Adjunctive analgesic drugs: beyond NSAIDS and opioids (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.
KetamineA 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 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 block, 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 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.