Lack of pre-emptive analgesic effect of (R)-ketamine in laparoscopic cholecystectomy. Evaluation of the safety and efficacy of epidural ketamine combined with morphine for postoperative analgesia after major upper abdominal surgery. Intraoperative intravenous ketamine in combination with epidural analgesia: postoperative analgesia after renal surgery. Small-dose ketamine enhances morphine-induced analgesia after outpatient surgery. 'Balanced analgesia' in the perioperative period: is there a place for ketamine? Preoperative epidural ketamine in combination with morphine does not have a clinically relevant intra- and postoperative opioid-sparing effect. The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair. Comparison of postoperative analgesic effects of preemptively used epidural ketamine and neostigmine. Adding ketamine in a multimodal patient-controlled epidural regimen reduces postoperative pain and analgesic consumption. Preoperative ketamine improves postoperative analgesia after gynecologic laparoscopic surgery. Effect of i.v. ketamine in combination with epidural bupivacaine or epidural morphine on postoperative pain and wound tenderness after renal surgery. Improvement of pain treatment after major abdominal surgery by intravenous S+-ketamine. Supplementing desflurane-remifentanil anesthesia with small-dose ketamine reduces perioperative opioid analgesic requirements. Postoperative pain management with intravenous patient-controlled morphine: comparison of the effect of adding magnesium or ketamine. Can ketamine potentiate the analgesic effect of epidural morphine, preincisional or postincisional administration? Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain. Intraoperative small-dose ketamine enhances analgesia after outpatient knee arthroscopy. Small-dose S(+)-ketamine reduces postoperative pain when applied with ropivacaine in epidural anesthesia for total knee arthroplasty. Does ketamine have preemptive effects in women undergoing abdominal hysterectomy procedures? Ketamine reduces swallowing-evoked pain after paediatric tonsillectomy. Morphine-sparing effect of ketoprofen after abdominal surgery. Epidural ketamine reduces post-operative epidural PCA consumption of fentanyl/bupivacaine. The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Double-blind randomized controlled trial of caudal versus intravenous S(+)-ketamine for supplementation of caudal analgesia in children. Postoperative analgesia with i.v. patient-controlled morphine: effect of adding ketamine. Preemptive analgesia by intravenous low-dose ketamine and epidural morphine in gastrectomy: a randomized double-blind study. Analgesic effects and pharmacokinetics of a low dose of ketamine preoperatively administered epidurally or intravenously. PCA ketamine and morphine after abdominal hysterectomy. A randomised, controlled study of peri-operative low dose s(+)-ketamine in combination with postoperative patient-controlled s(+)-ketamine and morphine after radical prostatectomy. Effect of the addition of ketamine to morphine in patient-controlled analgesia. Effects of ketamine on precipitated opiate withdrawal.
This study evaluated the pre-emptive analgesic effect of intravenous (i.v.) (R)-ketamine in laparoscopic cholecystectomy. (R)-ketamine was used due to the lower incidence of side-effects.
                Sixty patients who underwent surgery under general anesthesia were randomly allocated to 3 groups and studied in a double-blind manner. Two i.v. injections were administered: one after induction of anesthesia, approximately 3 min before surgery, and one after surgery. The placebo group (PLA, n = 20) received saline in both injections. The preoperative group (PRE, n = 20) received (R)-ketamine 1 mg/kg and then saline. The postoperative group (POST, n = 20) received saline and then (R)-ketamine 1 mg/kg. Postoperatively, the patients used a patient-controlled analgesia (PCA) pump. Pain was evaluated with a visual analog scale (VAS) at 30 min and every hour for 4 h and with a verbal rating scale (VRS) at 24 h and after 7 days.
                There were no occurrence of side-effects from (R)-ketamine. VAS and VRS at 1, 2, 3, and 4 h postoperatively showed no statistical differences. In the POST group, extubation was delayed and pain score (VAS) at 30 min postoperatively was significantly lower (P < 0.05) than the two other groups. There were no statistical differences in meperidine consumption during the first 4 h postoperatively and no differences in consumption of analgesics at 24 h and 7 days.
                In this study a 1 mg/kg dose of (R)-ketamine given at the end of surgery exerted a short-lasting hypnotic and analgesic effect. The same dose given preoperatively did not show postoperative analgesic effect or pre-emptive effect. To evaluate the efficacy of the combination of epidural ketamine and morphine compared with epidural morphine alone for postoperative pain relief following major upper abdominal surgery.
                Prospective, randomized, double-blinded study.
                Tertiary care referral and teaching hospital.
                46 ASA physical status I and II patients who underwent major upper abdominal procedures.
                Patients were randomly allocated to one of the two treatment groups: patients in Group 1 received epidural morphine 50 microg/kg whereas patients in Group 2 received epidural ketamine 1 mg/kg combined with 50 microg/kg of morphine postoperatively.
                A blinded observer using a visual analog scale (VAS) for pain assessment followed up patients for 48 hours postoperatively. Top-up dose of epidural morphine was provided when VAS was higher than 4. Analgesic requirements and side effects were compared between the two groups.
                Only 40 patients completed the study. There were no differences between the two groups with respect to age, gender, weight, duration, or type of surgical procedure or intraoperative opioid requirements. Onset of analgesia was faster (p < 0.001) in Group 2 (11 min) than in Group 1 patients (25 min). The time for first requirement of analgesia was significantly (p < 0.01) longer (19.8 +/- 9.8 hours) in Group 2 patients than Group 1 (12.8 +/- 6.2 hours). Total number of supplemental doses of epidural morphine required in the first 48 hours postoperatively was also significantly less (p < 0.005) in Group 2 compared to Group 1. Patients in Group 2 had higher sedation scores than Group I patients for the first 2 hours postoperatively. None of the patients in either group developed hallucinations or respiratory depression. Other side effects such as pruritus, nausea, and vomiting were also similar in both groups.
