Answering Your Questions: Practical analgesia in cats

Q What criteria do you use to determine the need for analgesia in cats?

Because cats are relatively quiet creatures, that is, they don't bark, whine, and announce themselves, their analgesic needs are often ignored or forgotten. Evaluating pain in cats is challenging and requires intense and prolonged observation, intuition, interaction with the animal, and knowledge of the various feline behaviors that may signal pain. Sometimes the owner can best evaluate a cat's pain, as he or she knows the animal's normal behavior better than anyone else. Cats have evolved to hide their pain, so their behaviors associated with pain may be subtle.

Behaviors that may signal pain in cats include lack of grooming; sleeping a lot; lack of interest in food, water, or their environment; sleeping in only one position; wanting to be left alone; growling or hissing when stroked, touched, palpated, or moved; relentless purring; abnormal body postures such as a hunched-back, head-in-the-corner stance; and restlessness. Cats may also change their preferred sleeping places, food preferences, or litter box habits. This is only a partial list of behaviors cats might exhibit when analgesics are needed.

I like to use analgesics as a tool to evaluate a cat's pain, especially when the presence of pain is not clear-cut. Of course, if a cat has recently undergone surgery that is expected to be painful, such as an orthopedic procedure, I never withhold analgesics, even if the cat's behavior seems normal. But if a cat has vague clinical signs or several days have elapsed since a painful surgery, I administer an analgesic and observe the resulting behavior as a way to assess whether pain was a component of the clinical presentation.

For example, a cat with gingivitis and periodontal disease may be inappetent, dehydrated, depressed, or just "not doing right," but it may not demonstrate clear signs of pain. A short course of low-dose opioid analgesia (e.g. buprenorphine hydrochloride for at-home oral transmucosal administration or a preplaced fentanyl patch) may improve the cat's attitude and appetite. This results in a normally hydrated cat that feels better and is now a better candidate for general anesthesia and its dental procedure.

Q What opioids are best for cats? Are morphine side effects dose-dependent?

The choice of the most appropriate opioid for cats depends on personal preference, the degree of analgesia required, the desired duration of effect, the practical routes of administration under the circumstances, and the availability of the drug. All of the agonist opioids available in the United States (e.g. morphine sulfate, oxymorphone hydrochloride, hydromorphone hydrochloride, and fentanyl) are good analgesics for moderate to severe pain when given at appropriate doses. Buprenorphine, a partial agonist, is appropriate for moderate pain in cats, and some studies suggest it provides analgesia superior to oxymorphone, morphine, and meperidine hydrochloride.1-3 Buprenorphine is well-absorbed when given by the oral transmucosal route,4 making it easy to prescribe for at-home use. I do not find injectable butorphanol tartrate, a mixed agonist-antagonist opioid, useful for severe pain in cats, but it is beneficial when minor pain relief is needed for a short duration (i.e. one or two hours). Oral butorphanol is not well-absorbed and likely provides little to no analgesia.

For major surgeries, my opioid preference in cats is oxymorphone (0.05 to 0.1 mg/kg intramuscularly or intravenously). For animals that are medically compromised, geriatric, or just mellow, I find oxymorphone provides moderate sedation in combination with low doses of acepromazine maleate (i.e. 0.01 to 0.05 mg/kg) or midazolam hydrochloride (0.1 mg/kg) given intramuscularly for preanesthetic medication and preemptive analgesia. Acepromazine should be used at the lowest suggested dose (i.e. 0.01 mg/kg) if the cat has severe systemic disease. During surgical recovery after procedures I presumed to be painful, I then repeat a half to a full dose of the initial oxymorphone dose to maintain good analgesia.

The concern about side effects with morphine stems largely from literature dating from the late 1800s and early 1900s when 100-fold doses of the drug were given experimentally to animals. These doses caused severe cardiorespiratory depression and bizarre behavioral effects. It is true that the agonist opioids can cause excitement or euphoria in some cats. This effect seems to be an individual cat response. It is more often seen in young, healthy cats and is more obvious with higher doses. In my experience, this side effect is usually moderated by adding a sedative, such as acepromazine, or an anxiolytic, such as midazolam. If the cat has undergone a painful procedure, I am reluctant to reverse the agonist opioid with a drug such as butorphanol or naloxone hydrochloride. The cat may seem better because the butorphanol or naloxone relieves the cat's dysphoria. The cat, however, may in fact be more uncomfortable and may exhibit subtle signs of pain that are easy to ignore now that it is quiet. Interestingly, research on butorphanol's behavioral effects in healthy cats not experiencing pain has shown that butorphanol can cause more dysphoria than the pure agonist opioid hydromorphone.5,6

A common misconception, again based on old literature, is that morphine and other agonist opioids cause respiratory depression. To my knowledge, no recent studies have examined the incidence of respiratory depression in cats receiving clinically relevant doses of opioids; the clinical impression is that there are not significant increases in partial pressure of carbon dioxide (PaCO2) or decreases in partial pressure of oxygen (PaO2) in arterial blood after administration of opioids within the reference ranges suggested.

