NSAIDS-what to choose (Proceedings)

Non-steroidal anti-inflammatories, or NSAIDs, are unique drugs that provide analgesia by decreasing peripheral inflammatory enzyme conversion and reducing central pain perception. These drugs may also possess anti-inflammatory and anti-pyretic activity. Objectives of this lecture are to review the mechanism of action, pharmacokinetics, desirable and undesirable side effects, species differences and briefly the specific NSAIDs in clinical use, as they relate to acute pain management.

Mechanism of action

The mechanism of action of NSAIDs result from their effects when a cell's phospholipid membrane is damaged. NSAIDs will inhibit cyclooxygenase (COX) production, which will result in a decrease in both prostaglandin (PG) formation and thromboxane (TX) production. However, besides inflammation, COX enzymes play a part in many other homeostatic functions, as does thromboxane. Therefore, detrimental effects can result from inhibition of these enzymes. To fully understand this, we must discuss the different isoenzymes.

     1. COX-1 is sometimes referred to as a "constitutive" enzyme. This means this enzyme is fundamental to normal homeostatic functions, and consistently present. Examples of COX-1 mediated functions include gastrointestinal (GI) protection (PGI2 and PGE2), platelet function and blood flow regulation (TXA2 and PGI2), and kidney protection (PGE2); therefore, inhibition of COX-1 has potential deleterious consequences in the normal patient.

     2. COX-2 is referred to as an "inducible" (although there is some evidence for it being constitutive in the brain and kidney) enzyme, and mediates functions such as pain, inflammation and fever. Inhibition of these enzymes can potentially have benefit.

     3. However, don't forget this is an over-simplification. For example, once an ulcer has formed, COX-2 is necessary for it to heal. Therefore, we must be cautious about selecting appropriate patients to receive NSAIDs, rather than selecting one NSAID that is safe for all patients.

     4. Selectivity ratios allow for comparison between NSAIDs in regards to their COX-1 and COX-2 activity. While often written as COX-1:COX-2, one must verify this information when reviewing pertinent literature. This selectivity ratio uses values for the Inhibitory Concentration on 50% of enzymatic activity (IC50); this is done in a whole blood assay. Keep in mind, it is not possible to target COX-2 mediated function without some impact on COX-1 function.

     5. Thromboxane, an eicosanoid, is derived from prostaglandins synthesized by TXA2 in platelets, and thus inhibition can result in platelet clotting dysfunction.

     6. Lipoxygenase is an activator of leukotrienes. Lipoxygenase enzymes are considered pro-inflammatory mediators, but have a relatively novel/ill defined contribution to the inflammatory pathway; that is to say, COX-2 appears to play a much larger part in signaling the inflammatory cascade. However, there is intense research looking at the benefits from blockade of these enzymes.

Pharmacokinetics

One of the most important points when reviewing relevant literature regarding NSAIDs is that the plasma concentration of these drugs may be low to non-existent although the NSAID still exhibits its effects . . . this is because it is concentration at the tissue site that is the most important factor for determining drug action and duration.

Effects

     1. Desired side effects include their usefulness for as analgesic. Their inhibition of COX (and in some cases LOX) enzymes will reduce the conversion of arachidonic acid into prostaglandins and leukotrienes. Many of these drugs are also anti-pyretic as well.

     2. Adverse side effects highlight the critical role that a veterinarian plays: it is incumbent on the veterinarian to select the appropriate patient to receive these drugs. The FDA allows reporting of adverse effects by lay people and veterinarians alike; this website offers a very extensive list of adverse events reported for specific NSAIDs, with most common adverse events listed first:

        http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm055394.htm

Species differences

Not all NSAIDs are licensed for use in both the cat and dog; for instance, although carprofen is used by some veterinarians in the cat, it is not licensed for administration in the cat in this country. Meloxicam is currently the only licensed NSAID in the cat in the USA although soon robenacoxib may become available as well. Further reading and discussion on NSAIDs in the cat, which goes into much more detail than this lecture can cover, is available in a 2007 review (see Non-steroidal anti-inflammatories in the cat: A review; VAA, 2007; 34, 228–250).

NSAIDs of clinical importance

When presented with a patient who may benefit from therapy with a NSAID, it is prudent to screen the patient appropriately, add adjunctive GI protection as necessary, choose an NSAID licensed for that species, and counsel the owner on the side effects to look for.

The debate: Pre-operative versus post-operative NSAID administration

One heavily debated topic in veterinary pain management is the timing of NSAID administration. It is important to realize there is no single right answer; there are pros and cons to each choice. Pre-operative administration provides preemptive analgesia, resulting in greater patient comfort. While this is a noble goal, there is the possibility that the intended procedure may not go smoothly. Blood loss is a possibility of many orthopedic and soft tissue surgeries, and hypotension is common with anesthesia. Because there is no reversal agent for NSAIDs, and all NSAIDs have at least partial COX-1 inhibition, blood loss and hypotension after administration can have serious consequences in terms of renal perfusion and inability to achieve hemostasis, which can have long term consequences for the patient. On the other hand, if NSAIDs are administered after the procedure, COX-2 mediated events (such as pain and inflammation) have begun, and will only be moderated by NSAIDs, not prevented. Prudence dictates assessing the risk of hypotension and blood loss for each patient, as well as the experience level of the surgeon and difficulty of the surgery, and selecting pre- vs. post-operative administration on a case-by-case basis.