                The addition of epidural ketamine 1 mg/kg to morphine 50 microg/kg improved analgesia after major upper abdominal surgery without increasing side effects. We designed this double-blinded, randomized, controlled study to evaluate the effect of small-dose ketamine IV in combination with epidural morphine and bupivacaine on postoperative pain after renal surgery. An epidural catheter was inserted, and the administration of morphine and bupivacaine was started before surgery. Forty patients were assigned to one of two groups (ketamine or control). The ketamine group was administered a ketamine bolus and infusion during surgery. The median visual analog pain scale (VAS) scores at rest were significantly lower in the ketamine group during the first 6 h (P < 0.01). VAS pain scores on coughing were also significantly lower in the ketamine group (P < 0.01). Cumulative postoperative total analgesic consumption was less in the ketamine group on Days 1 and 2 (P < 0.001). The first analgesic demand time was shorter in the control group (9.2 +/- 11.5 min) than in the ketamine group (22.3 +/- 17.1 min) (P < 0.0001). The incidence of nausea and pruritus was more frequent in the control group (P < 0.05). In conclusion, postoperative analgesia was more effective when spinal cord and brain sensitization were blocked by a combination of epidural morphine/bupivacaine and IV ketamine.
                Renal nociception conducted multisegmentally by both the spinal nerves (T10 to L1) and the vagus nerve cannot be blocked by epidural analgesia alone. We demonstrated that IV ketamine had an improved analgesic or opioid-sparing effect when it was combined with epidural bupivacaine and morphine after renal surgery. Small-dose ketamine may enhance the analgesic effect of opiates. We studied the effect of IV coadministration of small-dose ketamine 50-100 microg/kg with morphine 50 microg/kg on postoperative morphine requirements and pain in 140 patients undergoing outpatient surgery. Midazolam 1-2 mg was administered in the holding area. Anesthesia was induced with propofol 2-2.5 mg/kg and was maintained with desflurane in a nitrous oxide/oxygen mixture. Patients received morphine 50 microg/kg with placebo (Group 1, n = 35) or ketamine 50 microg/kg IV (Group 2, n = 35), 75 microg/kg IV (Group 3, n = 35), or 100 microg/kg IV (Group 4, n = 35) 15 min before the end of the operation. Pain and drowsiness were assessed using visual analog scales on arrival in the recovery room, then every 15 min until the time of discharge to phase 2 recovery (phase 1 recovery). Morphine consumption in Groups 3 and 4 was approximately 40% less than that in the control group (91+/-9 and 89+/-8 microg/kg vs. 145+/-9 microg/kg; P<0.05 for both). Pain scores in Groups 3 and 4 were approximately 35% less than those in the control group at all time periods (P<0.0001 for all). There was no significant group difference in drowsiness scores. Small-dose ketamine 75-100 microg/kg IV, enhanced morphine-induced analgesia after outpatient surgery. Simultaneous use of small doses of ketamine with morphine enhances the pain relief produced by morphine.
                Simultaneous use of small doses of ketamine with morphine enhances the pain relief produced by morphine. We investigated whether intraoperative 'subanesthetic doses' of ketamine have a postoperative anti-hyperalgesic and an analgesic effect and which is the preferential route of administration, either systemic (intravenous, i.v.) or epidural. One hundred patients scheduled for rectal adenocarcinoma surgery under combined epidural/general anesthesia were included. Before skin incision all the patients received an epidural bolus followed by an infusion of continuous bupivacaine/sufentanil/clonidine mixture. They were randomly assigned to receive no ketamine (group 1), i.v. ketamine at the bolus dose of 0.25 mg/kg followed by an infusion of 0.125 mg/kg per h (group 2), 0.5 mg/kg and 0.25 mg/kg per h (group 3), epidural ketamine 0.25 mg/kg and 0.125 mg/kg per h (group 4), or 0.5 mg/kg and 0.25 mg/kg per h (group 5). All i.v. and epidural analgesics were stopped at the end of surgery and patients were connected to an i.v. morphine patient-controlled analgesia (PCA) device. Short-term postoperative analgesia (72 h) was assessed by pain visual analog scale scores at rest, cough, and movements as well as by PCA requirements. Wound mechanical hyperalgesia was evaluated and residual pain was assessed by asking the patients at 2 weeks, and 1, 6, and 12 months. The area of hyperalgesia and morphine PCA requirements were significantly reduced in group 3. These patients reported significantly less residual pain until the sixth postoperative month. These observations support the theory that subanesthetic doses of i.v. ketamine (0.5 mg/kg bolus followed by 0.25 mg/kg per h) given during anesthesia reduce wound hyperalgesia and are a useful adjuvant in perioperative balanced analgesia. Moreover, they show that the systemic route clearly is the preferential route. In this prospective, randomized, and double-blinded clinical trial, we evaluated the efficacy of preincisional administration of epidural ketamine with morphine compared with epidural morphine alone for postoperative pain relief after major upper-abdominal surgery. We studied 50 ASA I and II patients undergoing major upper-abdominal procedures. These patients were randomly allocated to one of the two treatment groups: patients in Group 1 received epidural morphine 50 microg/kg, whereas those in Group 2 received epidural ketamine 1 mg/kg combined with 50 microg/kg of morphine 30 min before incision. Intraoperative analgesia was provided in addition, with IV morphine, and the requirement was noted. A blinded observer using a visual analog scale for pain assessment observed patients for 48 h after surgery. Additional doses of epidural morphine were provided when the visual analog scale score was more than 4. Analgesic requirements and side effects were compared between the two groups. There were no differences between the two groups with respect to age, sex, weight, or duration or type of the surgical procedures. The intraoperative morphine requirement was significantly (P = 0.018) less in Group 2 patients (median, 6.8 mg; range, 3-15 mg) compared with patients in Group 1 (median, 8.3 mg; range, 4.5-15 mg). The time for the first requirement of analgesia was significantly (P = 0.021) longer (median, 17 h; range, 10-48 h) in Group 2 patients than in Group 1 (median, 12 h; range, 4-36 h). The total number of supplemental doses of epidural morphine required in the first 48 h after surgery was comparable (P = 0.1977) in both groups. Sedation scores were similar in both groups. One patient in Group 2 developed hallucinations after study drug administration. None of the patients in either group developed respiratory depression. Other side effects, such as pruritus, nausea, and vomiting, were also similar in both groups. Although the addition of ketamine had synergistic analgesic effects with morphine (reduced intraoperative morphine consumption and prolonged time for first requirement of analgesia), there was no long- lasting preemptive benefit seen with this combination (in terms of reduction in supplemental analgesia) for patients undergoing major upper-abdominal procedures.