Q What do we need to know about lidocaine hydrochloride and bupivacaine hydrochloride use in cats?

Both lidocaine and bupivacaine have a relatively narrow margin of safety in cats.7,8 As antiarrhythmic drugs, they are rarely, if ever, indicated for use in cats. Both are useful for local anesthetic infiltration, particularly as a ring block for declaw procedures. Lidocaine has caused signs of toxicosis in cats (e.g. central nervous system depression, seizures, cardiovascular depression) at intravenous doses as low as 0.5 mg/kg.7 Doses of lidocaine approaching 10 mg/kg when infiltrated subcutaneously for local anesthetic blocks may cause neurologic signs in cats.8 In my clinical experience, bupivacaine doses less than 2 mg/kg, infiltrated subcutaneously, are generally safe. To be safe, always calculate the total dose of the drug in mg/kg before administering local anesthesia in cats. If it is necessary to administer a certain volume, dilute the drug with 0.9% saline solution to keep the volume adequate while limiting the mg/kg dose.

Q What do we need to know about the use of epidurals in cats (e.g. morphine, lidocaine, and morphine with xylazine hydrochloride)?

Epidurals can be safely performed in cats and offer an extremely effective analgesic alternative to systemic drugs. Cats differ anatomically from dogs in that the feline spinal cord does not end until the first or second sacral vertebral body. So when performing a lumbosacral epidural, you have a greater chance of advancing the needle into the subarachnoid space. If this occurs and cerebrospinal fluid wells up into the hub of the epidural needle, administer half the calculated dose of morphine (i.e. 0.05 mg/kg vs. 0.1 mg/kg).

In my practice, preservative-free morphine is the drug we most commonly use as an epidural analgesic in cats. The recommended epidural dose is 0.1 mg/kg at a total administered volume of 0.2 ml/kg injected over 60 seconds. The expected time to onset of effect is 45 to 60 minutes, with an expected duration of about 12 hours. Morphine injected into the lumbosacral epidural space provides good analgesia for hindlimb, perineal, and abdominal surgeries and may provide some analgesic benefit for thoracotomies.

Venous absorption of lidocaine from the epidural space occurs quickly in people (i.e. within two minutes after injection), and epidurally administered lidocaine may be associated with toxic venous concentrations in cats.9 Although epidural lidocaine administration in cats has been recommended in the literature,10 exercise caution when deciding on the dose and total number of injections to administer.

The use of epidural xylazine in cats has not been reported, although the use of epidural medetomidine (also an alpha2 agonist) in cats caused marked systemic cardiorespiratory depression and sedation.11,12 Xylazine would probably have similar effects if given epidurally to cats.

Q Is concomitant use of epidurals and inhalant anesthesia safe in cats?

Yes. In fact, epidural morphine has an inhalant-sparing effect because of the marked regional analgesia it provides. Therefore, epidural morphine not only provides long and effective caudal analgesia, it reduces the amount of inhalant required to maintain a surgical plane of anesthesia by about 30% to 50%. So the cardiorespiratory depressant effects of the inhalants are reduced, resulting in safer anesthesia overall. Of course, no anesthetic is truly safe without close and expert monitoring.

Q Can you provide a few tips for relief practitioners who may be working in practices that use few or no analgesics in cats?

Opioids are the safest and most effective analgesic agents available in modern medicine. Unfortunately, many practitioners fear the manageable side effects of opioids (e.g. bradycardia, mild respiratory depression). So first I would try to persuade these practitioners that increasing the availability of different opioid options is in their patients' best interest. With a little enlightenment, the practice owner might take your advice and start providing more opioid options.

