AS part of the effort to develop mechanisms-based approaches to pain therapy, renewed interest has focused on the use of ketamine for treatment of acute and chronic pain. In particular, the role of N -methyl-d-aspartate (NMDA) excitatory glutamate receptors in nociceptive transmission has been established in humans.1–3NMDA receptors participate in the development and maintenance of what can be called “pathologic pain” after tissue injury: increased pain perception as a result of pain sensitization, in part from synaptic plasticity.1–3Ketamine binds noncompetitively to the phencyclidine binding site of NMDA receptors4but also modifies them via allosteric mechanisms.5When studied at subanesthetic doses, its analgesic efficacy correlates well with its inhibiting action on NMDA receptor-mediated pain facilitation4,6and a decrease in activity of brain structures that respond to noxious stimuli.7Ketamine therefore represents a promising modality in several perioperative strategies to prevent pathologic pain.Another reason for the renewed interest in ketamine is the availability of S(+) ketamine. Ketamine has a chiral center at the carbon-2 atom of the cyclohexanone ring, and therefore exists as the optical stereoisomers S(+) and R(-) ketamine.4Until recently, ketamine was marketed as a racemate, containing equimolar amounts of the enantiomers. S(+) ketamine has a fourfold greater affinity for NMDA receptors than does R(-) ketamine.4This difference results in a clinical analgesic potency of S(+) ketamine approximately two times greater than that of racemic and four times greater than that of R(-) ketamine, whereas S(+) ketamine has a shorter duration of action.4,6,8We discuss the perioperative use of ketamine as an adjunct to general and regional anesthesia and to postoperative pain therapy. Focus will be on the administration of the drug at subanesthetic concentrations; we will refer to this as “subanesthetic ketamine.”Intravenous subanesthetic ketamine, when added as an adjunct to general anesthesia, reduced postoperative pain and opioid requirements in a variety of settings, from outpatient surgery to major abdominal procedures (level II evidence) (table 1).9–16However, some studies did not show this benefit (level II evidence) (table 1).17,18Two factors may explain these failures. First, beneficial effects of ketamine may be masked when the drug is used in small doses (<0.15 mg/kg) against the background of multimodal or epidural analgesia.17Second, the dosing schedule may be inadequate. Studies have compared the effects of ketamine administration before surgery with those of one ketamine administration at the end of surgery to test its “preemptive” analgesic properties. However, nociceptive and inflammatory signals are generated throughout surgery and after the procedure. A single injection of a short-acting drug such as ketamine either before or after incision will therefore not provide analgesia that lasts far into the postoperative period.18To prevent pathologic pain, ketamine needs to be applied at least throughout the operation and likely for a period of time into the postoperative phase, in an attempt to reduce sensitization of central and peripheral pain pathways. Thus, the adequacy of the ketamine administration schedule is a crucial component for pain prevention (fig. 1).Dosing of ketamine when used for this purpose is affected by variety of factors, including the expected amount of pain, whether general or epidural anesthesia will be used, and whether ketamine will be applied intraoperatively or intraoperatively and postoperatively (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 0.25 mg·kg−1·h−1reduced postoperative morphine needs and the incidence of residual pain until the sixth postoperative month.13However, this was not the case when the drug was used at half the dose. After gastrectomy12or major renal surgery14with general or epidural anesthesia, ketamine improved postoperative pain relief after an intraoperative infusion of 500 μg·kg−1·h−1preceded by a preincisional bolus of 1 mg/kg14or 0.5 mg/kg.12In patients undergoing major pelvic visceral procedures with general or epidural anesthesia, we found less postoperative pain when 0.5 mg/kg preincisional S(+) ketamine was followed by repeated 0.2 mg/kg boluses, as compared with preincisional S(+) ketamine alone.16After radical prostatectomy with general anesthesia, opiate needs and pain at rest were reduced after a 0.1 mg/kg preoperative S(+) ketamine bolus and an intraoperative infusion of 120 μg·kg−1·h−1, followed by patient-controlled analgesia (PCA) with boluses of 1 mg morphine and 0.5 mg S(+) ketamine.15In less painful surgery such as nephrectomy, a preincisional bolus of 0.5 mg racemic ketamine followed by a 24 h-infusion of 120 μg·kg−1·h−1and then of 60 μg·kg−1·h−1for 48 h reduced hyperalgesia surrounding the incision.11The following dosing schedule can therefore be proposed: In painful procedures, a 0.5 mg/kg slow bolus injection of ketamine before or after induction of general anesthesia, but before incision, may be used; this may be followed by