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


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.

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.


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.


Opioid receptors are distributed ubiquitously throughout the body and can be found in most central and peripheral tissues. Several opioid different receptor types and subtypes have been isolated, each with a variant effect; activation of an opioid receptor inhibits presynaptic release and postsynaptic response to excitatory neurotransmitters. The proposed mechanism includes opioid receptor coupling with the membrane-associated G protein; this leads to decreased intracellular formation of cAMP which diminishes calcium channel phosphorylation (closing off the channel) and opens potassium channels enhancing potassium influx. The resulting effect is hyperpolarization of the neuron and blockade of Substance P release. Nociceptive transmission is thus greatly impeded.

Similarly, a number of different opioid drugs are available which vary in their relative potency and receptor affinity, and a complete discussion of their similarities and differences are available in a number of resources. Briefly, however, of the pure mu agonists, morphine remains the prototype in widest use; it has no ceiling effect on analgesia or respiratory depression, elicits histamine release, and causes vomiting at low doses (higher doses, IV doses, and chronic use do not elicit vomiting, presumptively by interaction with mu receptors in the antiemetic center). Cats lack glucoronate metabolism, resulting in minimal production of the analgesic M6G metabolite, therefore morphine may not be the ideal opioid for use in this species. Oxymorphone (Numorphan) and hydromorphone (Dilaudid) do not elicit histamine release (therefore may be wiser choice in cases of hypovolemia e.g. trauma, dehydration), and nausea may be less pronounced, but they have a much shorter duration of action than morphine; also, hydromorphone in particular is implicated in episodes of hyperthermia in cats. Fentanyl in a transdermal patch (Duragesic) remains useful in veterinary medicine though a number of studies have demonstrated wide kinetic variability in veterinary patients due to species, body condition score, body temperature, surgical procedure, where and how well the patch is placed, etc. Buprenorphine is a partial agonist on the mu receptor though it has greater affinity than morphine (and will displace it if given together). A great benefit of the drug in veterinary medicine is that its pKa (8.4) closely matches the pH of the feline oral mucosa (9.0), which allows for nearly complete absorption when given buccally in that species, with kinetics nearly identical to IV and IM administration, and eliciting very little sedation. Butorphanol is a mu agonist and a kappa antagonist; it's very short duration of action in the dog (approx. 30-40 min) makes it a poor choice for an analgesic in this species, though used parenterally it has utility as an adjunct with other medications such as alpha-2 agonists. Tramadol (Ultram) is another mostly non-scheduled (for now) opioid with 1/100th of the affinity for the mu receptor as morphine but a much better analgesic effect than this would predict. This is likely due to the combined effect of a highly active M1 metabolite and serotonin (an inhibitory neurotransmitter) agonism. Recent work demonstrates that it appears to have a very short half-life (1.7 hours) in the dog, so for full effectiveness it may need to be given as often as every 6 hours, which may or may not be an obstacle for short-term administration. However, tramadol has also become a popular adjunct to chronic pain management in both human and veterinary medicine, though its dosing interval long-term is not likely to be sustained at maximum frequency. The incidence of dependence in humans may be substantially higher than previously suspected, meaning that the drug may move to a controlled status (in some states it already has). Tramadol should not be used with other serotoninergic medications such as tricyclic antidepressants.

Opioids for all their effectiveness may create clinical challenges as well. In the acute setting, opioid-induced dysphoria, hyperalgesia, and respiratory depression may be encountered; recognizing and having strategies for counteracting their signs will minimize the complications that they present.

Alpha 2 agonist

Medetomidine and dexmedetomidine binds opioid-like receptors on C- and A-delta fibers, especially in the central nervous system. Binding pre-synaptically, NE production is reduced and sedation occurs; binding post-synaptically, analgesia is produced, and is profoundly synergistic with opioids. It also blocks NE receptors on blood vessels, resulting in vasoconstriction; the resulting hypertension parasympathetically induces bradycardia, which is extended by a subsequent direct decrease in sympathetic tone. However, central perfusion is maintained and the author has found a wide use for these alpha-2 agonists in acute and peri-operative setting, though only in combination with opioids and at doses much lower than suggested by the manufacturer. One particularly novel and user-friendly utility is IV micro-doses intra- and post-operatively, 0.25 – 1.0 mcg/kg. This may result in intravenous volumes of only 0.01 – 0.03 ml in even the largest of dogs.


A phencyclidine dissociative anesthetic, the evidence is building for its pre-emptive and preventive effects when given at subanesthetic doses in an intravenous constant rate infusion. Ketamine binds to a phencyclidine receptor inside the NMDA receptor, i.e. the calcium channel would already have to be open and active for ketamine to exert its effect. However, once bound, it decreases the channel's opening time and frequency, thus reducing Ca+ ion influx and dampening secondary intracellular signaling cascades. Hence it is unlikely (and has not been shown) to be truly analgesic in nature. Rather, it appears to be protective against hyperalgesia and central hypersensitization in the post-operative setting., including in the dog.

Local anesthetics

Local anesthetics were once a mainstay of pain management in veterinary medicine, and may now be one of the most under-utilized modalities. A comprehensive discussion of their various uses, both traditional and novel, is covered in other sessions.


Gabapentin is labeled for use as an anti-convulsant drug but is in widespread human use for its analgesic properties. While structurally similar to GABA, it is not a direct agonist, although it may have indirect effects on GABA metabolism such as increasing intracellular stores. Another leading hypothesis is that it exerts effect through interaction with the alpha-2-delta subunit of the voltage gated calcium channel. In a study of women undergoing hysterectomy, only the patients receiving both NSAID and gabapentin were completely satisfied with their post-operative pain management, when compared to women receiving either NSAID or gabapentin alone, and in a meta-analysis of 896 patients undergoing a variety of surgical procedures, gabapentin significantly reduced pain at both 4 and 24 hours post-op when compared to placebo. Pharmacokinetic studies in dogs reveal that it may have a half-life of 3-4 hours in the dog, suggesting a TID administration schedule. The primary adverse effect in dogs appears to be somnolescence (as in humans) which usually will spontaneously resolve over a few days acclimation time, but this AE not been a frequent occurrence in the author's experience.


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