Ⅵ CLINICAL CONCEPTS AND COMMENTARY Richard B. Weiskopf, M.D., Editor Anesthesiology 2005; 102:211–20 © 2004 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Ketamine for Perioperative Pain Management Sabine Himmelseher, M.D.,* Marcel E. Durieux, M.D., Ph.D.† AS part of the effort to develop mechanisms-based ap- Anti-nociceptive Therapy with Ketamine proaches to pain therapy, renewed interest has focused during Anesthesia on the use of ketamine for treatment of acute and Intravenous Ketamine as an Analgesic Adjunct to chronic pain. In particular, the role of N-methyl-D-aspar- General Anesthesia tate (NMDA) excitatory glutamate receptors in nocicep- Intravenous subanesthetic ketamine, when added as tive transmission has been established in humans.1–3 an adjunct to general anesthesia, reduced postoperative NMDA receptors participate in the development and pain and opioid requirements in a variety of settings, maintenance of what can be called “pathologic pain” from outpatient surgery to major abdominal procedures after tissue injury: increased pain perception as a result (level II evidence) (table 1).9–16 However, some studies of pain sensitization, in part from synaptic plasticity.1–3 did not show this benefit (level II evidence) (table Ketamine binds noncompetitively to the phencyclidine 1).17,18 Two factors may explain these failures. First, binding site of NMDA receptors4 but also modifies them beneficial effects of ketamine may be masked when the via allosteric mechanisms.5 When studied at subanes- drug is used in small doses (Ͻ0.15 mg/kg) against the thetic doses, its analgesic efficacy correlates well with its background of multimodal or epidural analgesia.17 Sec- inhibiting action on NMDA receptor-mediated pain facil- ond, the dosing schedule may be inadequate. Studies itation4,6 and a decrease in activity of brain structures have compared the effects of ketamine administration that respond to noxious stimuli.7 Ketamine therefore before surgery with those of one ketamine administra- represents a promising modality in several perioperative tion at the end of surgery to test its “preemptive” anal- strategies to prevent pathologic pain. gesic properties. However, nociceptive and inflamma- Another reason for the renewed interest in ketamine is tory signals are generated throughout surgery and after the availability of S(ϩ) ketamine. Ketamine has a chiral center at the carbon-2 atom of the cyclohexanone ring, the procedure. A single injection of a short-acting drug and therefore exists as the optical stereoisomers S(ϩ) such as ketamine either before or after incision will 4 therefore not provide analgesia that lasts far into the and R(-) ketamine. Until recently, ketamine was mar- 18 keted as a racemate, containing equimolar amounts of postoperative period. To prevent pathologic pain, ket- the enantiomers. S(ϩ) ketamine has a fourfold greater amine needs to be applied at least throughout the oper- affinity for NMDA receptors than does R(-) ketamine.4 ation and likely for a period of time into the postopera- This difference results in a clinical analgesic potency of tive phase, in an attempt to reduce sensitization of S(ϩ) ketamine approximately two times greater than central and peripheral pain pathways. Thus, the ade- that of racemic and four times greater than that of R(-) quacy of the ketamine administration schedule is a cru- ketamine, whereas S(ϩ) ketamine has a shorter duration cial component for pain prevention (fig. 1). of action.4,6,8 Dosing of ketamine when used for this purpose is We discuss the perioperative use of ketamine as an affected by variety of factors, including the expected adjunct to general and regional anesthesia and to post- amount of pain, whether general or epidural anesthesia operative pain therapy. Focus will be on the administra- will be used, and whether ketamine will be applied tion of the drug at subanesthetic concentrations; we will intraoperatively or intraoperatively and postoperatively refer to this as “subanesthetic ketamine.” (level II evidence) (table 1). In a long-term outcome trial on adenocarcinoma surgery with general or epidural anesthesia, racemic ketamine injected as a 0.5 mg/kg preincisional bolus followed by an infusion of * Anesthesiologist, Klinik fuer Anaesthesiologie, Klinikum rechts der Isar, Ϫ1 Ϫ1 Technische Universität München, Germany; † Professor, Department of Anesthe- 0.25 mg·kg ·h reduced postoperative morphine siology, University of Virginia Health System, Charlottesville, Virginia. needs and the incidence of residual pain until the sixth Received from the Department of Anesthesiology, University of Virginia postoperative month.13 However, this was not the case Health System, Charlottesville, Virginia. Submitted for publication February 25, 