Analgesics in cats: what makes them different? (Proceedings)

Our selection of analgesic options for the feline is influenced by the species' characteristic physiology and individual variation. The increasing popularity of the cat fuels exploration of this complex animal's unique attributes. Because veterinarians want to choose the best therapy for their patients, this lecture provides a review of these differences with the goal of improving analgesic therapy for the feline patient.

Feline physiology is distinct

Like their personality, cats have a physiology that is uniquely their own. When exploring pharmacologic analgesic options for patients, one must understand how a drug is metabolized and excreted. The cat's hepatic metabolism is distinctive in several ways. The first phase of drug metabolism renders a drug active or inactive (depending on the drug), and is largely carried out by cytochrome P-450 microsomal enzymes (CYP450). As compared to other mammals, the feline has relatively low CYP450 activity, meaning there will be a decrease in this first phase of metabolism. The second phase of metabolism involves preparing the product of Phase I metabolism for excretion by making it more water-soluble. The most common pathway for this preparation is conjugation of the end product via the glucuronide pathway. Cats have relatively low levels of glucuronyl transferases (common in carnivores). While it is fair to say, as a generality, cats have a reduced hepatic metabolism, it is important to keep in mind that the consequence of feline hepatic metabolism ultimately depends on the drug. There are some drugs that the cat can efficiently glucuronidate, or conjugate via an alternative pathway.

Once a drug is metabolized, it is important to clear the drug. This is most commonly (but not exclusively) done by the kidney. The feline's drug clearance is impacted by the drug administered and the level to which the drug product is broken down. For drugs that are excreted from the body unchanged, such as gabapentin in the human, there is less difference in drug disposition. However, for a drug such as ketamine, which is only metabolized to norketamine (an active metabolite) in cats, clearance can have a major impact on the duration of a drug's effects. Indeed, some drugs are suspected of directly negatively impacting renal function. Non-steroidal anti-inflammatory drugs are those most commonly implicated. In a study performed on cats receiving meloxicam (orally at 0.2mg/kg once on day one and orally at 0.1mg/kg once a day for days two through five), there was no difference in the glomerular filtration rate—suggesting meloxicam in healthy cats does not alter clearance (Goodman et al. 2009).

Often doses are extrapolated from one species to another, but this does not account for the difference in feline metabolism and clearance. The concept of allometric scaling suggests that the cat would have a higher metabolism than other larger species (for example, the canine), and thus a larger dosage or a more frequent drug administration is necessary to maintain adequate plasma drug levels. Additionally, because the cat is a carnivore, extrapolating drug dosages based on research done in other carnivores is prudent for accuracy.

Without a doubt, the most accurate information comes from studies performed on cats themselves. Cats tend to have a smaller volume of distribution, which would alter the drug dosages necessary to maintain adequate concentrations. However, feline pharmacokinetic studies are small in number.

Individual variation is an important factor in analgesia

Genetic diversity plays an intensifying role in human analgesia. For example, females or people with red hair may have an altered response to pentazocine—two examples highlighting the major role genetic diversity may have in a patient's response to analgesics. Pharmacogenetics is gaining prominence in the veterinary field, with one study in the veterinary field examining differences in single nucleotide polymorphism in canine m receptors (Hawley and Wetmore 2010). While the cat genome has been mapped, there still remain opportunities for further research into feline pharmacogenetics.

Feline response to analgesic drugs is distinct

Researcher have developed models to investigate pain in a laboratory setting, to provide preliminary research for drugs that might address clinical pain. When reviewing studies looking at models of pain in the feline, it is important to understand what these models represent. For example, a nerve transection model may more accurately assess neuropathic pain than force plate analysis would. One debunked myth in the cat is an analgesic drug is correlated with the reduction in the minimum alveolar concentration (MAC) value; a recent study (Brosnan et al. 2009) was clearly able to demonstrate in spite of no real change in the amount of anesthetic required, the awake cat had a change in thermal threshold when given the m opioid agonist remifentanil. This breakthrough was a clear testament to the usefulness of m opioid agonists in cats, which some veterinarians are hesitant to use in light of the possibility of "morphine mania", a highly overrated phenomena that was present after excessively high doses of opioids were given to cats in the mid-1950s. The cat does exhibit differences in response to opioids, such as pupillary dilation as well as "euphoria", as opposed to sedation. Additionally, if a cat experiences intraoperative hypothermia after opioid administration, they may exhibit a rebound hyperthermia in the post-operative period. This should not discourage practioners from including opioids as part of the pre-emptive analgesic plan for the feline, but should encourage the use of devices to assist with maintaining normal body temperature (circulating warm water blankets, forced air warming, etc).

