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Multimodal analgesia: not "too many" drugs, rather a safe and effective synergy (Proceedings)

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Aug 01, 2011

Pain can be protective, but through the stress response it may also contribute significantly to patient morbidity and even mortality. Anxiety may contribute directly to the hyperalgesic state through cholecystikinin-mediated "nocebo" effect. Furthermore, a recent study in humans reveals that in people undergoing routine ambulatory surgery such as groin hernia repair, breast surgery, and digit amputation, acute postoperative pain is followed by persistent pain in 10-50% of patients, and chronic pain will be severe in 2-10% of these individuals. Thus the priority clinicians should place upon pain management in the acute and peri-operative setting is not only to minimize discomfort in that immediate period for its own sake, but to prevent whenever possible the debilitating effects of discomfort that may result from it in the time quite distant from the original insult.

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.

NSAID

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, hepatoxicity 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 or corticosteroids. Notable in this last category is client use of aspirin in their pets, which may be unbeknownst to the clinician unless specifically queried in a thorough history. Unique to aspirin, this NSAID produces a cyto-protective lipoxin through the COX pathway; thus when COX is inhibited through the use of another, concurrently-given NSAID, the potential for GI toxicity is considerably enhanced. 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. Acetaminophen may elicit some of its analgesic effects by inhibiting the COX3 variant, and recent studies suggest that it may also inhibit COX2-mediated production of PGE2. Lipooxygenase also metabolizes arachadonic acid, but instead of prostaglandins the byproducts are leukotrienes, which are potent attractors of PMN's and promote their adherence to endothelium. One commercial veterinary NSAID, tepoxalin, inhibits LOX as well as balanced COX enzymes. In any use of NSAID's, the potential for adverse effects needs to be made clear to pet owners, and for any extended use, regular metabolic monitoring should be performed.