ulceration, and not receiving corticosteroids. Two or more NSAIAs should not be administered concurrently. While these are general guidelines, future studies may indicate that short-term management of acute pain using COX-1 sparing NSAIAs may prove safe in animals with compromised liver or renal function.
The pre-emptive use of NSAIAs is controversial due to their potential for harm. Various studies using pre- operative administration of NSAIAs in veterinary patients did not specifically screen for adverse reactions.14,15 Studies specifically assessing efficacy and safety of NSAIAs given pre-operatively, in a variety of surgical procedures where intra-operative fluid therapy was administered and patient monitoring conducted, noted adverse reactions with some of the NSAIAs.16–19 Adverse effects noted included acute renal failure with the combination of methoxyflurane and flunixin meglumine,g and incisional oozing in some dogs receiving ketoprofen. However, a recent study conducted at the Ontario Veterinary College demonstrated no ill effects with the administration of meloxicam or carprofen prior to orthopedic or soft tissue surgery in both cats (meloxicam) and dogs (meloxicam and carprofen) (unpublished data). In these studies, the pre-operative administration of an NSAIA provided very good to excellent analgesia. The possible benefit for pre-operative use of NSAIAs is the potential for a pre-emptive effect and the presence of analgesia upon recovery. When NSAIAs are administered upon recovery, opioids should be administered concurrently as 45 minutes are required for therapeutic effect of the NSAIA. Another potential approach in the prolonged surgical procedures could be to administer the NSAIA 45 minutes prior to extubation, where possible. The NSAIA can be given orally, once the patient can swallow, although administration of the NSAIA on an empty stomach may predispose to local gastric irritation.
Plasma levels of NSAIAs are effectively reached within one hour after oral administration.20–22 When given orally, NSAIAs must be given with food to protect the gastric mucosa. If food is not present in the stomach the contact area of the tablet on the mucosa results in a high localized concentration of the drug increasing the potential for ulcer formation. Potential for ulceration exists with all NSAIAs regardless of the route of administration. To reduce the risk of ulcers, the dose of NSAIAs should be given at the lowest possible dose that will confer analgesia. If evidence of gastric ulcers exist, aggressive sucralfate therapy is necessary (e.g. 1–2 gh−1 for 3–4 h, reducing to q 4 h for 24 h, and then q 8 h for 7 days). The sucralfateh emulsion is preferred. If the emulsion is not available, crush the tablets and mix with 10 mL water prior to administration. Intravenous fluid therapy should continue for a minimum of 24 hours after diagnosis of gastric ulceration. NSAIA-induced renal insufficiency is usually temporary and reversible with drug withdrawal and administration of IV fluids.
Indications for NSAIA use in pain management
The indications proposed here assume there are no contraindications to their use.
(1) Post-operative pain: NSAIDs are valuable in selected orthopedic15,17,23,24 and soft tissue surgical procedures,16–19,25–31 especially where extensive inflammation or soft tissue trauma is present. Opioid administration is preferred immediately after any surgical procedure, due to the sedative/analgesic effects and to ensure a smooth recovery. Injectable NSAIAs, (e.g. carprofen, ketoprofen, meloxicam or tolfenamic acid) can be initially co-administered with an opioid and subsequently used alone following orthopedic and selected soft tissue surgery. The initial dose of NSAIAs depends on the expected severity of pain. For example, a difficult fracture repair would require the labelled recommended loading dose of some NSAIAs (e.g. carprofen, meloxicam ketoprofen), but a laparotomy without complications could be successfully treated with half this dose which is the label recommendation for maintenance.
(2) Inflammatory conditions: For relief of pain due to meningitis, bone tumors (especially after biopsy), soft tissue swelling (e.g. mastitis), polyarthritis, cystitis, otitis, severe inflammatory dermatologic diseases or injury (e.g. degloving, animal bites), NSAIAs appear to be more efficacious than opioids (unpublished observations). As many of these patients may be more prone to NSAIA toxicity, careful patient selection and management is advised. Combination low dose opioids and low dose NSAIAs are also effective in these conditions. An exception is necrotizing fasciitis where NSAIAs may increase morbidity and mortality.32
(3) Osteoarthritis: Few long term studies of the adverse effects of NSAIAs have been completed. The major adverse effects associated with long-term use of carprofen,33 meloxicam,34 or etodolac35 for osteoarthritis are predominantly associated with the gastrointestinal tract. Gastroduodenal pathology associated with buffered aspirin, carprofen, etodolac, and placebo has been evaluated in healthy dogs after a 28-day course. Two independent studies concluded that carprofen, etodolac or placebo resulted in significantly less gastroduodenal lesions than in dogs receiving buffered aspirin.36,37 Similar studies comparing ketoprofen with aspirin and placebo38 and carprofen, meloxicam, ketoprofen compared to aspirin and placebo39 noted that the test NSAIAs produced mild to moderate gastrointestinal lesions which were similar to placebo but significantly less severe than those produced by aspirin.