                Ketamine added to epidural morphine given before surgery can decrease postoperative pain by its preemptive effect, opioid potentiation, and prevention of acute opioid tolerance. A single epidural bolus of 1 mg/kg of ketamine with morphine given before major upper-abdominal surgery did not result in a clinically relevant reduction in postoperative pain relief. In a randomized, double-blinded study with three parallel groups, we assessed the analgesic effect of intraoperative ketamine administration in 45 ASA physical status I or II patients undergoing elective arthroscopic anterior ligament repair under general anesthesia. The patients received either IV ketamine 0.15 mg/kg after the induction of anesthesia and before surgical incision and normal saline at the end of surgery (PRE group); normal saline after the induction of anesthesia and before surgical incision and IV ketamine at the end of surgery (POST group); or normal saline at the beginning and the end of surgery (CONT group). Anesthesia was performed with propofol (2 mg/kg for induction, 60-200 microg x kg(-1) x min(-1) for maintenance), sufentanil (0.2 microg/kg 10 min after surgical incision, followed by an infusion of 0.25 microg x kg(-1) x h(-1) stopped 30 min before skinclosure), vecuronium (0.1 mg/kg), and 60% N2O in O2 via a laryngeal mask airway. Postoperative analgesia was initially provided with IV morphine in the postanesthesia care unit, then with IV patient-controlled analgesia started before discharge from the postanesthesia care unit. Pain scores, morphine consumption, side effects, and degree of knee flexion were recorded over 48 h and during the first and second physiotherapy periods, performed on Days 1 and 2. Patients in the ketamine groups required significantly less morphine than those in the CONT group over 48 h postoperatively (CONT group 67.7+/-38.3 mg versus PRE group 34.3+/-23.2 mg and POST group 29.5+/-21.5 mg; P < 0.01). Better first knee flexion (CONT group 35+/-10 degrees versus PRE group 46+/-12 degrees and POST group 47+/-13 degrees; P < 0.05) and lower morphine consumption (CONT group 3.8+/-1.7 mg versus PRE group 1.2+/-0.4 mg and POST group 1.4+/-0.4 mg; P < 0.05) were noted at first knee mobilization. No differences were seen between the PRE and POST groups, except for an increase in morphine demand in the PRE versus the POST group (P < 0.05) in the second hour postoperatively.
                We found that intraoperative small-dose ketamine reduced postoperative morphine requirements and improved mobilization 24 h after arthroscopic anterior ligament repair. No differences were observed in the timing of administration. Intraoperative small-dose ketamine may therefore be a useful adjuvant to perioperative analgesic management. To compare the analgesic and side effects of preemptively used epidural ketamine +bupivacaine, neostigmine +bupivacaine, and bupivacaine alone on postoperative analgesia after major abdominal surgery.
                Randomized, controlled study.
                Inpatient anesthesia at the department of surgery of a metropolitan hospital.
                30 ASA physical status I, II, and III patients scheduled for abdominal surgery.
                Group K received 1 mL (50 mg) ketamine and 5 mL (25 mg) bupivacaine epidurally, Group N received 1 mL (0.5 mg) neostigmine and 5 mL (25 mg) bupivacaine epidurally, and Group B received 1 mL saline and 5 mL (25 mg) bupivacaine epidurally 30 minutes before operation. All patients underwent anesthesia induction with thiopental and vecuronium; anesthesia was maintained with isoflorane and vecuronium. For postoperative analgesia, all patients received epidural morphine for 48 hours postoperatively.
                Standard monitoring included: 48 hours of analgesic requirement, visual analog scale (VAS), mean arterial pressure (MAP), and heart rate (HR) in the 1st, 2nd, 6th, 12th, 24th, and 48th hours. Data were analyzed using Kruskall-Wallis and Mann Whitney U tests, with a p < 0.05 considered statistically significant. No significant differences were observed regarding MAP and HR among the groups during the study period. In Group N, VAS was significantly lower than Group K and Group B. The total opioid consumption in Group N was significantly lower than in Groups K and B in the first 48 hours after the operation.
                Preemptive neostigmine can be a good choice for postoperative analgesia. We designed this double-blind study to evaluate the effect of adding small-dose ketamine in a multimodal regimen of postoperative patient-controlled epidural analgesia (PCEA). Ninety-one patients, ASA physical status I-III, undergoing major surgery, received a standardized general anesthesia and epidural catheterization in an appropriate intervertebral space after surgery. A PCEA device was programmed to deliver a regimen of morphine 0.02 mg/mL, bupivacaine 0.8 mg/mL, and epinephrine 4 microg/mL, with the addition of ketamine 0.4 mg/mL (ketamine, n = 45) or without (control, n = 46). The mean visual analog pain scale (VAS) scores during cough or movement for the first 3 days after surgery were higher in the control group than in the ketamine group (P < 0.05), whereas the mean VAS score at rest for the first 2 days were higher in the control group than in the ketamine group (P < 0.05). Furthermore, patients in the control group consumed more multimodal analgesics than patients in the ketamine group for the first 2 days (P < 0.05). The sedation scores and the incidence of side effects (pruritus, nausea, emesis, sleep deprivation, motor block, and respiration depression) were similar between the two groups. We conclude that adding ketamine 0.4 mg/mL in a multimodal PCEA regimen provides better postoperative pain relief and decreases consumption of analgesics. Implications: Many studies have evaluated one or a combination of two analgesics for postoperative pain control, but few have examined a multimodal approach using three or four different epidural analgesics. This study demonstrates an additive analgesic effect when ketamine is added to a multimodal analgesic treatment. In this study, we evaluated the preemptive effect of a small dose of ketamine on postoperative wound pain. In a randomized, double-blinded, controlled trial, we compared the analgesic requirement in patients receiving preincision ketamine with ketamine after skin closure or placebo after gynecologic laparoscopic surgery. One-hundred-thirty-five patients were randomly assigned to receive preincision or postoperative ketamine 0.15 mg/kg or saline IV. Anesthetic technique was standardized. Patients were interviewed regularly up to 4 wk after surgery. Pain score, morphine consumption, side effects, and quality of recovery score were recorded. Patients receiving preincision ketamine had a lower pain score in the first 6 h after operation compared with the postoperative (P = 0.001) or placebo groups (P < 0.001). The mean (95% confidence intervals) time to first request for analgesia in the preincision group, 1.8 h (1.4-2.1), was longer than the postoperative group, 1.2 h (0.9-1.5; P < 0.001), or the placebo group, 0.7 h (0.4-0.9; P < 0.001). The mean +/- SD morphine consumption in the preincision group, 1.5 +/- 2.0 mg, was less than that in the postoperative group, 2.9 +/- 3.1 mg (P = 0.04) and the placebo group, 3.4 +/- 2.7 mg (P = 0.003). There was no significant difference among groups with respect to hemodynamic variables or side effects. No patient complained of hallucinations or nightmares. We conclude that a small dose of ketamine is not only safe, but it also provides preemptive analgesia in patients undergoing gynecologic laparoscopic surgery.
