Nonsteroidal anti-inflammatory drugs, α2-adrenoceptor agonists, and opioids are the most commonly used drug classes to provide analgesia in horses. Although each of these can be effective individually or in combinations, they can also have substantial adverse effects.1–7 Equine clinicians continue to search for drugs to be used for pain management that cause less severe cardiovascular, gastrointestinal, or behavioral changes than currently available analgesics.
Ketamine hydrochloride is a noncompetitive antagonist at N-methyl-D-aspartate receptors in the spinal cord.8–11 It also has effects on opioid,12,13 monoaminergic,14 and muscarinic receptors,13,15,16 as well as voltage-sensitive Ca2+ channels.17,18 Following IV administration, ketamine undergoes widespread distribution.19 Biotransformation occurs in the liver where the drug is converted to norketamine.20 At anesthetic doses, ketamine has a variety of cardiovascular effects, including increases in cardiac index, mean aortic pressure, pulmonary arterial pressure, systolic and diastolic arterial pressure, and heart rate.21–24 Ketamine does not appear to have an effect on gastrointestinal motility and has only minimal and transient effects on ventilation.24,25 In fact, ketamine appears to decrease airway resistance in dogs and humans.26,27
Subanesthetic amounts of ketamine have been used to provide analgesia in small companion animal and human patients.28–32 Following oral or IM administration in people, serum concentrations of ketamine as low as 0.04 and 0.150 μg/mL, respectively, have been associated with analgesia.28 Ketamine has been evaluated for its use in human patients with asthma,33 limb amputations,34 and chronic pain. It has also been examined for its analgesic effects following ovariohysterectomy and limb amputations in dogs.29,30
In horses, ketamine has been used for more than 2 decades as an injectable anesthetic agent in conjunction with α2-adrenoceptor agonists such as xylazine. Ketamine is usually administered IV at a dose of 2.2 mg/kg, and anesthesia is maintained with circulating concentrations of approximately 1 μg of ketamine/mL.35 Infusions of ketamine have been shown to decrease the minimum alveolar concentration of halothane in horses.23 Without prior medication with drugs such as xylazine or diazepam, this dose of ketamine can cause undesirable excitation and muscular rigidity.36 More recently, ketamine has been used by caudal epidural injection to provide analgesia for the perineal region and locally for peripheral nerve blocks in the distal portion of the limbs of horses.37,38 Pharmacokinetic properties of a single dose of ketamine in horses, mules, and donkeys have been evaluated.35,39,40 The disappearance half-life ranged from 42 to 65 minutes in horses.35,39
To provide long-term analgesia in people, ketamine administration at 0.3 to 1.2 mg/kg/h as a CRI has been recommended.41 This regimen allows the effects of ketamine to be titrated as well as prevents substantial variation in analgesic effects as serum concentrations fluctuate between subsequent doses. To our knowledge, no reports exist on the pharmacokinetics or clinical assessment of a CRI of subanesthetic amounts of ketamine to horses.
Ketamine could represent an analgesic drug for use in equine patients that are systemically compromised from cardiovascular, respiratory, or gastrointestinal diseases. On the basis of clinical experience and research with other species, we hypothesize that ketamine can be used safely as an analgesic agent in horses. The purposes of the study reported here were to determine an appropriate dose, evaluate clinical physical examination and hemodynamic parameters associated with this dose, and describe the pharmacokinetics of CRI ketamine in horses.
Continuous rate infusion
High-performance liquid chromatography
Ketaset (100 mg/mL), Fort Dodge Animal Health, Fort Dodge, Iowa.
Baxter Flo-Gard 6200, Baxter Healthcare Corp, Deerfield, Ill.
Propaq 106 EL, Protocol Systems, Beaverton, Ore.
Universal load cell, RSC-50 lbs, Hottinger Baldwin Messtechnik Inc, Marlboro, Mass.
Signal processor, MVD 2630, Hottinger Baldwin Messtechnik Inc, Marlboro, Mass.
WinNonLin, version 3.0A, Pharsight Corp, Palo Alto, Calif.
InStat 3.0 for Windows, GraphPad Software Inc, San Diego, Calif.
Bueno AC, Cornick-Seahorn J & Seahorn TL, et al. Cardiopulmonary and sedative effects of intravenous administration of low doses of medetomidine and xylazine to adult horses. Am J Vet Res 1999;60:1371–1376.
Merritt AM, Burrow JA, Hartless CS. Effect of xylazine, detomidine, and a combination of xylazine and butorphanol on equine duodenal motility. Am J Vet Res 1998;59:619–623.