As many patients with osteoarthritis are geriatric, a rapid reduction of the dose to effect a comfortable state is advised to reduce potential toxicity. For example, decreasing to every third day therapy of meloxicam, with half of the label recommended dose, proved efficacious in some dogs during a 12-month period.34 If an individual patient requires persistent high doses of a particular NSAIA to manage its pain, prescribing a different NSAIA may be more effective due to individual variation in response to the different analgesics. For chronic severe pain, when the adverse effects of an NSAIA are a concern, reducing the dose and adding an opioid may be equally effective. However, for many geriatric animals with renal insufficiency, NSAIAs may be the only effective class of analgesic; for these animals, the quality of life is a major issue. In this situation, meloxicam at the lowest dose possible has been used in both cats and dogs with renal insufficiency with no apparent worsening of renal function over time (personal observations).
Some animals cannot tolerate NSAIAs, therefore during NSAIA therapy, all patients should be monitored for hematochezia or melena, vomiting, increased water consumption, and non-specific changes in demeanor. If this occurs, the owner should be instructed to stop the medication and consult their veterinarian. Intermittent monitoring of creatinine and alanine aminotransferase (ALT) is recommended when NSAIAs are prescribed for chronic use.
Another important consideration is the effect that NSAIAs may have on joint/cartilage metabolism. Studies investigating the effects of therapeutic doses of carprofen40,41 and meloxicam42 resulted in no toxicological or pharmacological actions on cartilage proteoglycan metabolism. In addition, meloxicam may have the potential for controlling cellular inflammatory reactions at inflamed sites in the joints of subjects with osteoarthritis.42
(4) Miscellaneous conditions: Other indications for the use of NSAIAs are panosteitis, hypertrophic osteodystrophy (HOD), cancer pain, (especially of bone), and dental pain. Non-steroidal anti-inflammatory analgesics should be used with caution after dental extractions where bleeding is or may be of concern. Meloxicam and carprofen have no anti-thromboxane activity and should, therefore, not interfere with platelet adhesion. For severe panosteitis and HOD the loading dose of a NSAIA is required to see an effect. The HOD in Weimeraners is poorly responsive to NSAIA therapy and is better treated with high dose, short term, corticosteroids provided infectious disease has been ruled out and clinical signs are consistent with HOD alone.43
Contraindications for the use of NSAIAs
Non-steroidal anti-inflammatory analgesics should not be administered to patients with acute renal insufficiency, hepatic insufficiency, dehydration, hypotension, conditions associated with low “effective circulating volume” (e.g. congestive heart failure, ascites), coagulopathies (e.g. factor deficiencies, thrombocytopenia, von Willebrand's disease), evidence of gastric ulceration (i.e. vomiting with or without the presence of ‘coffee ground material’, melena) or gastrointestinal disorder of any kind. Concurrent use of other NSAIAs (e.g. aspirin) or corticosteroids is not recommended. NSAIAs are contraindicated in patients with spinal injury (including herniated intervertebral disc) due to the potential for hemorrhage and neurologic deterioration. NSAIAs should never be administered to patients in shock, trauma cases upon presentation, or patients with evidence of hemorrhage (i.e. epistaxis, hemangiosarcoma, head trauma). Patients with severe or poorly controlled asthma or other moderate to severe pulmonary disease may deteriorate with NSAIA, as PGS mediate smooth muscle relaxation of the small airways. Although administration of NSAIAs in head trauma, pulmonary diseases or thrombocytopenia is generally contraindicated, COX-2 preferential/COX-1 sparing NSAIAs (e.g. meloxicam, etodolac, carprofen, tolfenamic acid) may prove to be safe with further study. NSAIAs may have effects on the reproductive tract and fetus. Indomethacin may block prostaglandin activity in pregnant women resulting in cessation of labor, premature closure of the ductus arteriosus in the fetus, and disruption of fetal circulation.3 These effects may occur in animals; therefore, NSAIAs should not be administered during pregnancy. As COX-2 induction is necessary for ovulation and subsequent implantation of the embryo,3 NSAIAs should also be avoided in breeding females during this stage of the reproductive cycle.