                In women undergoing laparoscopic gynecologic surgery, a small preoperative dose of ketamine (0.15 mg/kg) produced preemptive analgesia. There were no significant hemodynamic and psychological side effects with this dose. We studied 60 patients undergoing operation on the kidney with combined general and epidural anaesthesia, in a double-blind, randomized, controlled study. Patients were allocated to receive a preoperative bolus dose of ketamine 10 mg i.v., followed by an i.v. infusion of ketamine 10 mg h-1 for 48 h after operation, or placebo. During the first 24 h after surgery, all patients received 4 ml h-1 of epidural bupivacaine 2.5 mg ml-1. From 24 to 48 h after operation, patients received epidural morphine 0.2 mg h-1 preceded by a bolus dose of 2 mg. In addition, patient-controlled analgesia (PCA) with i.v. morphine (2.5 mg, lockout time 15 min) was offered from 0 to 48 h after operation. Patients who received ketamine felt significantly more sedated at 0-24 h, but not at 24-48 h after operation, compared with patients who received placebo (P = 0.002 and P = 0.127, respectively). There were no significant differences in pain (VAS) at rest, during mobilization or cough, PCA morphine consumption, sensory block to pinprick, pressure pain detection threshold assessed with an algometer, touch and pain detection thresholds assessed with von Frey hairs, peak flow or side effects other than sedation. The power of detecting a reduction in VAS scores of 20 mm in our study was 80% at the 5% significance level. We conclude that we were unable to demonstrate an (additive) analgesic or opioid sparing effect of ketamine 10 mg h-1 i.v. combined with epidural bupivacaine at 0-24 h, or epidural morphine at 24-48 h after renal surgery. The use of intraoperative racemic ketamine for pain prevention after abdominal surgery is controversial. We compared one preincisional i.v. injection of S(+)-ketamine with its preincisional and repeated intraoperative use in 45 patients undergoing surgery with epidural and general anesthesia. S(+)-ketamine is a new drug formulation that contains the more potent S(+)-stereoisomer of ketamine. Patients were randomized to receive placebo, 0.5 mg/kg preincisional S(+)ketamine, or 0.5 mg/kg preincisional and 0.2 mg/kg intraoperative S(+)-ketamine repeated at 20-min intervals. In the postoperative period, epidural ropivacaine (2 mg/mL; 0.12 mL.kg(-1).h(-1)) was infused for pain therapy. Patients who received repeated S(+)-ketamine reported smaller pain scores than those who received placebo after awakening and 3 and 6 h later (P < or = 0.05). Fewer patients with repeated S(+)-ketamine required additional analgesics than those with placebo (P < or = 0.05). Cumulative consumption of additional diclofenac and dextropropoxyphene at 24 h was less after single (P < 0.05) and repeated (P < 0.05) S(+)-ketamine versus placebo. After awakening, patients who received repeated S(+)-ketamine reported being in a better mood than those in the other groups (P < 0.05). No psychotomimetic side effects were noted. In conclusion, preincisional and repeated intraoperative small-dose S(+)-ketamine added to general and epidural anesthesia causes better postoperative pain relief than general and epidural anesthesia alone.
                After major visceral surgery, preincisional and repeated intraoperative small-dose S(+)-ketamine added to general and epidural anesthesia causes better postoperative pain relief than general and epidural anesthesia alone. Relative large-dose intraoperative remifentanil could lead to the need for more postoperative analgesics. Intraoperative N-methyl-D-aspartate receptor antagonists, such as ketamine, decrease postoperative opioid use. We therefore tested the hypothesis that intraoperative small-dose ketamine improves postoperative analgesia after major abdominal surgery with remifentanil-based anesthesia. Fifty patients undergoing abdominal surgery under remifentanil-based anesthesia were randomly assigned to intraoperative ketamine or saline (control) supplementation. The initial ketamine dose of 0.15 mg/kg was followed by 2 microg. kg(-1). min(-1). In both groups, desflurane was kept constant at 0.5 minimum alveolar anesthetic concentration without N(2)O, and a remifentanil infusion was titrated to autonomic responses. All patients were given 0.15 mg/kg of morphine 30 min before the end of surgery. Pain scores and morphine consumption were recorded for 24 postoperative h. Less of the remifentanil was required in the Ketamine than in the Control group (P < 0.01). Pain scores were significantly larger in the Control group during the first 15 postoperative min but were subsequently similar in the two groups. The Ketamine patients required postoperative morphine later (P < 0.01) and received less morphine during the first 24 postoperative h: 46 mg (interquartile range, 34-58 mg) versus 69 mg (interquartile range, 41-87 mg, P < 0.01). No psychotomimetic symptoms were noted in either group. In conclusion, supplementing remifentanil-based anesthesia with small-dose ketamine decreases intraoperative remifentanil use and postoperative morphine consumption without increasing the incidence of side effects. Thus, intraoperative small-dose ketamine may be a useful adjuvant to intraoperative remifentanil.
