Gynaecological abdominal surgery is associated with moderate to severe postoperative pain [1,2] and needs effective analgesic protocols to improve postoperative rehabilitation and to reduce morbidity and mortality. Morphine is often used intravenously (i.v.) with a patient-controlled analgesia device or subcutaneously. However, with both routes there may be morphine-related adverse effects that may have a major impact on postoperative recovery [3,4]. In addition, opioids, when used alone in large doses, may induce tolerance that may lead to increased pain [5,6]. The concept of multimodal analgesia suggests that both improved analgesia and a reduction of the opioid dose, and, thus a reduction of opioid-related adverse effects, may be achieved by combining different analgesics . Developed in the late 1980s, the concept of multimodal or balanced analgesia takes advantage of an additive or potentially, synergistic, effect of combining multiple analgesics [8,9]. In animals, a synergy between i.v. morphine and nonsteroidal anti-inflammatory drugs , and between morphine and ketamine [11,12], has been demonstrated. Numerous clinical studies have shown that nonsteroidal anti-inflammatory drugs may reduce postoperative pain scores and opioid requirements, with a 30-50% sparing effect on morphine consumption and a reduction in the incidence of morphine-related adverse effects .
Ketamine, which is chemically related to phencyclidine and cyclohexamine, is a noncompetitive N-methyl-d-aspartate (NMDA) channel blocker . Excitatory neurotransmitters acting through NMDA receptors have been incriminated in the development of hyperalgesia and allodynia after tissue injury . In animal models, sub-anaesthetic doses of ketamine greatly alleviated provoked pain by preventing hyperalgesia and the development of opioid tolerance [6,16,17]. In patients, low-dose ketamine is usually defined as a bolus dose of less than 1 mg kg−1 via the i.v. route . Over the last 20 yr, numerous studies have suggested the benefits of administering ketamine concomitantly with opioids in severe postoperative pain states and for the prevention of opioid tolerance [6,19]. However, no properly randomized controlled study has been performed to assess the efficacy of the combination of ketamine with a nonsteroidal anti-inflammatory drug and morphine after a surgical procedure. Similarly, a few studies only have assessed the effects of ketamine on mood, memory and cognitive functioning after surgery, notably when ketamine was added to morphine in an i.v. patient-controlled analgesia device [18,20].
We performed a prospective randomized, double-blind, placebo-controlled study to examine the potential beneficial effects of low-dose ketamine on postoperative pain management in patients receiving morphine and a nonsteroidal anti-inflammatory drug after major gynaecological surgery. The study also assessed the effects of ketamine on mood, memory and cognitive function.
The study was conducted between May 2003 and October 2004. The study protocol was approved by our Institutional Review Board (Comité de Protection des Personnes se Prětant à la Recherche Biomédicale Pitié-Salpětrière, Paris, France). The trial was conducted according to the standards of Good Clinical Practice and the Helsinki Declaration. Written informed consent was obtained from all patients. This was a randomized, double-blind, placebo-controlled study.
Women, aged 18-70 yr, ASA Grade I-II, weighing between 50 and 100 kg, and undergoing elective abdominal gynaecological surgery were included. Surgery was performed using a standardized technique, using either an abdominal or a vaginal approach without laparoscopy. Surgery comprised abdominal hysterectomy with or without salpingo-oophorectomy, myomectomy or vaginal prolapse repair. Exclusion criteria were preoperative administration of morphine, allergy or contraindication to morphine, ketamine, or nonsteroidal anti-inflammatory drugs, renal failure (serum creatinine >120 μmol L−1), hepatic failure (transaminases or alkaline phosphatase >3 times of the upper normal value and/or prothrombin time <60% of control), scheduled regional anaesthesia, and emergency surgery. Patients with delirium or dementia or who were not French speaking and those who did not understand the pain, mood, memory and cognition scales that were used in the study were not considered.
Patients received oral hydroxyzine (50 or 100 mg) or midazolam (2.5 or 5 mg) 1 h before surgery. After i.v. cannulation, anaesthesia was induced with propofol (2.5 mg kg−1) and remifentanil (1 μg kg−1 bolus during 30-60 s, followed by an infusion of 0.5 μg kg−1 min−1). Tracheal intubation was performed after muscle relaxation had been achieved with atracurium (0.5 mg kg−1). Anaesthesia was maintained with propofol and remifentanil; doses were adjusted to achieve adequate anaesthesia. Patients were ventilated with an oxygen-air mixture (50%/50%). Before surgical incision, ketamine 0.15 mg kg−1 (racemic ketamine chlorhydrate 50 mg 5 mL−1, Panpharma, Paris, France) or the same volume of saline was administered i.v. Thirty minutes before the end of the operation, 0.20 mg kg−1 of morphine and 50 mg of ketoprofen (Profenid; Laboratoire Sanofi-Aventis, Paris, France) were administered i.v. After satisfactory spontaneous ventilation and awakening, the trachea was extubated, and the patient was transferred to the postanaesthesia care unit.