If you just don't have access to opioids or some of the newer nonsteroidal anti-inflammatory drugs (NSAIDs), consider using local anesthetic blocks, alpha2 agonists, and ketamine hydrochloride. If appropriate for the surgical procedure, a local anesthetic block with bupivacaine (infiltrated subcutaneously at a total dose of less than 2 mg/kg) can block pain for up to 12 hours. Keep in mind, however, that local anesthetics applied to a vascular area (e.g. the peritoneal cavity or pleural space as a splash block) will be systemically absorbed almost as quickly as an intravenous injection.13 Examples of when a local anesthetic block might be appropriate for a cat include a ring block for wound management or a declaw procedure or a line block for abdominal surgery.

The alpha2 agonists bind to alpha2 receptors in the dorsal horn of the spinal cord and modulate the release of various neurotransmitters involved in processing pain. This class of drugs is analgesic in cats, but the strong sedative effects of alpha2 agonists will mask obvious pain behaviors. So do not assume that an animal sedated with an alpha2 agonist is completely pain-free. Alpha2 agonists can be used quite effectively as adjuncts to the mildly analgesic opioids, such as butorphanol, in healthy patients with no cardiovascular or respiratory compromise. For example, in a healthy cat, 0.2 mg/kg of butorphanol could be combined with 2 to 10 µg/kg of medetomidine as an intramuscular premedication for preemptive analgesia for surgical procedures such as ovariohysterectomy and dentistry. These combinations, however, are likely not adequate for major orthopedic surgery.

Ketamine is another drug commonly found in private practice that can be used for its analgesic effects. Again, not a traditional analgesic, ketamine acts by antagonistic effects at the N-methyl-D-aspartate (NMDA) receptor. Like the alpha2 agonists, ketamine (e.g. 5 to 10 mg/kg intramuscularly) is most effective when used in combination with an opioid for analgesia. When ketamine is administered without opioids, its primary analgesic effect is to prevent spinal cord dorsal horn wind-up, where neurocellular processes change quickly with a painful event to amplify the sensation of pain. Ketamine is also a dissociative and hallucinogenic drug, which, although not specifically analgesic, may prevent memory of a painful event. So adding ketamine to the anesthetic protocol may help decrease the amount of pain perceived, prevent the wind-up of that pain, and provide the patient with dissociative anesthesia perioperatively.

The opioid-like drug tramadol may be useful in treating chronic pain in cats. Tramadol may exert mild opioid effects within the spinal cord, but it also works by inhibiting reuptake of norepinephrine. Anecdotally, doses of 1 to 4 mg/kg given orally every eight hours have been effective in cats with chronic pain, such as arthritis.

Q What NSAIDs can be used preoperatively and postoperatively in cats? What are the recommended dosages?

Little scientific, well-controlled research has been done on the long-term use of NSAIDs in cats. Many studies have documented the utility of NSAIDs (e.g. ketoprofen, carprofen, meloxicam) for short-term use in cats.14-19 The use of NSAIDs in cats is considered extralabel, except for the use of meloxicam (Metacam—Boehringer Ingelheim). The injectable form of meloxicam is now FDA-approved for one-time-only use in cats. This does not preclude the use of NSAIDs in cats but does imply that there is much to learn about their physiologic effects and side effects in cats. There are many possible drug interactions between commonly used medications and NSAIDs in people. Such interactions have not been widely studied in cats and other animals, but it is safe to assume that the risk of drug interaction exists in veterinary patients as it exists in people.

Of the many NSAIDs available, the three most commonly used in cats are ketoprofen, carprofen, and meloxicam. The recommended preoperative or postoperative doses (one time only) are

• Ketoprofen, 2 mg/kg subcutaneously or 1 mg/kg orally;

• Carprofen, 4 mg/kg orally;

• Meloxicam, 0.3 mg/kg subcutaneously or orally.

Ketoprofen administration has been associated with decreases in platelet adhesion and increased incidence of bleeding, probably because of its inhibitory effects on the constitutive platelet COX-1 isoenzyme.15 Carprofen and meloxicam are relatively selective for blocking the inducible COX-2 isoenzyme responsible for a component of the inflammatory response. This does not mean that they are completely safe under all circumstances. We can assume that carprofen and meloxicam have some inhibitory effect on COX-1 systems. For example, in an in vitro system, carprofen in feline whole blood was more selective for inhibiting COX-2 than COX-1, but it did have some COX-1 inhibitory effects.20 The same results have been reported for meloxicam.20