                Supplementing remifentanil-based anesthesia with small-dose ketamine decreased intraoperative remifentanil use and postoperative morphine consumption. These data demonstrate that N-methyl-D-aspartate antagonists, such as ketamine, can be a useful adjuvant to intraoperative remifentanil. This double-blind randomized study tested whether the addition of magnesium or ketamine to morphine for intravenous patient-controlled analgesia resulted in improved analgesic efficacy and lower pain scores compared with morphine patient-controlled analgesia alone after major abdominal surgery.
                Ninety patients (3 x 30) were randomly allocated to receive either morphine 0.4 mg mL(-1) (Group M) by patient-controlled analgesia, morphine 0.4mg mL(-1) + MgSO4 30mg mL(-1) (Group MM) or morphine 0.4 mg mL(-1) + ketamine 1 mg mL(-1) (Group MK). Postoperative analgesia was started when the verbal rating scale was > or = 2. Patients were first given a standardized loading dose (0.05 mg kg(-1)) of the study solution. They were then allowed to use bolus doses of this solution (0.0125 mg kg(-1) every 20 min without time limit). Discomfort, sedation, pain scores, cumulative morphine consumption and adverse effects were recorded up to 24 h after the start of the patient-controlled analgesia.
                The level of discomfort, level of sedation and verbal rating scores decreased significantly with time in all groups (P < 0.05). Both verbal rating and discomfort scores were significantly lower in Groups MM and MK at 15, 30 and 60 min compared with Group M (P < 0.001). Cumulative morphine consumption after 12 and 24 h was significantly higher in Group M alone (median 26 and 49 mg, respectively) compared with Group MM (24.2 and 45.7 mg) and Group MK (24.4 and 46.5 mg).
                In the immediate postoperative period, the addition of magnesium or ketamine to morphine for intravenous patient-controlled analgesia led to a significantly lower consumption of morphine. However, these differences are unlikely to be of any clinical relevance. A randomized controlled trial was conducted to determine the effect of adding epidural ketamine to epidural morphine comparing between giving ketamine at preincisional time and postincisional time on postoperative analgesia in patients undergoing gynecological operations. Eighty patients scheduled for gynecological operation under combined epidural-general anesthesia were randomly divided into 4 groups. Group 1 received epidural morphine 3 mg before skin incision. Group 2 received epidural morphine 3 mg after skin incision. Group 3 received epidural morphine 3 mg and ketamine 30 mg before skin incision. Group 4 received epidural morphine 3 mg and ketamine 30 mg after skin incision. Lidocaine 2 per cent with epinephrine 1:200,000 was used as the main anesthetic agent during the operation in all groups. Postoperative analgesics were pethidine 1 mg/kg intramuscularly or paracetamol 1,000 mg oral. The time to the first analgesic requirement and pain during 48 h were recorded. The amount of pethidine and paracetamol required and the time to the first dose of analgesic requirement were not significantly different among the groups. There were no differences in the incidences of pruritus, nausea, vomiting and nightmare. We concluded that adding ketamine to epidural morphine either by preincisional or postincisional administration did not potentiate the analgesic effect of epidural morphine. Ketamine has been administered epidurally and intrathecally for operative and post-operative pain control. Animal studies showed potentiation of analgesia induced by ketamine and morphine. We hypothesized that intrathecal ketamine would potentiate the effects of intrathecal morphine in the treatment of cancer pain.
                A double blind, cross over study was designed to evaluate the effect of ketamine on spinal morphine analgesia in terminal cancer pain patients. A two-phase protocol was used; phase M, intrathecal morphine alone twice daily; phase M + K, co-administration of ketamine (1.0 mg) with morphine intrathecally twice daily. The dose of morphine was titrated upwards until acceptable pain relief was achieved, defined by numeric rating scales (0-10) < or = 3, and the rescue dose of morphine was less than 5 mg after each intrathecal administration for two days. The dose of intrathecal morphine was defined as the effective dose.
                The effective dose of intrathecal morphine in phase M of 0.38 +/- 0.04 mg.day-1 was higher than that in phase M + K (0.17 +/- 0.02 mg.day-1) (P < 0.05). The average pain scales were 7.95 +/- 0.25 before intrathecal drug administration. Pain scales were decreased to 2.2 +/- 0.17 (P < 0.05) in phase M and 1.95 +/- 0.20 (P < 0.05) in phase M + K after the effective dose of morphine had been reached. No serious side effects were observed in this study.
