Sheilah Robertson, BVMS (Hons), PhD, DACVAA, DECVAA, DACAW, DECAWBM (WSEL), MRCVS
Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
Surgery or trauma produces local inflammation and a change in sensitivity to noxious stimuli. As the local area of tissue injury becomes more sensitive, the threshold for subsequent stimuli decreases; this is termed primary or peripheral hyperalgesia and is a result of inflammatory mediators sensitizing local nociceptors. Hypersensitivity does not remain localized to the original site of injury but spreads to other parts of the body; this is termed secondary hyperalgesia. For example, following an ovariohysterectomy there is a decrease in the mechanical nociceptive threshold (sensitivity to touch) at the incision site but also at remote sites such as the forelimb. When neurons in the dorsal horn are repeatedly stimulated, their rate of discharge dramatically increases with time; this is called central hypersensitization. The barrage of signals that arrive in the spinal cord from the periphery cause changes in the dorsal horn neurons, which become "wound up". As a result of these changes, the response to subsequent incoming signals is altered. Activation and modulation of N-methyl-D-aspartate receptors by the excitatory neurotransmitter glutamate is thought to be the primary mechanism in the development of central sensitization and secondary hyperalgesia. The goals of perioperative pain management are to prevent both primary and secondary hyperalgesia.
Ketamine was traditionally considered solely as a dissociative anesthetic but its role as a potential analgesic has evolved over the years in both human and veterinary medicine.1,2 Ketamine is a non-competitive N-methyl-D-aspartate receptor antagonist and can modulate central sensitization and exert an anti-hyperalgesic effect. Ketamine may also have activity at opioid, monoaminergic and muscarinic receptors and at voltage sensitive Ca++ channels and although these mechanisms are not fully understood they may also contribute to its analgesic actions. These effects occur at sub-anesthetic doses and in a clinical setting ketamine is most often given as a continuous infusion and at the rates used, adverse side-effects are rare and the classic signs of dissociative anesthesia (muscle rigidity and salivation) are not observed.
Several clinical studies in dogs have shown beneficial effects of ketamine on pain. In a study of female dogs undergoing ovariohysterectomy dogs received a subanaesthetic dose of ketamine (2.5 mg/kg intramuscularly) pre-operatively or post-operatively (at extubation), or saline.3 Other analgesic agents were not given and induction of anesthesia was with thiopental which has no analgesic properties. Mechanical nociceptive thresholds were measured and pain scores recorded before premedication and post-operatively for up to 18 hours after extubation. Dogs in the control (saline) group required more rescue analgesics, showed more wound sensitivity and had higher pain scores throughout the post-operative period than those in the two ketamine groups. Administration of ketamine before surgery was more effective that administration after surgery. Ketamine should not however be the sole agent used to alleviate acute pain but can be used as part of a multimodal perioperative pain management plan for major surgery or in trauma patients. Treatment should be started prior to surgery and continued for up to 24 hours after surgery. In trauma patients treatment should begin as soon as possible after initial triage. Wagner and colleagues studied the effects of adding a low dose ketamine infusion (a control group received saline infusion) to an already established analgesic protocol that included pre-operative morphine and fentanyl infusion in dogs that underwent forelimb amputation.4 The ketamine protocol used was: 0.5 mg/kg IV (bolus) given before surgery followed by 10 µg kg-1 min-1 during surgery and 2 µg kg-1 min-1 for 18 hours after surgery. At 12 and 18 hours after surgery the dogs that had received ketamine had lower pain scores and on the third post-operative day this group were also significantly more active. In another clinical study that involved major soft tissue surgery (mastectomy) two dosing regimens of ketamine given intravenously after surgery (low dose: 150 µg kg-1 followed by 2 µg kg-1 min-1, high dose: 700 µg kg-1 followed by 10 µg kg-1 min-1: Both infusions were given for 6 hours) were compared to a control group that received saline. All dogs received pre- operative morphine. There was no difference in the post- operative pain scores or in the postoperative morphine requirements between the 3 groups. However, the "high dose" ketamine protocol improved feeding behaviour.
Another popular regimen is the combination of morphine, lidocaine and ketamine (MLK) as a continuous infusion.5 This is anesthetic sparing (decreases inhalant anesthesia requirements) in dogs. Lidocaine infusion should not be used in cats due to adverse cardiovascular effects.6 Ketamine has been shown to reduce C-reactive proteins in dogs with pyometra7 and may have immunomodulating effects in the face of endotoxemia.8
These clinical studies combined with extensive data in other species supports the use of ketamine in the perioperative period, in trauma patients and in patients with sepsis.
Less is known about low dose ketamine protocols in cats. In a research setting ketamine had a minimal effect on thermal thresholds, however this may not be the correct model for assessing ketamine's analgesic properties.9 Clinical experience suggests that ketamine can provide some analgesia in cats undergoing surgery, but as in dogs, ketamine is not sufficient as a sole analgesic agent for surgery.
Recommended Doses
Dogs - bolus (loading dose); 0.5–1.0 mg/kg IV followed by constant rate infusion (CRI) at 2–10 µ (micro)g kg-1 minute-1; the higher infusion rates are used during surgery and then tapered following surgery.
Cats - bolus (loading dose); 0.5 mg/kg IV followed by constant rate infusion at 5–20 µ (micro)g kg-1 minute-1; some cats will be sedated at these doses.
Contraindications: Use with caution in animals with head trauma and eye injuries or glaucoma as ketamine can increase intracranial and intraocular pressure; however, it is thought that the low doses used for analgesia are unlikely to cause problems, but erring on the lower end of the dose range may be prudent in these patients.
References
1. Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks. Anesth Analg. 1998;87(5):1186–1193.
2. Pozzi A, Muir WW, Traverso F. Prevention of central sensitization and pain by N-methyl-D-aspartate receptor antagonists. J Am Vet Med Assoc. 2006;228(1):53–60.
3. Slingsby LS, Waterman-Pearson AE. The post-operative analgesic effects of ketamine after canine ovariohysterectomy–a comparison between pre- or post-operative administration. Res Vet Sci. 2000;69(2):147–152.
4. Wagner AE, Walton JA, Hellyer PW, Gaynor JS, Mama KR. Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs. J Am Vet Med Assoc. 2002;221(1):72–75.
5. Muir WW, 3rd, Wiese AJ, March PA. Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane. Am J Vet Res. 2003;64(9):1155–1160.
6. Pypendop BH, Ilkiw JE. Hemodynamic effects of sevoflurane in cats. Am J Vet Res. 2004;65(1):20–25.
7. Liao PY, Chang SC, Chen KS, Wang HC. Decreased postoperative C-reactive protein production in dogs with pyometra through the use of low-dose ketamine. J Vet Emerg Crit Care (San Antonio). 2014;24(3):286–290.
8. DeClue AE, Cohn LA, Lechner ES, Bryan ME, Dodam JR. Effects of subanesthetic doses of ketamine on hemodynamic and immunologic variables in dogs with experimentally induced endotoxemia. Am J Vet Res. 2008;69(2):228–232.
9. Ambros B, Duke T. Effect of low dose rate ketamine infusions on thermal and mechanical thresholds in conscious cats. Vet Anaesth Analg. 2013;40(6):e76–82.