In all species, NSAIDs can impair renal blood flow and may complicate renal compromise, worsen congestive heart failure because of their antidiuretic effects, and increase the nephrotoxicity of other drugs. Most of the veterinary literature, including that on cats, has examined the analgesic efficacy of various NSAIDs in healthy patients. Thus, when treating a geriatric patient with potentially limited renal reserve, use NSAIDs with caution. Cats with known renal disease should probably not receive NSAIDs at all. Although COX-2 selective NSAIDs have a safer profile with respect to gastrointestinal ulceration, these drugs still have the potential to cause gastrointestinal ulcers, particularly in patients that are stressed, inappetent, or critically ill. Finally, NSAIDs are highly protein-bound and may displace other protein-bound drugs, resulting in a more profound effect of the displaced drug. For example, in people given aspirin who then received the highly protein-bound drug midazolam, there was an enhanced sedative effect from the benzodiazepine.21

In studies evaluating the analgesic efficacy of the various NSAIDs, typically for surgical procedures for which postoperative pain is expected to subside within 24 to 36 hours (e.g. ovariohysterectomy, castration), the modern NSAIDs ketoprofen, carprofen, and meloxicam performed well. In one study comparing the use of carprofen, ketoprofen, and meloxicam (all given once only), there was no difference among treatments in pain scores of cats after ovariohysterectomy; overall pain scores were generally low, albeit higher than baseline values.17 In another study comparing butorphanol with carprofen, the researchers found no difference in analgesia between the two drugs, although cats given either drug had significantly higher pain scores than their baseline scores through 12 hours postoperatively.22

The use of NSAIDs for analgesia in cats should be reserved for healthy cats undergoing only moderately painful procedures (e.g. teeth cleaning, castration, treatment of simple abscesses) if the NSAID is used as the sole analgesic agent. Combine NSAIDs with opioid analgesics for major visceral or orthopedic procedures, such as ovariohysterectomy and fracture repair. In cats receiving glucocorticoids, avoid administering NSAIDs because of the combined risk for gastrointestinal ulceration. Do not use NSAIDs in cats with renal compromise, congestive heart failure, preexisting gastrointestinal ulceration, or severe systemic disease. Use them only with caution in geriatric cats. Finally, administer intravenous fluids to cats undergoing general anesthesia expected to last longer than 20 to 30 minutes that have received an NSAID perioperatively. Intravenous fluid administration helps preserve renal blood flow in the face of the NSAID's potentially adverse effect on renal perfusion by blocking prostaglandin-mediated renal vasodilation that occurs in response to the reduced renal blood flow from the effects of general anesthesia (e.g. decreased cardiac output and blood pressure).

Q How effective is meloxicam as an analgesic in cats? What dosages are recommended for various situations and conditions?

Meloxicam is not more effective against pain in cats than any of the other modern NSAIDs described in the last section, but its oral syrup formulation seems to be more palatable to cats and, thus, owner compliance is better.

The recommended initial dose for meloxicam is 0.1 to 0.2 mg/kg given subcutaneously (injectable formulation), intravenously (injectable formulation), or orally (syrup formulation), followed by 0.1 mg/kg given orally once a day for no more than three days, followed by 0.1 mg/cat or 0.025 mg/kg (based on lean body weight) either twice weekly or every other day.14 Meloxicam is FDA-approved in cats in only the injectable formulation for a one-time-only dose of 0.3 mg/kg subcutaneously. Thus, long-term use of meloxicam, or the use of the syrup, is extralabel in cats. The syringe that comes with meloxicam is too large to be useful in cats, so take time to instruct owners on proper administration when dispensing meloxicam.

For painful perioperative conditions (e.g. orthopedic surgery), use the higher end of the dose range (i.e. 0.2 to 0.3 mg/kg subcutaneously one time), but use the lower end of the range (e.g. 0.1 mg/kg) for soft tissue pain or when initiating analgesic treatment for chronic pain. The one study examining use of meloxicam in cats with chronic arthritic pain found that a once-daily dose given for no more than five days (0.3 mg/kg orally on Day 1, followed by 0.1 mg/kg orally on Days 2 through 5) provided significant improvement and no observed side effects.14 Renal function was not clinically assessed.14 These researchers found the same results with ketoprofen (1 mg/kg orally once daily for five days),14 but noted that meloxicam's palatability made it more attractive for long-term use.

Q Which NMDA-receptor antagonists can be used as analgesics in cats? What are the dosages and how effective are they?