2004. Accepted for publication June 24, 2004. Support for this research was when the drug was used at half the dose. After gastrec- provided solely from institutional and/or departmental sources. tomy12 or major renal surgery14 with general or epidural Address reprint requests to Dr. Durieux: Department of Anesthesiology, Uni- versity of Virginia, P.O. Box 800710, Charlottesville, VA 22908-0710. Address anesthesia, ketamine improved postoperative pain relief Ϫ1 Ϫ1 electronic mail to: [email protected]. after an intraoperative infusion of 500 ␮g·kg ·h pre- Anesthesiology, V 102, No 1, Jan 2005 211 212 S. HIMMELSEHER AND M. E. DURIEUX Anesthesiology, V 102, No 1, Jan 2005 KETAMINE FOR PERIOPERATIVE PAIN MANAGEMENT 213 Fig. 1. For prevention of pathologic pain after severe tissue injury, ketamine ad- ministration should cover the entire du- ration of high-intensity noxious and in- flammatory stimulation, not simply the initial trauma. N-methyl-D-aspartate recep- tors should be blocked during ongoing intraoperative as well as postoperative transmission of nociceptive impulses. Postoperative mobilization may elicit de- layed waves of afferent painful stimuli. Re- garding acute opiate tolerance-related phe- nomena, it is as yet unclear whether ketamine is best administered before first use of opioids. ceded by a preincisional bolus of 1 mg/kg14 or 0.5 mg/kg.12 S(ϩ) ketamine bolus and an intraoperative infusion of In patients undergoing major pelvic visceral procedures 120 ␮g·kgϪ1·hϪ1, followed by patient-controlled analgesia with general or epidural anesthesia, we found less postop- (PCA) with boluses of 1 mg morphine and 0.5 mg S(ϩ) erative pain when 0.5 mg/kg preincisional S(ϩ) ketamine ketamine.15 In less painful surgery such as nephrectomy, was followed by repeated 0.2 mg/kg boluses, as compared a preincisional bolus of 0.5 mg racemic ketamine fol- with preincisional S(ϩ) ketamine alone.16 After radical lowed by a 24 h-infusion of 120 ␮g·kgϪ1·hϪ1 and then of prostatectomy with general anesthesia, opiate needs and 60 ␮g·kgϪ1·hϪ1 for 48 h reduced hyperalgesia surround- pain at rest were reduced after a 0.1 mg/kg preoperative ing the incision.11 Anesthesiology, V 102, No 1, Jan 2005 214 S. HIMMELSEHER AND M. E. DURIEUX The following dosing schedule can therefore be pro- caudal use, ketamine gains rapid access to the systemic posed: In painful procedures, a 0.5 mg/kg slow bolus circulation with high bioavailability (level III evi- injection of ketamine before or after induction of general dence).29–31 After preoperative use in children, caudal anesthesia, but before incision, may be used; this may be S(ϩ) ketamine reduced postoperative pain better than followed by repeated injections of 0.25 mg/kg ketamine intramuscular29 or intravenous S(ϩ) ketamine.30 As at 30-min time intervals or a continuous infusion of plasma concentrations are mostly similar after caudal 500 ␮g·kgϪ1·hϪ1. For procedures lasting longer than 2 h, and intramuscular ketamine,29 this benefit likely resulted drug administration ends at least 60 min before surgery from neuroaxial rather than systemic action. When to prevent prolonged recovery. In procedures expected 0.5 mg/kg epidural versus 0.5 mg/kg intravenous race- to be less painful, a 0.25 mg/kg ketamine bolus before mic ketamine were compared in adults undergoing gas- incision may be injected; this may be followed by 30-min trectomy, less postoperative pain was also found after injections of 0.125 mg/kg ketamine or an infusion of epidural use.31 Higher plasma concentrations and a 250 ␮g·kgϪ1·hϪ1. With S(ϩ) ketamine, doses can be longer elimination half-life but decreased maximum reduced to approximately 70% of the dose of racemic plasma concentrations were reported for 48 h after epi- ketamine when continuously administered; its use ends dural as compared with intravenous ketamine. 30 min before wound closure (table 2). It is advisable to Trials investigating intraoperative ketamine as an anal- administer the first bolus doses or the first 20 min of an gesic additive to epidural regimens have reported im- infusion under careful monitoring of patient hemody- proved analgesia and a local anesthetic or opioid-sparing namic response. With reduced nociception, many pa- effect that lasts into the postoperative period (level II tients show declines in blood pressure and heart rate. evidence) (table 3).21,22 Psychotomimetic effects and Further doses are then titrated according to the individ- postoperative nausea and vomiting were similar in ket- ual response. Under general anesthesia, less anesthetic amine-treated and control patients. When epidural sub- will be required when ketamine is used in this manner. anesthetic S(ϩ) ketamine combined with a local anes- After administration of subanesthetic