                The present study demonstrates that ketamine enhances the analgesic effect of morphine, thus reducing the dose of intrathecal morphine. Ketamine may prevent postoperative hyperalgesia. In patients undergoing arthroscopic meniscectomy using general anesthesia, we tested whether a single intraoperative dose of ketamine enhanced postoperative analgesia and improved functional outcome compared with a typical multimodal analgesic regimen. After the induction of anesthesia, 50 patients were randomly assigned to ketamine (0.15 mg/kg IV just after the induction of anesthesia) or a vehicle placebo. Standardized general anesthesia included propofol, alfentanil, and nitrous oxide. Bupivacaine (0.5%) and morphine (5 mg) were given intraarticularly at the end of surgery. Postoperative analgesia was initially provided with morphine and subsequently with naproxen sodium (550 mg orally twice daily) and Di-Antalvic (400 mg acetaminophen and 30 mg dextropropoxyphene) as needed. Pain scores, analgesic requirements, side effects, and ability to walk were assessed in the ambulatory unit and at home for three postoperative days. Times to awakening and to discharge were similar in the two groups. However, the Ketamine group had significantly less postoperative pain at rest and during mobilization on Days 0, 1, and 2. Furthermore, they consumed significantly fewer Di-Antalvic tablets than the control group (13 [7-17] vs 27 [16-32], median [25%-75% interquartile range]). Patients given ketamine were also able to walk for longer periods of time on the first postoperative day. In conclusion, adding small-dose ketamine to a multimodal analgesic regimen improved postoperative analgesia and functional outcome after outpatient knee arthroscopy. Reduction of nociceptive input through blockade of N-methyl-D-aspartate (NMDA) receptors has been reported. We compared the effects of epidural S(+)-ketamine versus placebo on postoperative pain in a randomized, double-blinded study in 37 patients undergoing unilateral knee arthroplasty. After lumbar epidural anesthesia with ropivacaine (10 mg/mL, 10-20 mL), 19 patients received 0.9% epidural saline, and 18 patients received 0.25 mg/kg epidural S(+)-ketamine 10 min before surgical incision. After surgery, patient-controlled epidural analgesia with ropivacaine was provided. During the first 8 h after surgery, visual analog scale pain rating was similar between groups. Twenty-four and 48 h after surgery, patients anesthetized with ropivacaine had higher visual analog scale ratings at rest and during movement (P < 0.05) than patients anesthetized with S(+)-ketamine and ropivacaine. Forty-eight hours after surgery, patients anesthetized with ropivacaine also consumed more ropivacaine (558 +/- 210 mg) (P < 0.01) than those anesthetized with S(+)-ketamine and ropivacaine (319 +/- 204 mg). Adverse events were similar between groups. Patients who received S(+)-ketamine and ropivacaine rated the quality of their pain therapy better than those who received ropivacaine alone (P < 0.05). We conclude that the combination of S(+)-ketamine and ropivacaine in epidural anesthesia increases postoperative pain relief when compared with ropivacaine.
                Epidural S(+)-ketamine applied with ropivacaine before surgery is a rational approach to decrease injury-induced pain sensitization. Epidural blockade with an N-methyl-D-aspartate receptor antagonist and a local anesthetic may provide better analgesia in the postoperative period than a local anesthetic alone. Ketamine may produce "preemptive" analgesia when administered before surgically induced trauma. Therefore, we hypothesized that pre- versus postincisional administration of ketamine would improve pain control after abdominal hysterectomy procedures. Eighty-nine patients were randomly assigned to one of three treatment groups according to a placebo-controlled, double-blinded protocol: Group 1 (placebo) received saline 0.04 mL/kg IV immediately before and after surgery; Group 2 (preincision), received ketamine 0.4 mg/kg IV before skin incision and saline at the end of the operation; and Group 3 (postincision), received saline before skin incision, and ketamine 0.4 mg/kg IV was given after skin closure. The general anesthetic technique was standardized in all three treatment groups. During the first postoperative hour, Group 3 experienced significantly less pain than Groups 1 and 2, as assessed by using both visual analog and verbal rating scales. There were no significant differences between Groups 1 and 2 with respect to pain scores, postoperative opioid analgesic requirements, and incidence of postoperative nausea and vomiting. We conclude that a single dose of ketamine 0.4 mg/kg IV fails to produce preemptive analgesic effects. Implications: Even though ketamine 0.4 mg/kg IV has short-lasting acute analgesic effects, it failed to produce a preemptive effect when given before abdominal hysterectomy procedures. Ketamine efficacy as an analgesic adjuvant has been studied in several clinical settings with conflicting results. The aim of this study was to investigate the effect of ketamine on spontaneous and swallowing-evoked pain after tonsillectomy.
                Fifty children were randomized to receive premedication with either ketamine 0.1 mg kg(-1) i.m. or placebo given 20 min before induction of a standard general anaesthesia. All children received rectal diclofenac 2 mg kg(-1) and fentanyl 1 micro g kg(-1) i.v. before surgery.
                The ketamine group showed significantly lower pain scores both at rest and on swallowing, with less total paracetamol consumption (P < 0.05) during the 24 h after surgery. Significantly more patients required postoperative morphine titration in the control group (P < 0.05). The time to the first oral intake, and duration of i.v. hydration, were significantly shorter and the quality of oral intake was significantly better in the ketamine group (P < 0.05). There were no differences in the incidence of vomiting or dreaming between the groups.
                Premedication with a small dose of ketamine reduces swallowing-evoked pain after tonsillectomy in children who received an analgesic regimen combining an opioid and a NSAID. In a double-blind, placebo-controlled clinical trial (power of 80% to detect a 30% reduction in morphine consumption, P < 0.05), we have determined that the administration of two doses of intravenous ketoprofen 100 mg, one at the end of surgery and the second 12 hours postoperatively, was associated with a significant reduction in morphine consumption at eight (P = 0.028), 12 (P = 0.013) and 24 hours (P = 0.013) but not four hours (P = 0.065) postoperatively, as compared to placebo, when assessed by patient-controlled analgesia. There was no difference between the groups in pain scores or in the incidence of nausea and vomiting. One patient in the placebo group suffered from excessive sedation while one patient from the ketoprofen group suffered from transient oliguric renal failure. There were no other adverse effects. The results of this study show that ketoprofen does provide a morphine-sparing effect in the management of postoperative pain after abdominal surgery. To study the analgesic effect of epidural ketamine on postoperative pain and epidural PCA consumption after total abdominal hysterectomy.
                Sixty-one ASA I-II patients, 34-60 yr were randomly assigned into three groups. Epidural catheters were inserted before induction of anaesthesia. Patients in group I and II received 30 mg ketamine epidurally before induction of anaesthesia or 20 min after skin incision: group III received placebo. Postoperatively, on first analgesia request, sedation score, Visual Analogue Scale (VAS), Prince Henry Score (PHS) and Bromage motor weakness score were taken and followed by an epidural bolus of 9 ml bupivacaine 0.25% + 50 micrograms fentanyl. Analgesia was maintained by PCA with a mixture of bupivacaine 0.1% + fentanyl 0.001% epidurally. Measurements were repeated at 1, 2, 4, 8, 12 and 24 hr.
