Multimodal approach to pain management analgesia: not "too much", rather a safe and effective synergy (Proceedings)
The framework of effective pain management systems rests solidly on the foundation of recognition/assessment, pre-emption, and using multiple modalities. Multiple modalities allow for intervention at several different places of the nociceptive pathway, increasing effectiveness and minimizing the need for high or protracted doses of any one particular drug. It is well-established in human medicine, for example, that the use of adjunct medications will minimize the use of PCA (patient-controlled analgesia) opioids with a resultant decreased incidence of adverse effects such as nausea and constipation.
The primary mode of action is to inhibit cyclooxygenase 2 (COX2), the enzyme that is expressed at site of inflammation and results in the production of pro-inflammatory and vasoactive prostaglandins. Also, through poorly understood mechanisms, likely by modulating multiple gene expression pathways, it may inhibit central perception of pain. Several superior products are now labeled for use in dogs (and some in cats), making them among the most popular of pain management medications in veterinary medicine. All seem to be effective, and head to head studies now emerging may help to reveal objective differences if they are present. The main limitation of all NSAID's revolves around the potential for adverse effects, since both COX 1 and COX 2 enzymes may be constitutive, that is, consistently present and crucial to the production of cyto-protective prostaglandins (COX1 especially in the GI tract and renal tubules, COX2 in the renal tubules). Thus the primary adverse effects of non-selective NSAID's may include GI erosion/ulceration and nephrotoxicity. COX1-sparing NSAIDS should have a dramatically diminished GI toxicity profile, but will maintain their risk for nephrotoxicity. Rarely and on an idiosyncratic basis, hepatotoxicity may occur. The GI and renal adverse effects can be expected to occur most commonly in higher risk patients, e.g.: hypovolemia, hypotension (including anesthetic procedures especially those not supported by intravenous fluids), pre-existing GI or renal disease, overusage, and the inappropriate combination with other NSAID's, corticosteroids, or other highly protein-bound drugs. Notable in adverse drug interactions is the client use of aspirin in their pets, which may be unbeknownst to the clinician unless specifically queried in a thorough history. The relative roles and molecular dynamics of COX1, COX2, and a possible new variant COX3, is still being elucidated and the "final word" on the optimal COX-selective or –sparing effect in order to maximize effectiveness and to limit toxicity, is yet to be heard.NSAID's, and the merits of using them in cases of chronic inflammatory conditions, e.g. osteoarthritis, are a familiar and well-established class of drug. However, their long-term use may increase the chances of adverse effects. In general, a 5-day washout between NSAID's is recommended, and 10 days specifically for aspirin and meloxicam. Where possible, the use of other modalities may allow lower NSAID doses which may in turn increase the safety profile. In all cases of NSAID use, the practice must consistently and reproducibly educate clients regarding the potential adverse effects of this class of drug. More than ¾ of individuals reporting adverse NSAID events to the FDA hotline feel that their veterinarian did not inform them adequately of possible side effects, and/or failed to give the client the drug information sheets provided by the pharmaceutical company.
A special word regarding the long-term use of NSAID in cats. In 2010 the AAFP and ISFM (International Society of Feline Medicine) released Consensus Guidelines on the long-term use of this class of drug in cats. The reader is referred to this manuscript in its entirety, but the authoring panel suggests the following points: withholding NSAID in cats with chronic pain may fulfill the "First, Do No Harm" paradigm but fails to recognize the harm of undermanaged chronic pain; and that NSAID's may be used long-term as a management tool with proper patient selection, monitoring, and seeking the lowest effective dose. Unfortunately, the "Black Box" placed on the label of meloxicam in the U.S. complicates the use of this product in cats.
Acetaminophen appears to have weak COX-1 and COX-2 inhibition, but may inhibit a centrally-expressed COX-3 and a partial COX1 (PCOX-1) enzymes, mediating an analgesic effect by dulling the pain sensory system. Acetaminophen is contraindicated in cats and in patients with liver disease, and should be used with caution, especially chronically, in dogs due to limited experience and diminished metabolism when compared to humans.