Topically applied non-steroidal anti-inflammatory analgesics were significantly more effective than placebo in many human clinical trials involving acute and chronic painful conditions.44 Topical NSAIAs were not associated with the gastrointestinal adverse effects seen with the same drugs taken orally.45 There are no published studies investigating the use of topical NSAIAs in the veterinary literature.
NSAIAs most commonly used in veterinary patients
The dosing regimens are listed in Table 1.
Table 1. Nonsteroidal analgesic dosing regimen per kg body weight*
|Ketoprofen||Surgical pain||Dogs ≤ 2.0 mg kg−1, IV,SC,IM,PO||Once|
|Cats ≤ 2.0 mg kg−1, SC||Postoperative|
|Dogs & cats ≤ 1.0 mg kg−1||Repeat q 24 hours|
|Chronic pain||Dogs & cats ≤ 2.0 mg kg−1, PO||Once|
|1.0 ≤ mg kg−1||Repeat q 24 hours|
|Meloxicam||Surgical pain||Dogs ≤ 0.2 mg kg−1 IV, SC||Once|
|≤ 0.1 mg kg−1 IV,SC,PO||Repeat q 24 hours|
|Chronic pain||Dogs ≤ 0.2 mg kg−1 PO||Once|
|≤ 0.1 mg kg−1 PO||Repeat q 24 hours|
|Surgical pain||Cats ≤ 0.2 (0.3) mg kg−1 SC,PO||Once|
|≤ 0.1 mg kg−1 SC,PO lean weight||Daily x 2–3 days|
|Chronic pain||Cats ≤ 0.2 (0.3) mg/kg SC,PO||Once|
|≤ 0.1 mg kg−1 PO lean weight||2–3 days|
|0.025 mg kg−1 PO (0.1 mg/CAT max) lean weight||3–5 x weekly|
|Carprofen||Surgical pain||Dogs ≤ 4.0 mg kg−1, IV,SC,IM ||Once upon induction|
|≤ 2.2 mg kg−1 PO||Repeat q 12–24 hours PRN|
|Cats ≤ 4.0 mg kg−1 SC lean weight||Once upon induction|
|Chronic pain||Dogs ≤ 2.2 mg kg−1 PO||q 12–24 hours|
|Etodolac||Chronic pain||Dogs: ≤ 10–15 mg kg−1||Once daily|
|Tolfenamic acid||Acute & Chronic pain||Cats & Dogs: ≤ 4 mg/kg SC,PO||Once daily for 3 days. 4 days off. Repeat the cycle.|
|Flunixin Meglumine||Surgical pain||Dogs ≤ 1.0 mg kg−1, IV,SC,IM |
Cats 0.25 mg kg−1, SC
|Once q 12–24 hours PRN for 1 or 2 treatments|
| ||Pyrexia||Dogs & cats 0.25 mg/kg||q 12–24 hours PRN for 1 or 2 treatments|
| ||Ophthalmological procedures||Dogs 0.25–1.0 mg kg−1||q 12–24 hours PRN for 1 or 2 treatments|
|Ketorolac||Surgical pain||Dogs 0.3–0.5 mg kg−1 IV,IM||q 8–12 hours for 1 to 2 treatments|
|Cats 0.25 mg kg−1 IM||q 12 hours for 1 to 2 treatments|
|Panosteitis||Dogs: 10 mg/DOG ≥ 30 kg, PO||Once daily for 2– 3 days|
|5 mg/DOG > 20 kg < 30 kg, PO || |
|Piroxicam||Inflammation of the lower urinary tract||Dogs 0.3 mg kg−1, PO||q 24 hours for 2 treatments, then q 48 hours|
|Acetaminophen||Acute or chronic pain||Dogs only 15 mg kg−1||q 8 hours|
|Aspirin||Acute or chronic pain||Dogs 10 mg kg−1||q 12 hours|
Meloxicam is a COX-2 preferential NSAIA approved for dogs in Europe and Canada. Its use in cats is under investigation with completed studies indicating safety and efficacy. Recent studies indicate no renal or hepatic abnormalities with acute administration18 and minimal to no anti-thromboxane activity,46 suggesting that hemostasis in normal animals may not be a problem. Adverse reactions reported to the Canadian Health Protection Branch are very few and primarily gastrointestinal. Meloxicam has been used for almost 2 years at the Ontario Veterinary College (OVC) and has proved to be very effective for pain control in a variety of surgical procedures, inflammatory conditions and chronic orthopedic problems. When administered pre-operatively to dogs and cats undergoing moderate to severely painful orthopedic procedures, approximately 70% were pain free for 24 hours or more (unpublished data). No adverse effects have been encountered with either pre- or post-operative administration. Analgesia is excellent when combined with an opioid.