                First analgesia request was 17 +/- 6.8 min in the control group compared with 31.4 +/- 23.8 and 44 +/- 23.1 min for groups I and II respectively. The differences between group III and group I (P < 0.05) and between group III and group II (P < 0.01) were statistically significant. Twenty four hour PCA consumption was 101.2 +/- 47.2, 87 +/- 27 and 162 +/- 38 ml for groups I, II and III respectively. The differences between group III and group I and that between group III and group II were statistically significant (P < 0.001).
                Epidural ketamine 30 mg reduces post hysterectomy pain as evidenced by prolongation of time to first analgesia request and reduction in postoperative epidural PCA consumption. This effect is manifest whether ketamine is given before induction or 20 min after skin incision. In a randomized, double-blinded study, we evaluated the analgesic effect of ketamine in the management of pain in a surgical intensive care unit after major abdominal surgery. Patients received morphine patient-controlled analgesia with either placebo (Group M) or ketamine (Group K). Morphine was administered with initial loading doses of 2 mg until the visual analog scale (VAS) score was <30 and thereafter with bolus doses of 1 mg and a lockout time of 7 min. Ketamine was administered with an initial bolus of 0.5 mg/kg followed by a perfusion of 2 micro g x kg(-1) x min(-1) during the first 24 h and 1 micro g x kg(-1) x min(-1) during the following 24 h. The 4-h cumulative morphine doses were measured over 48 h. The VAS scores at rest and at mobilization were measured every 4 h during 48 h. A total of 101 patients were enrolled, and 93 were analyzed (41 in Group K and 52 in Group M). VAS scores at rest and at mobilization were similar. The cumulative consumption of morphine was significantly smaller in Group K (P < 0.05). We concluded that small doses of ketamine were a valuable adjunct to opioids in surgical intensive care unit patients after major abdominal surgery. The postoperative analgesic efficacy of S(+)-ketamine after caudal or i.v. administration following sub-umbilical surgery in children was studied to investigate its principal site of analgesic action.
                Sixty children undergoing caudal block during general anaesthesia for hernia repair or orchidopexy were prospectively randomized to one of three groups: the bupivicaine group received plain bupivacaine 0.25% 1 ml x kg(-1); the caudal ketamine group received caudal plain bupivacaine 0.25% 1 ml x kg(-1) with S(+)-ketamine 0.5 mg x kg(-1); the i.v. ketamine group received caudal plain bupivacaine 0.25% 1 ml x kg(-1) plus S(+)-ketamine 0.5 mg x kg(-1) i.v. Postoperative measurements included analgesic requirements and modified objective pain score for the first 24 h.
                The median time to first analgesia was significantly longer in the caudal ketamine group (10 h) than in the i.v. ketamine (4.63 h) or bupivacaine (4.75 h) groups (P=0.01). Significantly fewer doses of analgesia were required over the first postoperative 24 h by subjects in the caudal ketamine group (median 1) compared with the i.v. ketamine (median 2) or bupivacaine (median 2.5) groups (P<0.05). There was no difference between the groups in the incidence of postoperative nausea and vomiting or psychomotor reactions.
                We have demonstrated that the addition of caudal S(+)-ketamine to bupivacaine prolongs the duration of postoperative analgesia. However, the same dose of i.v. S(+)-ketamine combined with a plain bupivacaine caudal provides no better analgesia than caudal bupivacaine alone, indicating that the principal analgesic effect of caudal S(+)-ketamine results from a local neuroaxial rather than a systemic effect. We have studied the effect of adding ketamine to i.v. morphine patient-controlled analgesia (PCA) for the treatment of pain after laparotomy. Thirty patients were allocated randomly to receive PCA with saline or ketamine in a double-blind, randomized study. Analgesia was started in the recovery room when visual analogue scale (VAS) scores were > 4. A bolus dose of morphine 3 mg was given to all the patients followed by i.v. PCA. Simultaneously, an infusion of ketamine 2.5 micrograms kg-1 min-1 or saline was started. Pain scores, morphine consumption and side effects were noted for up to 48 h after the start of PCA. VAS scores decreased significantly with time (P = 0.0001) and were similar (P = 0.3083) in both groups. Cumulative morphine consumption at 48 h was significantly lower in the ketamine group (28 mg) than in the control group (54 mg) (P = 0.0003). Nausea was less frequent in the ketamine group (P = 0.03). Morphine and ketamine may prevent central sensitization during surgery and result in preemptive analgesia. The reliability of preemptive analgesia, however, is controversial.
                Gastrectomy patients were given preemptive analgesia consisting of epidural morphine, intravenous low-dose ketamine, and combinations of these in a randomized, double-blind manner. Postsurgical pain intensity was rated by a visual analog scale, a categoric pain evaluation, and cumulative morphine consumption.
                Preemptive analgesia by epidural morphine and by intravenous low-dose ketamine were significantly effective but not definitive. With epidural morphine, a significant reduction in visual analog scale scores at rest was observed at 24 and 48 h, and morphine consumption was significantly lower at 6 and 12 h, compared with control values. With intravenous ketamine, visual analog scale scores at rest and morphine consumption were significantly lower at 6, 12, 24, and 48 h than those in control subjects. The combination of epidural morphine and intravenous ketamine provided definitive preemptive analgesia: Visual analog scale scores at rest and morphine consumption were significantly the lowest at 6, 12, 24, and 48 h, and the visual analog scale score during movement and the categoric pain score also were significantly the lowest among the groups.
                The results suggest that for definitive preemptive analgesia, blockade of opioid and N-methyl-d-aspartate receptors is necessary for upper abdominal surgery such as gastrectomy; singly, either treatment provided significant, but not definitive, postsurgical pain relief. Epidural morphine may affect the spinal cord segmentally, whereas intravenous ketamine may block brain stem sensitization via the vagus nerve during upper abdominal surgery. The aim of this study was to compare the analgesic effects and pharmacokinetics of epidural versus intravenous administration of low doses of ketamine.