repeated injections of 0.25 mg/kg ketamine at 30-min time intervals or a continuous infusion of 500 μg·kg−1·h−1. For procedures lasting longer than 2 h, drug administration ends at least 60 min before surgery to prevent prolonged recovery. In procedures expected to be less painful, a 0.25 mg/kg ketamine bolus before incision may be injected; this may be followed by 30-min injections of 0.125 mg/kg ketamine or an infusion of 250 μg·kg−1·h−1. With S(+) ketamine, doses can be reduced to approximately 70% of the dose of racemic ketamine when continuously administered; its use ends 30 min before wound closure (table 2). It is advisable to administer the first bolus doses or the first 20 min of an infusion under careful monitoring of patient hemodynamic response. With reduced nociception, many patients show declines in blood pressure and heart rate. Further doses are then titrated according to the individual response. Under general anesthesia, less anesthetic will be required when ketamine is used in this manner. After administration of subanesthetic ketamine as suggested, ketamine-treated versus control patients did not show an increase in postoperative adverse psychic effects, sedation, or nausea and vomiting.9–16,18Nevertheless, for premedication, a benzodiazepine such as 3.75–7.5 mg oral midazolam or 5–10 mg oral diazepam has been recommended.19To continue pain relief in the postoperative period, PCA with an analgesic plus ketamine combination may be beneficial (table 2).The addition of ketamine to a local anesthetic or other analgesics in peripheral or neuraxial anesthesia and analgesia improves or prolongs pain relief (level II evidence) (table 3).20–24A decrease in drug-related side effects (sedation, pruritus, or adverse psychological reactions) has also been found, mainly because the required drug doses could be reduced.25,26These effects may relate to blockade of central and peripheral NMDA receptors and/or an antinociceptive action complementary to that of the other drugs used. Central and peripheral sensitization may thus be prevented.Although peripheral human NMDA receptors have been identified1,2and ketamine shows local anesthetic-like properties, its peripheral effects at small doses (<0.15 mg/kg) do not provide profound local analgesia when used alone.27At neuraxial sites, ketamine exerts analgesia when used as a sole agent at higher doses, but its utility is limited by psychotomimetic reactions, at least in awake patients.28The resorption and uptake of peripheral or neuraxial ketamine has not yet been systematically analyzed. Based on data from epidural and caudal use, ketamine gains rapid access to the systemic circulation with high bioavailability (level III evidence).29–31After preoperative use in children, caudal S(+) ketamine reduced postoperative pain better than intramuscular29or intravenous S(+) ketamine.30As plasma concentrations are mostly similar after caudal and intramuscular ketamine,29this benefit likely resulted from neuroaxial rather than systemic action. When 0.5 mg/kg epidural versus 0.5 mg/kg intravenous racemic ketamine were compared in adults undergoing gastrectomy, less postoperative pain was also found after epidural use.31Higher plasma concentrations and a longer elimination half-life but decreased maximum plasma concentrations were reported for 48 h after epidural as compared with intravenous ketamine.Trials investigating intraoperative ketamine as an analgesic additive to epidural regimens have reported improved analgesia and a local anesthetic or opioid-sparing effect that lasts into the postoperative period (level II evidence) (table 3).21,22Psychotomimetic effects and postoperative nausea and vomiting were similar in ketamine-treated and control patients. When epidural subanesthetic S(+) ketamine combined with a local anesthetic was injected preincisionally in orthopaedic surgery, beneficial effects over 48 h were reported,22suggesting that a single injection of epidural or local S(+) ketamine may reduce pain beyond the intraoperative period. However, administration of epidural subanesthetic racemic ketamine and morphine before surgical incision did not result in a relevant postoperative effect as compared to use of morphine (although patients treated with ketamine received less intraoperative opioids).32When racemic ketamine was added to a local anesthetic in an interscalene brachial plexus block, no increase in postoperative analgesia was reported.33Thus, the concept that pain prevention requires repeated or continuous intraoperative drug use to counteract ongoing peripheral and spinal noxious stimulation appears to be as valid for regional anesthesia as for general anesthesia.Caudal analgesia added to general anesthesia is an effective regimen for pediatric surgery, but it may be associated with prolonged motor blockade and complications such as systemic toxicity after accidental intravascular injection of local anesthetics or with respiratory depression after opiate use. Studies assessing caudal ketamine have shown efficient analgesia for both intraoperative and postoperative periods (level II evidence) (table 3). Racemic ketamine provided improved pain relief of prolonged duration when added to local anesthetics,24and 0.5–1 mg/kg S(+) ketamine produced analgesia when administered alone or in combination with other anesthetics.23,29,30Postoperatively, no increase in psychotomimetic effects were reported after racemic ketamine ≤0.5 mg/kg or S(+) ketamine ≤1 mg/kg. This may be related to the fact that the children received general anesthesia during the time when systemic drug concentrations were high enough to cause undesired effects. Nevertheless, although there may be advantages over traditionally used caudal anesthetics, further data are needed to assure the safety of caudal ketamine in children at these young ages.Toxic reactions after prolonged neuraxial exposure to racemic ketamine formulations with preservatives (benzethonium chloride or chlorobutanol) have been reported in animal species. A case of spinal neurotoxicity after continuous intrathecal racemic ketamine infused over 3 weeks has been reported.34Despite controversy about the risk-benefit ratio of neuraxial use of ketamine in humans, several facts may help to reach a practical standpoint in this issue. First, chemical cytotoxicity from preservatives unrelated to ketamine has long been known. Only preservative-free preparations must therefore be employed for neuraxial use. Second, the risk of spinal toxicity is generally increased after extended drug exposure. However, dose-response studies in pigs did not reveal neurotoxicity after prolonged epidural preservative-free ketamine,35and patients with terminal cancer pain did not show signs of toxicity after repeated spinal preservative-free subanesthetic ketamine.36Third, physiologic NMDA receptor activity is necessary for cell survival and cerebral function, and rodent data suggest harmful consequences of profound NMDA receptor blockade.37Programmed death occurred in central neurons of the immature rat brain and vacuolization selectively developed in the cingulate and retrosplenial cortex of adult rats after high ketamine doses.37Importantly, coadministration of a gamma-aminobutyric acid receptor agonist prevented these effects. At this time, we think that lack of detailed toxicity data in noncancer patients only allows for preservative-free epidural ketamine use in smaller, subanesthetic doses and within the setting of clinical trials.In addition to inhibition of sensitization in nociceptive pathways, prevention of opiate-related activation of pronociceptive systems and opiate tolerance may be another mechanism of pain prevention by ketamine. The development of rapid tolerance and delayed hyperalgesia after intraoperative and postoperative use of different opioids has been reported in surgical patients.38–40Although the mechanisms that allow ketamine to be an analgesic and opiate-sparing agent after opiate exposure remain poorly understood, two emerging concepts may be important (fig. 2). First, at neuronal synapses, scaffolding proteins such as postsynaptic density protein-95 (PSD-95) and postsynaptic density protein-93 (PSD-93) connect NMDA receptors to the cytoskeleton and to key signaling systems, such as neuronal nitric oxide synthase.1Recent rodent data show obligatory involvement of PSD-95 and PSD-93 in NMDA receptor-mediated neuropathic and chronic pain41and critical roles for PSD-95 and neuronal nitric oxide synthase in opioid tolerance.42Second, in sensitization or developing tolerance, activated protein kinase C and tyrosine kinase cascades facilitate association of key signaling molecules with PSD proteins and NMDA receptors.1,43This activates protein kinases, resulting in NMDA receptor phosphorylation and up-regulation. Enhanced downstream signaling potentiates NMDA function and thus pain sensation. Rat studies in brain ischemia indicate that ketamine decreases injury-triggered increases in interactions between NMDA receptor, PSD-95, and protein kinases. This reduces nitric oxide-related neurotoxicity and finally brain damage.44Thus, a ketamine-induced decrease in unfavourable PSD interaction with protein kinases and pain signaling systems may represent a common mechanism underlying reduced pain sensitization and opiate tolerance phenomena.In the clinical situation, supplementing remifentanil-based anesthesia with preoperative subanesthetic ketamine reduced the need for both intraoperative remifentanil and postoperative opioid analgesia in abdominal surgery.45However, in another study,46a preincisional bolus of 0.5 mg/kg S(+) ketamine followed by an infusion of 120 μg·kg−1·h−1until 2 h after emergence from higher-dose remifentanil anesthesia did not decrease pain after cruciate ligament repair (level II evidence) (table 4). S(+) ketamine, however, was started after general anesthesia was induced with remifentanil. Therefore, it has to be clarified whether ketamine should be administered before or after first opioid use and whether ketamine doses must be adapted to opioid concentrations or the duration of opioid infusion.Perioperative management of opioid-resistant or severe