Meloxicam has been demonstrated to be beneficial in the treatment of sodium urate-induced synovitis47 and panosteitis48 in dogs and radiation-induced stomatitis in cats.49 After various soft tissue surgical procedures the number needed to treat (NNT; an ideal NNT is 1, where the treatment is 100% successful when compared to the ‘other’ treatment) to confer very good to excellent analgesia for up to 24 hours, was 1.3 (i.e. for every 1.3 patients treated with meloxicam, compared to the control, one dog was pain-free) when compared to butorphanol.i,18
Carprofen Recent studies indicate that carprofen is a COX-2 preferential NSAIA.50,51 Tablet form is available in Europe and North America; parenteral formulation is available in Europe. It is recommended for peri- operative and chronic pain management in dogs in Europe and North America. Carprofen is approved for single, peri-operative use in cats in Europe. Anti-thromboxane activity is minimal,46,52 suggesting that induced coagulopathy may not be a problem in patients with an intact hemostatic mechanism. According to the European literature, potential adverse effects of NSAIAs such as nephrotoxicity, hepatotoxicity, GI bleeding, or hemostatic deficiencies have not been reported with carprofen use.31 However, the adverse reactions reported to the United States FDA and Canadian Health Protection Branch include a rare acute hepatotoxicity and death. Acute hepatotoxicity and death after carprofen administration has been reported in dogs (Labrador retrievers highly represented) with previously reported normal liver function.53
Carprofen provides good analgesia for up to 1215 and 1825 hours after a variety of orthopedic procedures. In cats undergoing ovariohysterectomy, carprofen provided profound analgesia between 4 and 20 hours post-operatively.26 When administered pre-operatively to dogs undergoing various moderately painful orthopedic procedures at the OVC, carprofen was effective in controlling pain for 24 hours in approximately 70% of cases, not including Labrador retrievers; no adverse effects were encountered (unpublished data).
Ketoprofen is an inhibitor of both COX-1 and COX-2; therefore, unwanted side effects are a potential problem requiring careful patient selection. Ketoprofen is approved for postoperative and chronic pain in both dogs and cats in Europe and Canada. Although several studies using ketoprofen pre-operatively indicate its effectiveness in controlling post-operative pain,15,18,23 it is this author's opinion that ketoprofen should be reserved for post-operative use to reduce the potential for hemorrhage; this recommendation is supported by the drug company. Ketoprofen should not be administered to patients where hemorrhage is a potential problem. Ketoprofen may be administered to animals during closure of the incision after orthopedic procedures (e.g. fracture repair, cruciate repair, onychectomy) where a compressive bandage can be applied; however, it is advised to restrict administration until recovery after laparotomy or thoracotomy to ensure hemostasis is complete.
In a recent study investigating the efficacy of NSAIAs in controlling post-operative pain, the NNT for ketoprofen to confer a very good to excellent analgesic state was 1.5, when compared to butorphanol in maintaining an apparent pain-free state for up to 24 hours after administration.18 Ketoprofen is suggested for hypertrophic osteodystrophy and panosteitis in dogs. Misoprostolj should be co-administered. Occasional vomiting may be seen with chronic use.
Etodolac is approved in the United States for use in dogs for the management of pain and inflammation associated with osteoarthrits35 but could also be used in other painful conditions. The adverse effects appear to be restricted to the gastrointestinal tract.
Tolfenamic acid is available in tablet form and in a parenteral formulation. It is approved in Europe and Canada for use in cats and dogs for controlling acute post-operative and chronic pain. The dosing schedule is 3 days on and 4 days off which must be strictly adhered to. Reported adverse side effects are diarrhea and occasional vomiting. Tolfedine has significant anti-inflammatory and anti-thromboxane activity;54 therefore, post-traumatic and surgical hemostasis may be compromised during active bleeding after administration of this NSAIA. Although tolfenamic acid has been used in Europe in veterinary patients for several years, there is a paucity of clinical information available.
Flunixin meglumine is available in a parenteral formulation. It is approved for use in dogs in Europe but not North America. It is reported to be an effective analgesic for surgical pain.17,29 However, the potential for side effects such as increased ALT,16,17 nephrotoxicity,16,19,55 and gastric ulceration56 is of major concern. Flunixin meglumine is also used as an anti-inflammatory in selected ophthalmological surgical procedures. Potentially safer NSAIAs may be as effective.
NSAIAs not approved for use in veterinary patients (off label use).