                45 patients scheduled for selective gastrectomy were randomly assigned into 3 groups: 0.5mg/kg ketamine administered epidurally (Kepi group), 0.5 mg/kg ketamine administered intravenously (Kiv group), or 10ml normal saline administered epidurally (Ctr group). Analgesic effects were evaluated using Visual Analog Scale (VAS) pain scores at rest, time to first request for analgesic (TFA), and subsequent morphine consumption. The plasma concentration of ketamine was measured with high performance liquid chromatography (HPLC) in the Kepi and Kiv groups. The elimination half-life of ketamine was calculated.
                Patients in the Kepi group had significantly lower VAS pain scores, longer TFA, and lower morphine consumption than patients in the Kiv or Ctr groups. Compared with intravenous administration, epidural administration of ketamine resulted in higher plasma concentrations from 90 minutes to 48 hours after injection, and much longer elimination half-life of ketamine, but a lower maximum plasma concentration of ketamine.
                The results suggest that epidural administration of a low dose of ketamine provides more effective analgesic effects as seen post-operatively than intravenous administration. The prolonged half-life and high plasma sustained concentration of epidural ketamine might account for the difference in analgesic effects. Following a standardized general anaesthetic for total abdominal hysterectomy, patients received either patient controlled analgesia (PCA) with morphine 1 mg/ml (group M, n = 33) or morphine 1 mg/ml plus ketamine 2 mg/ml (group K, n = 37) for 48 hours in a randomized, double-blind fashion. In 43 women the area of allodynia around the scar was mapped as a measure of the degree of central sensitization. A significant reduction in the area of allodynia was found in those receiving ketamine with morphine (42 cm2 [interquartile range (IQR) 57] compared with 57 cm2 [IQR 82] z = -2.0, P = 0.04) in those receiving morphine alone. There were no significant differences between the two groups with respect to age, or weight, or between the subgroups within which the area of allodynia was measured with respect to length of incision. No significant differences were found between the groups with respect to pain scores, total or hourly drug consumption, patient satisfaction, nausea scores or antiemetic use. Patients in group K were more likely to require PCA for a shorter period than those in group M (median 40 hours, IQR 26 versus 48 hours IQR 7). Ten patients in group K were withdrawn because of side-effects (dysphoria n = 4, nausea n = 2, pruritus n = 4) compared with one in group M (nausea n = 1) (P = 0.006). The potential usefulness of ketamine after hysterectomy was offset by a high incidence of adverse effects and a lack of opioid-sparing effects, such that combined intravenous ketamine and morphine PCA as used in this study cannot be recommended for routine care. In a randomised, double-blind prospective study we compared the effects on postoperative pain and analgesic consumption of intra-operative s(+)-ketamine (100 microg.kg-1 bolus and a continuous infusion of 2 microg.kg-1.min-1) followed by postoperative patient-controlled analgesia with morphine (1 mg per bolus) plus s(+)-ketamine (0.5 mg per bolus), or intra-operative saline followed by postoperative patient-controlled analgesia morphine (1 mg per bolus) alone. A total of 28 male patients undergoing radical prostatectomy were studied. Morphine consumption, pain scores, pressure algometry and adverse effects were recorded for 48 h after surgery. Cumulative morphine consumption was significantly lower in the ketamine/morphine group (47.9 +/- 26.2 mg) than in the saline/morphine group (73.4 +/- 34.8 mg; p = 0.049). Pain scores at rest were significantly lower in the ketamine/morphine group across the 48-h study period (p = 0.01). No significant differences were found in pressure algometry measurements or the occurrence of adverse effects. This randomised, double-blind, prospective study compared morphine (1 mg x m(-1)) with the combination of morphine (1 mg x m(-1)) and ketamine (0.75 mg x m(-1)) via a patient-controlled analgesia system (PCAS) for postoperative pain control. A total of 42 female patients, ASA grade I and II, undergoing elective total abdominal hysterectomy was studied. During a standardised anaesthetic, a loading dose from the PCA syringe of 10 ml x m(-2) of body surface area was given. A PCAS with a background infusion was commenced postoperatively. Pain and side-effects were assessed using numerical scoring systems and cardiovascular and respiratory parameters were recorded. There was no statistically significant difference between the groups in total morphine consumption or pain scoring. Side-effect profiles and time to mobilisation were similar. This study concludes that the addition of ketamine to morphine, in this dosage regimen, administered via PCAS for postoperative pain control, does not confer benefit following total abdominal hysterectomy. N-methyl-D-aspartate antagonists were shown to be effective in suppressing the symptoms of opiate withdrawal. Intravenous anesthetic, ketamine, is the most potent N-methyl-D-aspartate antagonist available in clinical practice. The present study was designed to evaluate the effects of subanesthetic ketamine infusion, as little human data are available on ketamine in precipitated opiate withdrawal.
                A total of 58 opiate-dependent patients were enrolled in a randomized, placebo-controlled, double-blind study. Patients underwent rapid opiate antagonist induction under general anesthesia. Prior to opiate antagonist induction patients were given either placebo (normal saline) or subanesthetic ketamine infusion of 0.5 mg/kg/h. Further evaluations were divided into three phases: anesthetic, early postanesthetic (48 hours), and remote at 4 months after procedure. Cardiovascular, respiratory, renal, and gastrointestinal responses to opiate antagonist induction were monitored during anesthesia phase. Changes in plasma cortisol concentrations were measured as stress-response markers. Evaluations during early postanesthetic phase were based on Subjective and Objective Opiate Withdrawal Scales. Remote effects were assessed according to questionnaire based on Addiction Severity Index.
                Altogether, 50 patients were included in the final analysis. Ketamine group presented better control of withdrawal symptoms, which lasted beyond ketamine infusion itself. Significant differences between Ketamine and Control groups were noted in anesthetic and early postanesthetic phases. There were no differences in effects on outcome after 4 months.
                In this study, subanesthetic ketamine infusion was an effective adjuvant in the correction of acute precipitated opiate withdrawal although it had no long-term effects on treatment of opiate dependence.
Ketamine in subanaesthetic dose (that is a dose which is below that required to produce anaesthesia) is effective in reducing morphine requirements in the first 24 hours after surgery. Ketamine also reduces postoperative nausea and vomiting. Adverse effects are mild or absent.