chronic pain is a major clinical problem. Although there has been limited formal research on this topic, a recent study in postoperative surgical patients with morphine-resistant pain found that intravenous subanesthetic ketamine combined with morphine improved pain relief at smaller morphine doses than did morphine alone (table 4).40Moreover, ketamine-treated patients showed better oxygen saturation and greater wakefulness. Ketamine may also be used for pain therapy in the chronic opioid-tolerant patient, especially when other options have failed (level IV evidence).43Although controlled trials are lacking, a “challenge” with subanesthetic ketamine may even be attempted in opioid-addicted patients.47If pain is reduced, ketamine can be titrated to provide analgesia and prevent escalating opioid/analgesic needs. However, two recent reviews on ketamine as an analgesic adjunct in chronic pain patients conclude that further data are needed before routine use can be recommended (level I evidence).48,49After surgery, the combined use of ketamine and an opiate analgesic for intravenous PCA has been tested on general wards and in the intensive care unit. Although several studies reported less pain and decreases in analgesic need and adverse effects such as postoperative nausea and vomiting, sedation, or respiratory insufficiency,15,49–52some did not find remarkable benefits after ketamine (level II evidence) (table 4).53,54Although this has been explained by the nature of the insult (with less painful surgery requiring less postoperative pain therapy), two issues complicate the interpretation of the data. First, most of the drugs applied were chosen on purely empirical grounds with little knowledge of analgesic efficacy of ketamine-opiate combinations. Sometimes dosages were based on body surface area, ketamine bolus applications and background infusions were compared, or doses less than those known to be analgesic were used.54However, the dose of ketamine combined with morphine for PCA depends on the morphine dosing scheme, and interindividual variability in opiate drug requirement is well known. Second, patients were studied with rather global assessment tools such as pain ratings or immediate analgesic need after surgery. To identify long-term effects, parameters such as long-lasting hyperalgesia, patient convalescence, and outcome variables such as length of hospital stay need to be studied. The first issue has been approached with optimization models restricted by side effects for morphine combined with ketamine.51For lumbar spine and hip surgery, the model converged to a morphine:ketamine ratio of 1:1 and a lockout interval of 8 min for postoperative intravenous PCA. Very low pain scores and a negligible incidence of sedation, bradypnea, postoperative nausea and vomiting, pruritus, and psychotomimetic effects suggest that such combinations should be studied further. Nevertheless, after “painful” procedures, an infusion of low-dose (<150 μg·kg−1·h−1) intravenous ketamine combined with PCA appears to be the most promising analgesic technique11,50(level II evidence) (table 4).The most common concerns about ketamine as an analgesic agent are related to its mind-altering effects. This is of special relevance when the compound is to be used in conscious patients. Quiet, relaxed surroundings contribute to a reduced incidence of these side effects, and when ketamine is administered alone, the prophylactic use of a sedative agent such as 3.75–7.5 mg oral midazolam has generally decreased their incidence and severity.19In the setting of postoperative PCA, most trials did not find a difference in adverse psychotomimetic effects (level II evidence).11,50–52,54Effects were dose-dependent and less likely with small doses (<0.15 mg/kg). When ketamine was used as an infusion at less than 10 mg/h, cognitive impairment was negligible.11,50Side effects appear to be similar after S(+) versus racemic ketamine, but volunteers who received equianalgesic doses of both reported less tiredness and impaired cognitive capacity after S(+) ketamine.55In the recovery period, improved mood was found in patients who received intraoperative S(+) ketamine16or propofol and racemic ketamine.56Pain therapy can be improved using intraoperative and postoperative ketamine in a variety of surgical procedures and anesthetic techniques. In particular, the intraoperative use of intravenous subanesthetic ketamine in general anesthesia provides pain prevention in the postoperative period. The most important limitation to the available studies is the lack of evaluation of long-term outcome measures. We do not know whether ketamine use will translate into better recovery profiles or improved functional outcome. There is also insufficient evidence to show a clear benefit of S(+) ketamine as compared with racemic ketamine. For future study, the evaluation of intravenous ketamine as an adjunct to general anesthesia appears to be a priority given the promising results and the ease with which such a regimen could be implemented.
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