All nurses in the postanaesthesia care unit were trained to assess pain using the visual analogue scale (VAS; 0-100 mm, handheld slide-rule type)  and the numeric rating scale (NRS; 0-100 mm) . The two scales were regarded as equivalent . A strict protocol was implemented following a preliminary study that determined the optimal regimen of morphine titration . The protocol defined the appropriate dose and the interval between boluses, the VAS (or NRS) thresholds that were required to administer morphine and criteria to stop titration. There was no limitation in the total dose. After arrival in the postanaesthesia care unit, patients were questioned about the presence of pain (at least every 15 min before the onset of morphine titration) and were asked to rate their pain intensity on the VAS or the NRS. When the values were above 30, morphine was titrated i.v. every 5 min using 3 mg boluses (2 mg in patients weighing ≤60 kg) and pain was assessed every 5 min until pain relief (defined as a VAS or NRS ≤ 30). When the patient was asleep, no attempt was made for arousal; the patient was then considered as having adequate pain relief and was assigned a score of 0. When the pain was too severe to obtain a VAS or NRS (patient refusal), it was scored as 100. Clinical monitoring included respiratory rate, pulse oximetry, sedation according to the Ramsay score , arterial pressure and heart rate (HR). Morphine titration was stopped if the patient had a respiratory rate below 12 breaths min−1, or pulse oximetry was lower than 95%, or when she had a serious adverse event that was most likely related to morphine (for instance, an allergic reaction with cutaneous rash with or without arterial hypotension, vomiting, severe itching). In case of severe ventilatory depression (respiratory rate <10 breaths min−1), i.v. naloxone 0.04 mg was administered until the rate was above 12 min−1. Severe postoperative pain was defined as VAS ≥ 70 .
Immediately after morphine titration, patients were connected to a patient-controlled analgesia pump (9300 pump, Smiths Medical SA, Orly, France). Patients in the ketamine group received a combination of morphine 1 mg mL−1 and ketamine 0.5 mg mL−1. Patients in the placebo group received morphine 1 mg mL−1 alone. The bolus was set at 1 mL, the lockout interval at 7 min, and there was no 4 h dose limitation. HR, arterial pressure, respiratory rate, sedation, pain scores, the administered dose of morphine and the number of demands per patient were recorded hourly during the first 4 h and then every 4 h until 48 h. Sedation was assessed using the Ramsay sedation scale. Adverse effects, such as nausea and vomiting, sedation (Ramsay scale > 2) and respiratory depression (respiratory rate < 12 breaths min−1 or peripheral oxygen saturation <95% despite 3 L min−1 oxygen, or apnoea or periodic breathing), dizziness, cognitive dysfunction (hallucinations, nightmares, pleasant dreams or visual disturbances), itching and urinary retention requiring urine drainage were recorded.
Assessment of mood, cognitive state and memory
We used a VAS for self-rating of mood within 16 dimensions . Dimensions were alert-drowsy; calm-excited; strong-feeble; muzzy-clear-headed; well-coordinated-clumsy; lethargic-energetic; contented-discontented; troubled-tranquil; mentally slow-quick-witted; tense-relaxed; attentive-dreamy; incompetent-proficient; happy-sad; antagonistic-amicable; interested-bored; withdrawn-gregarious. Dimensions were presented as 100-mm lines with the two extremes written at each end, and participants marked their current state on each line. Factors of ‘alertness', ‘contentedness', ‘calmness' and ‘tranquility' were calculated according to the method of Bond and colleagues .
Cognition was evaluated using the Mini-Mental State Examination (MMSE 0-30) that assesses five areas of cognitive function (orientation (0 to 10), registration (0 to 3), recall (0 to 3), attention (0 to 5) and language fluency (0 to 9)) .