An NMDA-receptor antagonist common in veterinary medicine is ketamine. There is a paucity of scientific literature regarding ketamine's analgesic effect in veterinary patients. One study in dogs that received ketamine constant-rate infusion as adjunctive analgesia to fentanyl constant-rate infusion found some benefit.23 Owners reported improved postoperative outcome in their dogs during the period immediately after an amputation compared with dogs that received saline solution infusions as an adjunct to fentanyl.23 This benefit has not been scientifically established in cats.

Given that the NMDA receptor participates in the spinal cord dorsal horn wind-up that occurs with peripheral somatic, neural, or visceral injury, it is probably valid to use ketamine in the perioperative period in cats to attenuate that wind-up. So there is probably no harm in using ketamine in the anesthetic protocol as an adjunct to other analgesic agents. It can be given intramuscularly as a premedication for its NMDA-receptor antagonistic effects. I have also used subanesthetic doses of ketamine as a constant-rate infusion during surgery in cats to supplement my inhalant anesthetic and other injectable opioid analgesics. I administer a 0.5 mg/kg intravenous bolus, followed by 2 to 10 µg/kg/min given intravenously. I cannot say with assurance, however, that there is a clear analgesic benefit to this practice.

Q Which injectable or oral analgesics that can be used in cats have the longest duration of action?

Meloxicam and ketoprofen each have a duration of action of 24 hours after one oral dose but should not be given for more than five consecutive days. As I discussed earlier, these should be administered cautiously.

Among the opioids, buprenorphine has the longest duration and has higher receptor affinity than other opioids, such as oxymorphone. Buprenorphine has a dose range of 0.005 to 0.02 mg/kg and, at the higher doses, probably lasts about six hours after oral transmucosal administration.4 This drug has a slow onset of action, taking about 45 minutes for peak effect after intramuscular or subcutaneous administration, with somewhat faster absorption and onset of action after transmucosal administration.24 For effective and predictable analgesia, use the higher dose range transmucosally because it provides more reliable absorption than the subcutaneous or intramuscular routes.4

Q What are the most common interactions to be aware of regarding analgesics and other drugs in cats?

Most drug interaction information is taken from research in people and extrapolated to veterinary patients. Because of species differences in drug response, distribution, and metabolism, extrapolating from one species to another is not always an accurate or appropriate approach. Cats in particular metabolize drugs differently than many other species since they do not synthesize glucuronide metabolites. This means that drugs undergoing glucoronidation for metabolism will have prolonged effects in cats.

Regarding the opioids, a synergistic central nervous system sedative effect occurs in all species when opioids are combined with sedative or anxiolytic drugs. In general, when using opioids for pain management, reduce concurrent doses of acepromazine, alpha2 agonists, or benzodiazepines. Similarly, if the opioid is already on board, then reduce concurrent injectable and inhalant anesthetic doses. This can be viewed as a beneficial drug interaction because opioids allow dose reductions of drugs with cardiopulmonary depressant effects (e.g. isoflurane). No specific drug interactions with opioids preclude their use, but be mindful of additive physiologic effects when using opioids with other medications. For example, when used repeatedly or in high doses, opioids may cause urinary retention or gastrointestinal ileus. So in patients receiving atropine, which is known to cause ileus, and then an opioid, markedly decreased gastrointestinal motility may occur, necessitating closer monitoring of those patients' water and food intake.

NSAIDs have more potential drug interactions that could preclude their use. The relatively selective COX-2 agents (e.g. meloxicam, carprofen) can increase the toxicity of warfarin, methotrexate sodium, valproic acid, furosemide, spironolactone, and sulfonylureas.25 NSAIDs may decrease the efficacy of furosemide, thiazides, ACE inhibitors, and beta-blocking agents.24 Finally, relatively selective COX-2 agents are more likely to be toxic when administered with aminoglycosides, furosemide, cyclosporine, and glucocorticoids.25

Lesley J. Smith, DVM, DACVA

Department of Surgical Sciences

School of Veterinary Medicine

University of Wisconsin

Madison, WI 53706

REFERENCES

1. Dobbins S, Brown NO, Shofer FS. Comparison of the effects of buprenorphine, oxymorphone hydrochloride, and ketoprofen for postoperative analgesia after onychectomy or onychectomy and sterilization in cats. J Am Anim Hosp Assoc 2002:38:507-514.

2. Slingsby LS, Waterman-Pearson A. Comparison of pethidine, buprenorphine, and ketoprofen for postoperative analgesia after ovariohysterectomy in the cat. Vet Rec 1998;143:185-189.