Nolan AM, Besley W & Reid J, et al. The effects of butorphanol on locomotor activity in ponies: a preliminary study. J Vet Pharmacol Ther 1994;17:323–326.
Sojka JE, Adams SB & Lamar CH, et al. Effect of butorphanol, pentazocine, meperidine, or metoclopramide on intestinal motility in female ponies. Am J Vet Res 1988;49:527–529.
Adams SB, Lamar CH, Masty J. Motility of the distal portion of the jejunum and pelvic flexure in ponies: effects of six drugs. Am J Vet Res 1984;45:795–799.
MacAllister CG, Morgan SJ & Borne AT, et al. Comparison of adverse effects of phenylbutazone, flunixin meglumine, and ketoprofen in horses. J Am Vet Med Assoc 1993;202:71–77.
Orser BA, Pennefather PS, MacDonald JF. Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors. Anesthesiology 1997;86:903–917.
Salt TE, Wilson DG, Prasad SK. Antagonism of N-methyl-asparate and synaptic responses of neurons in the rat ventrobasal thalamus by ketamine and MK-801. Br J Pharmacol 1988;94:443–448.
Hall R, Murdoch J. Brain protection: physiological considerations. Part II: the pharmacology of brain protection. Can J Anaesth 1990;37:762–777.
Brockmeyer DM, Kendig JJ. Selective effects of ketamine on amino acid-mediated pathways in neuronal rat spinal cord. Br J Anaesth 1995;74:79–84.
Smith DJ, Bouchal RL & DeSanctis CA, et al. Properties of the interaction between ketamine and opioid binding sites in vivo and in vitro. Neuropharmacology 1987;26:1253–1260.
Hurstveit O, Maurset A, Øye I. Interaction of the chiral forms of ketamine with opioid, phencyclidine, and muscarinic receptors. Pharmacol Toxicol 1995;77:355–359.
Crisp T, Perrotti JM & Smith DL, et al. The local monoaminergic dependency of spinal ketamine. Eur J Pharmacol 1991;194:167–172.
Mimura MA, Namiki R & Kishi T, et al. Central cholinergic action produces antagonism to ketamine anaesthesia. Acta Anaesthesiol Scand 1992;36:460–462.
Baum VC, Tecson ME. Ketamine inhibits transsarcolemmal calcium entry in guinea pig myocardium: direct evidence by single cell voltage clamp. Anesth Analg 1991;73:804–807.
Yamakage M, Hirshman CA, Croxton TL. Inhibitory effects of thiopental, ketamine, and propofol on voltage-dependent Ca2+ channels in porcine tracheal smooth muscle cells. Anesthesiology 1996;83:1274–1282.
Adams JD, Baillie TA & Trevor AJ, et al. Studies on the biotransformation of ketamine. 1-Identification of metabolites produced in vitro from rat liver microsomal preparations. Biomed Mass Spectrom 1981;8:527–538.
Idvali J, Ahlgren I & Aronsen KF, et al. Ketamine infusions: pharmacokinetics and clinical effects. Br J Anaesth 1979;51:1167–1172.
Muir WW, Sams R. Effects of ketamine infusion on halothane minimal alveolar concentration in horses. Am J Vet Res 1992;53:1802–1806.
Fass J, Bares R & Hermsdorf V, et al. Effects of intravenous ketamine on gastrointestinal motility in the dog. Intensive Care Med 1995;21:584–589.
Hirshman CA, Downes H & Farbood A, et al. Ketamine block of bronchospasm in experimental canine asthma. Br J Anaesth 1979;51:713–718.
Huber FC, Reves JG & Gutierrez J, et al. Ketamine: its effect on airway resistance in man. South Med J 1972;65:1176–1180.
Grant IS, Nimmo WS, Clements JA. Pharmacokinetics and analgesic effects of IM and oral ketamine. Br J Anaesth 1981;53:805–810.
Wagner AE, Walton JA & Hellyer PW, et al. 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;221:72–75.
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;69:147–152.
Bhattacharya A, Gurnani A & Sharma PK, et al. Subcutaneous infusion of ketamine and morphine for relief of postoperative pain: a double-blind comparative study. Ann Acad Med Singapore 1994;23:456–459.
Gurnani A, Sharma PK & Rautela RS, et al. Analgesia for acute musculoskeletal trauma: low-dose subcutaneous infusion of ketamine. Anaesth Intensive Care 1996;24:32–36.
