Adjunctive analgesic use for acute and chronic pain (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.
Chronic pain is not merely acute pain of extended duration. Rather, it is a maladaptive state whereby the discomfort transcends the original injury or stimulus, and becomes instead an innate feature of the central nervous system. Normal nociception is replaced by a constellation of microanatomic, physiologic, and molecular changes both centrally and peripherally, which result in an increased sensitivity to both noxious and non-noxious stimuli.
OpioidsOpioid 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 (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) though other commonly used parenteral formulations exist. 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. Tramadol (Ultram) is another 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- and norepinephrine (inhibitory neurotransmitters) 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. One unpublished study on the effectiveness of tramadol administered once daily in canine osteoarthritis appears encouraging 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.
As effectiveness diminishes and dose requirements escalate, undesirable adverse effects become more likely (most commonly reported in humans by far is constipation; but abnormal pain sensitivity, hormonal changes, and immune modulation are also reported though their mechanisms are not fully established), and the practitioner must also always be vigilant regarding drug diversion. Historically, opioid use in chronic pain has been most commonly reserved for palliative care and breakthrough pain (BTP), often of cancer patients. However, as opioid interaction with a variety of non-opioid receptors (e.g. NMDA, alpha2 adrenergic) has become more evident, the role of opioids is being redefined for their utility in a multi-modal approach to chronic pain conditions, including osteoarthritis. Furthermore, novel Peripherally Acting Mu Opioid Receptor Antagonists (PAMOR) are in the final stages of development; taken with an oral opioid, PAMORs will permit the central analgesic effect of the opioid but block their effect on gastrointestinal motility. Such medications hold great promise in minimizing constipation, which commonly forces the withholding of opioids. Hydrocodone, codeine (alone and in combination with acetaminophen), and sustained-released forms of oral opioids include morphine (MSContin), oxycodone (Oxycontin), and oxymorphone (Opana ER) are all available by prescription, though pharmacokinetics and pharmacodynamics in dogs and cats is less established. Rectal suppository opioid formulations may also be prescribed, but appear to provide little advantage in bioavailability over the oral route in the dog.
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.