3. Stanway G, Taylor P, Brodbelt D. A preliminary investigation comparing pre-operative morphine and buprenorphine for postoperative analgesia and sedation in cats. Vet Anaesth Analg 2002;29:29-35.

4. Lascelles BD, Robertson SA, Taylor P, et al. Comparison of the pharmacokinetics and thermal antinociceptive pharmacodynamics of 20 µg/kg buprenorphine administered sublingually or intravenously in cats. Vet Anaesth Analg 2003;30:109.

5. Lascelles BD, Roberson SA. Antinociceptive effects of hydromorphone, butorphanol, or the combination in cats. J Vet Intern Med 2004;18:190-195.

6. Lascelles BD, Robertson SA. Use of thermal threshold response to evaluate the antinociceptive effects of butorphanol in cats. Am J Vet Res 2004;65:1085-1089.

7. Brock KA, Webb AI. Intravenous lidocaine kinetics in cats and dogs, in Proceedings. 3rd Int Cong Vet Anesth 1988;A61.

8. Heavner JE. Local anesthetics. In: Thurmon JC, Tranquilli WJ, Benson GJ, eds. Lumb and Jones veterinary anesthesia. 3rd ed. Baltimore, Md.: Williams & Wilkins, 1996;330-336.

9. Giasi RM, D'Agostino E, Covino BG. Absorption of lidocaine following subarachnoid and epidural administration. Anesth Analg 1979;58:360-363.

10. Lamont LA. Feline perioperative pain management. Vet Clin North Am Small Anim Pract 2002;32:747-763.

11. Duke T, Cox AM, Remedios AM, et al. The analgesic effects of administering fentanyl or medetomidine in the lumbosacral epidural space of cats. Vet Surg 1994;23:143-148.

12. Duke T, Cox AM, Remedios AM, et al. The cardiopulmonary effects of placing fentanyl or medetomidine in the lumbosacral epidural space of isoflurane-anesthetized cats. Vet Surg 1994;23:149-155.

13. Kushner LI, Trim CM, Madhusudhan B, et al. Evaluation of the hemodynamic effects of interpleural bupivacaine in dogs. Vet Surg 1995;24:180-187.

14. Lascelles BD, Henderson AJ, Hackett IJ. Evaluation of clinical efficacy of meloxicam in cats with painful locomotor disorders. J Small Anim Pract 2001;42:587-593.

15. Lees P, Taylor PM, Landoni FM, et al. Ketoprofen in the cat: pharmacodynamics and chiral pharmacokinetics. Vet J 2003;165:21-35.

16. Parton K, Balmer TV, Boyle J, et al. The pharmacokinetics and effects of intravenously administered carprofen and salicylate on gastrointestinal mucosa and selected biochemical measurements in healthy cats. J Vet Pharmacol Therap 2000;23:73-79.

17. Slingsby LS, Waterman-Pearson AE. Postoperative analgesia in the cat after ovariohysterectomy by use of carprofen, ketoprofen, meloxicam, or tolfenamic acid. J Small Anim Pract 2000;41:447-450.

18. Slingsby LS, Waterman-Pearson AE. Comparison between meloxicam and carprofen for postoperative analgesia after feline ovariohysterectomy. J Small Anim Pract 2002;43:286-289.

19. Taylor PM, Delatour P, Landoni FM, et al. Pharmacodynamics and enantioselective pharmacokinetics of carprofen in the cat. Res Vet Sci 1996;60:144-151.

20. Brideau C, Van Staden C, Chan CC. In vitro effects of cyclooxygenase inhibitors in whole blood of horses, dogs, and cats. Am J Vet Res 2001;62:1755-1760.

21. Dundee J, Halliday N, McMurray T. Aspirin and probenicid pretreatment influences the potency of thiopentone and the onset of action of midazolam. Eur J Anaesthesiol 1986;3:247-251.

22. Al-Gizawiy MM, Rude EP. Comparison of preoperative carprofen and postoperative butorphanol as postsurgical analgesics in cats undergoing ovariohysterectomy. Vet Anaesth Analg 2004;31:164-174.

23. Wagner AE, Walton JA, Hellyer PW, et al. Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs. J Am Vet Med Assoc 2002;221:72-75.

24. Robertson SA, Taylor PM, Sear JW. Systemic uptake of buprenorphine after oral mucosal administration in cats. Vet Rec 2003;152:675-678.

25. Trepanier LA. Potential interactions between NSAIDs and other drugs. J Vet Emerg Crit Care 2005:in press.