Ketorolac is included for the benefit of those working in the research setting associated with human hospitals, where the availability of ketorolac is more likely than other NSAIAs. Ketorolac is comparable to oxymorphone in efficacy and to ketoprofen in duration and efficacy in managing post-laparotomy and orthopedic pain in dogs.17 Only 1–2 doses should be administered due to potential for gastric ulceration in dogs and cats which is more of a concern in most anesthetic than in the non-anesthetic setting. Ketorolac has been used successfully for the treatment of severe panosteitis in dogs where all other therapies had failed. Ketorolac given with food for 2 to 3 days eliminated clinical signs in approximately 99% of these dogs; in the other 1%, signs recurred within a few days to months (unpublished observations). Misoprostol should be co-administered.
Piroxicamk is available in capsules of 10 and 20 mg. Its most valuable use in dogs is for the anti-inflammatory effects on the lower urinary tract in patients with transitional cell carcinoma or cystitis and urethritis. Misoprostol is recommended with piroxicam.
Acetaminophen1 is available in tablet and oral suspension forms. It should not be administered to cats. It can be used in dogs as an antipyretic and analgesic for mild pain and can be used in combination with opioids for a synergistic analgesic effect or opioid-sparing effect. These can be prescribed as individual drugs (which the author prefers in order to allow more flexibility in dosing of the opioid) or in combination such as codeine and acetaminophen or oxycodone and acetaminophen. Acetaminophen is an effective antipyretic agent.
Aspirinm is available in tablet form. It is most commonly used as an analgesic for osteoarthritic pain in dogs. It is formulated in combination with opioids, aspirin and codeine, or aspirin and oxycodone, for a synergistic effect for the treatment of moderate pain, or can be administered for an opioid-sparing effect. It is also used as an antipyretic and anticoagulant in dogs and cats.
Dipyronen is available as a solution for injection and tablets. It is approved for use in cats and dogs in Europe and Canada. Dipyrone should be given intravenously to avoid the irritation experienced when given intramuscularly. In the author's experience, the analgesia produced is not adequate for moderate to severe post-operative pain, and dipyrone is reserved for use as an antipyretic in cases where other NSAIAs are contraindicated (i.e. animals with the potential for gastric ulceration and renal injury). Nephrotoxicity or gastric ulceration is not a major concern in the short term even in critically ill patients.
NSAIAs of the future
Recently approved NSAIAs which are approaching COX-2 specificity, rofecoxib, and celecoxib appear to be more gastroprotective in human patients than the less COX-2-specific NSAIAs when used for 8 days to 3 months.57 A good review of ‘The Coxibs’ is available.58 There are no reports assessing efficacy and safety of COX-2-specific NSAIAs in the veterinary patient population. Most NSAIAs that inhibit COX have been shown to result in diversion of arachidonate to the 5-lipooxygenase pathway. This results in an excessive production of leukotrienes, which have been implicated in the creation of NSAIA-induced ulcers.59,60 A dual COX-2-selective and 5-lipooxygenase inhibitor (RWJ63556) inhibited eicosanoid and leukotriene production in a dog model of inflammation,61 suggesting that the development of these NSAIAs may contribute to an enhanced safety profile and may confer even greater analgesic efficacy due to broader anti-inflammatory and anti-nociceptive effects.
For a more indepth discussion of pharmacologic considerations for non-steroidal anti-inflammatory drugs, refer to Papich M: Pharmacologic considerations for opiate analgesic and non-steroidal anti-inflammatory drugs. Vet Clin North Am Small Anim Pract, July 2000; 30(4): 815–837.
Part of this information is previously published in KA Mathews: Non-steroidal anti-inflammatory analgesics: Indications and contraindications. Vet Clin North Am Small Anim Pract, July 2000; 30(4): 783–804 and is published here with permission.
Ketoprofen, Merial, Quebec, Canada
Ketorolac, ToradolTM, Hoffman-LaRoche, Mississauga, Ontario, Canada
Meloxicam, MetacamTM, Boehringer-Ingelheim, Burling-ton, Ontario, Canada
Carprofen, RimadylTM, Pfizer, London, Ontario, Canada
Etodolac, EtogesicTM, Fort Dodge, IA
Tolfenamic acid, TolfedineTM, Vetoquinol, Lavaltrie, Quebec, Canada
Flunixin meglumine, FlunixinTM, Schering, Pointe-Claire, Quebec, Canada
Sucralfate, Carafate, Aventis Pharmaceuticals, Kansas City, MO
Butorphanol, TorbugesicTM, Ayerst, Guelph, Canada
Misoprostol, Misoprostol Cytotec, Pharmacia (formerly Searle), Peapack, NJ
Piroxicam, Piroxicam Feldene, Pfizer, New York, NY
Dipyrone, Vetoquinol, Lvaltrie, Quebec, Canada