Memory was assessed using the digital-symbol substitution test that represents a code of nine matched digits and symbols at the top of the test sheet . Patients were asked to record the symbol below a digit to match the code. The number of correct items completed in 90 s constituted the score. In addition, for assessment of verbal and nonverbal working memory, we used a forward and backward digit span from the Wechsler Adult Intelligence Scale . Pairs of lists of numbers were read to the patients. Each pair of lists was one digit longer than the previous one. At the conclusion of each list, the subjects were asked to repeat the numbers from the list in the original order (forward) or in the reverse order (backwards). If the subjects incorrectly repeated the digits from only one of the pair of lists, the test was continued. If the subjects incorrectly repeated the digits from both pairs of lists, the test was stopped and the digit span score (the longest sequence that the subject was able to repeat correctly) was recorded. Different pairs of lists were used for each testing session. This task is sensitive to effects on immediate memory .
Psychometric evaluations were performed before and after surgery, at day 1 in the morning, at day 2 in the morning and at day 2 in the afternoon (end of the study).
Randomization and blinding
Randomization was performed using a random number table and was equilibrated after every 10 patients. No interim analysis was performed. Opaque sealed allocation envelopes were opened by a nurse not involved in the care of the patients just before surgical incision and just before the administration of patient-controlled analgesia. This nurse prepared the solutions of ketamine or placebo (saline) and provided the blinded solution to the anaesthesiologist who cared for the patients in the operating room and the postanaesthetic care unit.
The main end-point was cumulative morphine consumption over the first 24 h. The secondary efficacy end-points were the consumption of morphine during the titration period and with the patient-controlled analgesia device, the number of demands, the number of boluses received and the number of morphine-related adverse effects. The secondary safety end-points were the number of ketamine-related adverse effects and the results of the psychometric tests.
According to our previous studies , we estimated that morphine consumption in the placebo group, in the postanaesthetic care unit, was 12 ± 7 mg. Thus, 50 patients would be needed in each group to be able to detect a 40% difference in postoperative morphine consumption with 90% certainty (1−β) and a two-sided 5% significant level (α) (NQuery 3.0; Statistical Solutions Ltd, Cork, Ireland). An intention-to-treat analysis was performed. Data were expressed as means ± SD or medians and 95% confidence intervals (time delay, duration, morphine doses), unless specified otherwise. Comparison of two means was performed using the unpaired t-test, comparison of two medians using the U-test. Comparison of several means was performed using repeated measures two-way (groups, time) analysis of variance. The Greenhouse-Geisser correction was applied when more than two levels were present in a ‘within' factor  and the interaction was used to test differences between the two groups. The Fisher's exact method was used for categorical variables. All comparisons were two-tailed and a P-value <0.05 was required to rule out the null hypothesis. Statistical analysis was performed using NCSS 2001 software (Statistical Solutions Ltd).
A total of 102 patients consented to participate and were randomly assigned to one of the two study groups. Twelve (12%) patients were excluded because they did not fulfil the criteria for inclusion (n = 5, modification of the surgical procedure), they refused to participate in the study during the postoperative period (n = 3), or they experienced postoperatively surgical complications that required re-operation or prolonged ventilation and critical care (n = 4). Thus, 90 patients were considered for analysis, 45 in the ketamine group and 45 in the placebo group (Fig. 1).
Groups were well-balanced with regard to patient characteristics, ASA status, anaesthetic and analgesic drug doses, and durations of anaesthesia and surgery (Table 1). Body mass index was significantly lower in the placebo group (Table 1). Types of surgery did not differ between the groups (Table 1). Hysterectomy was performed in 64 (71%) patients, myomectomy in 18 (20%) and prolapse surgery in 8 (9%). Fourteen patients underwent surgery for cancer (15%).
VAS/NRS thresholds before i.v. morphine titration was commenced, at the end of morphine titration, at the end of the stay in the postanaesthetic care unit and during the entire study period were similar between groups (Fig. 2). The number of patients with adequate pain relief (VAS ≤ 30) did not significantly differ between groups.
Morphine requirements in the postanaesthetic care unit and during 48 h were not significantly different between groups (Table 2, Fig. 3). The number of dose requests of morphine was comparable in the two groups (Fig. 3). The incidence of adverse effects that may have been related to ketamine or morphine was not significantly different between groups (Table 3). One patient in the ketamine group developed arrhythmia.
We did not observe any significant difference in mood. When we associated the 16 items of the Norris score in four subgroups (i.e. ‘alertness', ‘contentedness', ‘calmness' and ‘tranquility'), we did not observe any significant differences between the two groups. Also, there were no significant differences between groups or assessment points on the ‘anxiety' factors of the mood rating scale. The digital-symbol substitution test was not significantly impaired by ketamine (Table 4). There was no difference in postoperative memory or orientation, registration, attention, recall and language between groups. Lastly, the forward and backward digit spans from the Wechsler Adult Intelligence Scale were not significantly different between the two groups (Table 4).
