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.

Opioids

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 (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.

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.

Ketamine

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. They exert their action by binding to a hydrophilic site within sodium channels, thereby blocking it and disallowing the Na+ influx; thus neurons may not depolarize and thus the effect can be complete anesthesia to a site rather than mere analgesia. Various local anesthetics will have variable onsets and duration of action, and they may be combined for a rapid and extended effect. The locality of administration is often limited only by the clinician's ability to learn various utilities and anatomic landmarks; few are outside the scope of any clinician to master. They include, but are not limited to local line or paraincisional blocks, regional blocks such as carpal ring, dental nerve, and intercostal blocks, subcutaneous diffusion blocks, testicular blocks, intra-articular blocks, epidurals, transdermals (EMLA, Lidoderm). Lidocaine administered intravenously has been shown in humans to speed the return of bowel function, decreases postoperative pain, minimize opioid consumption, and shorten the hospital stay after abdominal surgery; Systemic, intravenous infusion of lidocaine has also been shown to elicit a sustained effect on neuropathic pain in humans, and may have a specific point of action in the brain.

Gabapentin

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.

Gabapentin has become a popular in human medicine since its introduction in 1994 for many chronic and neuropathic pain conditions. However, a TID administration schedule may be difficult to sustain long-term, and no veterinary studies are currently published on its use. However, anecdotally, BID administration does appear to achieve a clinical effect in dogs. Interestingly, in a rat model there is recent evidence a gabapentin-like analog has reduced the development of experimental osteoarthritis. The adverse effect of somnolescence can be mitigated by starting off at quite low doses and tapering upwards. Pregabelin (Lyrica) is new generation compound, labeled for use in diabetic neuropathy and post-herpetic neuralgia; its utility in animals remains unknown at this time.

Amantadine

NMDA receptor antagonism remains a research focus for chronic pain in humans, but no clinical studies report on its use for osteoarthritis. Amantadine is an anti-viral (influenza-A) compound use in humans as for treatment of Parkinson's disease due to its dopaminergic effects, and is reported to exert an analgesic effect through NMDA receptor antagonism. One study in dogs with osteoarthritis demonstrated greater improvement over 12 weeks of treatment with amantadine with meloxicam, compared to meloxicam alone. Toxicity and kinetic studies have been performed in humans, but not in dogs. Anecdotally in dogs and cats, diarrhea is commonly noted and agitation less frequently.

Tricyclic antidepressants

TCA's exert their analgesic activity by blocking norepinephrine and serotonin (5-HT) reuptake in the dorsal horn synaptic cleft of inhibitory neurons that have descended from the medulla oblongata and mesencephalon; this allows these inhibitory neurotransmitters to exert a prolonged and more pronounced effect. Since depression (pain-related and otherwise) is also mediated through NE and serotonin, patients may have benefit of TCA's from these co-existing but distinct mechanisms. Other additional effects include interaction with NMDA activity and sodium channel blockade. As a class, TCA's are a first-line medication for neuropathic pain in humans, and amitryptiline is the most commonly used TCA in both humans (primarily for diabetic neuropathy) and animals (primarily for chronic feline interstitial cystitis). It has a balanced NE and serotonin effect, and thus is among the more sedating, anti-cholinergic, and effective of various TCA's. Newer TCA's such as duloxetine (Cymbalta) developed for diabetic neuropathy have more strict serotonin (i.e. NE-sparing) activity, diminishing their adverse effects; its clinical use in animals has not been documented. TCA's should not be used with other serotoninergic medications such as tramadol.

DMOAA

Disease-modifying osteoarthritic agents are products that are not FDA-approved medications or are not known to have a primary analgesic mechanism of action, or both, but which seem to have a positive influence on patients with osteoarthritis. The polysulfated glycosaminoglycans exert their action by inhibiting collagenase and promoting the formation of fibrocartilage, which should have the dual effect of improving the clinical status of the patient as well as slowing the course of osteoarthritis. While not entirely a settled matter in humans, evidence is beginning to accumulate that the combination of glucosamine and chondroitin (not either one used alone) exerts a positive structure-modifying effect on the cartilage, thus interfering with the progression of OA. The only FDA-approved drug in this category is Adequan, which in the author's hands has a more rapidly demonstrable and reproducible effect than oral supplements. Adequan may be administered (off-label) via a subcutaneous route with similar bio-availability as the IM route, allowing it to be dispensed for the owner to give at home. This decreases considerably the cost and inconvenience to the owner, which in turn adds greatly to compliance. The author also uses it regularly (off-label, currently) in cats.

Cancer pain

Neoplasia remains a special subset of patients suffering from chronic pain, with osteosarcoma as the prototype in dogs. Certainly soft-tissue inflammation, necrosis, nerve compression, lymphatic obstruction are all indirect contributors to cancer pain. With osteosarcoma, pathology to the periosteum is a direct contributor to the pain associated with this type of cancer. Tumors may also secrete a number of bioactive molecules which sustain and enhance the nociceptive pathways in ways distinct from other sorts of chronic inflammatory conditions. Lastly, our therapeutic interventions may elicit pain as well. For this reason, it is important to access the practitioners' entire pain-modulating arsenal, and where possible, at the higher end of tolerated doses (e.g. tramadol, gabapentin). The anti-neoplastic effects of certain NSAIDs in humans and in dogs have been well-established and appear to be mediated through the up-regulation and over-expression of the COX2 enzymes in some neoplasms of these species. It is unknown across what spectrum of other NSAIDs, species, and neoplasms this effect might occur; in fact most of the neoplasms evaluated in cats have little if any COX2 expression. However, NSAID in cancer pain would seem to exert a positive benefit if only by it's anti-inflammatory and analgesic effect. Bisphosphonates are compounds which may palliatively alleviate OSA-related pain by decreasing osteoclast activity and inhibiting calcium and phosphorus dissolution, with pamidronate in most common use for dogs., Infusions are given approximately once weekly in patients whose owners elect to forgo surgery and chemotherapy. Anecdotally, 60% of dogs will be responsive within a week, and about half of those will be durable i.e. > 4 months; it appears most effective when administered as part of multi-modal therapy. Nephrotoxicosis is reported to be a limiting adverse effect. Oral opioids were once considered to be generally poorly absorbed, short-acting, and prone to tolerance and adverse effects. While their long-term use in animals is currently limited, methadone and newer extended-release and transmucosal opioids, as well as novel opioid combinations which minimize constipation, may have a role in palliative care and break-through cancer pain (see above). Recent studies in a rat model suggest pain resulting from bone neoplasia is better attenuated by systemically-administered delta- (rather than mu) opioids.

Systematic reviews of neuropathic pain in humans recommend a treatment algorithm, regardless of etiology, that includes drugs of first choice tricyclic anti-depressants, gabapentin, and opioids. However, these papers are drawn mainly from trials involving diabetic neuropathy and post-herpetic neuralgia, conditions yet to be documented in animals, and effectiveness of these medications has not been demonstrated for the most common neuropathic pain condition in humans, lumbar radicular pain (sciatica).

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