Petrillo TM, Fortenberry JD & Linzer JF, et al. Emergency department use of ketamine in pediatric status asthmaticus. J Asthma 2001;38:657–664.
Nikolajsen L, Hansen CL & Nielsen J, et al. The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input. Pain 1996;67:69–77.
Muir WW. Intravenous anesthetics and anesthetic techniques in horses. In:Muir WW, Hubbell JAE, ed.Equine anesthesia monitoring and emergency therapy. St Louis: Mosby Year Book Inc, 1991;281–309.
Gomez de Segura IA, De Rossi R & Santos M, et al. Epidural injection of ketamine for perineal analgesia in the horse. Vet Surg 1998;27:384–391.
López-Sanromán FJ, Cruz JM & Santos M, et al. Evaluation of the local analgesic effect of ketamine in the palmar digital nerve block at the base of the proximal sesamoid (abaxial sesamoid block) in horses. Am J Vet Res 2003;64:475–478.
Waterman AE, Robertson SA, Lane JG. Pharmacokinetics of intravenously administered ketamine in the horse. Res Vet Sci 1987;42:162–166.
Matthews NS, Taylor TS & Hartsfield SM, et al. Pharmacokinetics of ketamine in mules and mammoth asses premedicated with xylazine. Equine Vet J 1994;26:241–243.
Kamerling SG, Dequick DJ & Weckman TJ, et al. Dose-related effects of ethylketazocine on nociception, behaviour and autonomic responses in the horse. J Pharm Pharmacol 1986;38:40–45.
Carroll GL, Matthews NS & Hartsfield SM, et al. The effect of detomidine and its antagonism with tolazoline on stress-related hormones, metabolites, physiologic responses, and behavior in awake ponies. Vet Surg 1997;26:69–77.
Carroll GL, Boothe DM & Hartsfield SM, et al. Pharmacokinetics and pharmacodynamics of butorphanol in llamas after intravenous and intramuscular administration. J Am Vet Med Assoc 2001;219:1263–1267.
Moens Y, Lanz F & Doherr MG, et al. A comparison of the antinociceptive effects of xylazine, detomidine and romifidine on experimental pain in horses. Vet Anaesth Analg 2003;30:183–190.
Schatzman U, Ambruster S & Strucki F, et al. Analgesic effect of butorphanol and levomethadone in detomidine sedated horses. J Vet Med A Physiol Pathol Clin Med 2001;48:337–342.
Lizarraga I, Castillo F & Valderrama ME, et al. An analgesic evaluation of isoxsuprine in horses. J Vet Med A Physiol Pathol Clin Med 2004;51:370–374.
Huang C, Li HT & Shi YS, et al. Ketamine potentiates the effect of electroacupuncture on mechanical allodynia in a rat model of neuropathic pain. Neurosci Lett 2004;368:327–331.
Parry BW, McCarthy MA, Anderson GA. Survey of resting blood pressure values in clinically normal horses. Equine Vet J 1984;16:53–58.
Schwieger IM, Szlam F, Hug CC. The pharmacokinetics and pharmacodynamics of ketamine in dogs anesthetized with enflurane. J Pharmacokin Biopharm 1991;19:145–156.
Kaka JS, Hayton WL. Pharmacokinetics of ketamine and two metabolites in the dog. J Pharmacokin Biopharm 1980;8:193–202.
Waterman AE. Influence of predmedication with xylazine on the distribution and metabolism of intramuscularly administered ketamine in cats. Res Vet Sci 1983;35:285–290.
Waterman AE. The pharmacokinetics of ketamine administered intravenously in calves and the modifying effect of premedication with xylazine hydrochloride. J Vet Pharmacol Ther 1984;7:125–130.
Rowland M, Rozer TN. Distribution kinetics. In:Rowland M, Tozer TN, eds.Clinical pharmacokinetics: concepts and applications. 3rd ed.Baltimore: The Williams & Wilkins Co, 1995;313–339.
Hijazi Y, Bodonian C & Bolon M, et al. Pharmacokinetics and haemodyanmics of ketamine in intensive care patients with brain or spinal cord injury. Br J Anaesth 2003;90:155–160.
Kawamanta M, Ujike Y & Miyabe M, et al. Continuous infusion of ketamine and midzolam for prolonged sedation in the intensive care unit [in Japanese]. Masui 1991;40:1793–1798.
Matsuki A, Ishihara H & Kotani N, et al. A clinical study on total intravenous anesthesia with droperiodol, fentanyl and ketamine—2. Pharmacokinetics following the end of continuous ketamine infusion [in Japanese]. Masui 1991;40:61–65.