Clinical relevance of feline nuances

What do all these differences mean for us clinically? Many pearls of wisdom have come from exploration of feline nuances.

Morphine appears to have a biphasic effect on the cardiovascular system of cats. Low doses can produce a decrease in heart rate and blood pressure, while higher doses (greater than 8mg/kg) may have the opposite effect. Catecholamine release from the adrenal glands likely mediates this increase in blood pressure and heart rate. This can be antagonized with a reversal agent (i.e. naloxone).

Cats have a high degree of individual variability in response to analgesic drugs/modes of analgesic administration. For example, there is a wide range of variability in response to epidural administration of opioids in cats. This has been demonstrated with older, less available analgesic drugs such as nitrous oxide. Clinically, this means that a "cookie cutter" approach, with a "one drug or mode" fits all strategy is inappropriate, and response to analgesics should guide analgesic plans for interventions and conditions which may be uncomfortable or painful in the cat.

Opioids are not the only drug class with individual variability. Non-steroidal anti-inflammatory drugs (NSAIDs) can have a wide range of half-lives in the feline, with carprofen having a variable half-life of anywhere from 9 to 49 hours in the cat (Lascelles et al. 2007)! A review of NSAIDs done by Lascelles et al (see references) is the most complete resource for specific NSAID information. NSAIDs that are oxidized, such as meloxicam, may be preferable in light of the reduced hepatic metabolism of the feline.

Local anesthetics are also incorporated into feline analgesic plans. While local blocks of specific nerves remain useful modalities, further investigation into the systemic (constant rate infusion) administration of lidocaine suggests that as we approach a relevant concentration of local anesthetic in plasma, there is also a dose-dependent reduction in cardiac output, making a constant rate infusion of lidocaine a potentially undesirable choice if cardiac output is already compromised (e.g. anesthesia).

Gabapentin has received recent attention in regards to its possible analgesic use in cats. Pharmokinetic studies have given us information about its usage in cats, but additional work using thermal threshold models (Pypendop, Siao and Ilkiw 2010) have not validated its use as a "generic" addition to an analgesic regimen. The thermal threshold model may not be the most suitable model for neuropathic pain in the cat, however.

In conclusion, analgesic plans for the feline present challenges and opportunities for improvement. When formulating a plan, a thorough understanding of the unique physiology and individual variability of the cat allows rational drug choices, which will improve quality of care.

References

Brosnan, R. J., B. H. Pypendop, K. T. Siao & S. D. Stanley (2009) Effects of remifentanil on measures of anesthetic immobility and analgesia in cats. Am J Vet Res, 70, 1065-71.

Goodman, L. A., S. A. Brown, B. T. Torres, L. R. Reynolds & S. C. Budsberg (2009) Effects of meloxicam on plasma iohexol clearance as a marker of glomerular filtration rate in conscious healthy cats. Am J Vet Res, 70, 826-30.

Hawley, A. T. & L. A. Wetmore (2010) Identification of single nucleotide polymorphisms within exon 1 of the canine mu-opioid receptor gene. Vet Anaesth Analg, 37, 79-82.

Lascelles, B. D., M. H. Court, E. M. Hardie & S. A. Robertson (2007) Nonsteroidal anti-inflammatory drugs in cats: a review. Vet Anaesth Analg, 34, 228-50.

Pypendop, B. H., K. T. Siao & J. E. Ilkiw (2010) Thermal antinociceptive effect of orally administered gabapentin in healthy cats. Am J Vet Res, 71, 1027-32.