In this study, ketamine, in combination with morphine and ketoprofen, did not improve postoperative pain scales, did not reduce morphine consumption and did not decrease the incidence of morphine-related adverse effects during the first 48 h after surgery. However, ketamine did not induce either any significant adverse effects and did not significantly modify mood, cognitive, and memory functioning.
Excitatory neurotransmitters, via activation of the NMDA receptors, have been incriminated in the development and maintenance of hyperalgesia and allodynia after tissue injury. High-dose morphine may activate NMDA receptors and cause hyperalgesia and subsequently enhance postoperative pain . Low-dose i.v. infusions of ketamine during and after surgery may reduce mechanical punctuate hyperalgesia surrounding the surgical incision and may prevent central sensitization caused by nociceptive input during and after surgery [16,33]. Nevertheless, in our study, we were unable to demonstrate any significant advantage of ketamine in association with the drugs that are usually administered after major surgery, morphine and nonsteroidal anti-inflammatory drugs.
Despite several randomized trials indicating significant efficacy of ketamine in perioperative care, the role of ketamine, as a component of analgesia, remains unclear . Moreover, evidence for a clinically relevant analgesic effect remains controversial. In a randomized, placebo-controlled study, Burstal and colleagues  assessed the effect of ketamine (2 mg mL−1) on the degree of sensitization in women undergoing total abdominal hysterectomy and treated with a patient-controlled analgesia device with morphine (2 mg mL−1). A significant reduction in the area of allodynia was found in patients receiving ketamine, but no significant reductions were noted between groups with respect to pain scores, total or hourly drug consumption, patient satisfaction, and incidence of nausea. It was notable that the potential usefulness of ketamine was offset by a high incidence of adverse effects (notably dysphoria) and a lack of opioid-sparing effects and consequently the authors were unable to recommend the combination of i.v. morphine and ketamine in a patient-controlled analgesia device for routine care . Similarly, Murdoch and colleagues  assessed the efficacy of a combination of morphine (1 mg mL−1) and ketamine (0.75 mg mL−1) in a patient-controlled analgesia device after elective abdominal hysterectomy. There was no difference in total morphine consumption and pain scores compared with patients who received morphine alone. Adverse effect profiles and time to mobilization were also similar . Thus, although patient-controlled analgesia using a morphine-ketamine combination appears to be safe , it does not always confer any benefit, notably after abdominal gynaecologic surgery [35,36].
There are a number of explanations for the observed lack of differences in pain scores, morphine consumption and the incidence of adverse effects. First, it is possible that the dose of ketamine and the method of administration were inadequate. The dose of ketamine in the patient-controlled analgesia device (0.5 mg mL−1) may have been too low, and thus the cumulative dose of ketamine consumed by the patients is insufficient after painful major surgery. This low dose may explain why we did not find any difference in favour of ketamine. However, using meta-analysis, Elia and colleagues  did not find any evidence of a relationship between the dose of ketamine and its analgesic efficacy. In comparison to patient-controlled analgesia, continuous i.v. infusion of ketamine might be more efficacious after major gynaecological surgical procedures since these patients receive larger total doses with higher steady-state blood levels . Second, the efficacy of ketamine is linked to the antagonism of the NMDA receptor. In case of adequate perioperative analgesia, NMDA receptor activation is likely to be suppressed. As a consequence, ketamine administration may become ineffective . It is possible that efficacious analgesia using a combination of an appropriate i.v. morphine regimen and nonsteroidal anti-inflammatory drugs limits the activation of the NMDA receptor. Nonsteroidal anti-inflammatory drugs are thought to be effective in relieving postoperative pain and decreasing morphine-related adverse effects, particularly when prostanoid activity is enhanced, for example after gynaecological surgery [40,41]. Additionally, nonsteroidal anti-inflammatory drugs have shown synergistic effects with morphine and significantly decreased postoperative nausea, vomiting and sedation, which are the main morphine-related adverse effects . The combination of morphine and nonopioid analgesics may provide effective postoperative pain relief, thereby reducing the use of systemic morphine, and subsequently opioid-related adverse effects. Adding yet another analgesic (for instance, paracetamol ) or an antihyperalgesic drug may thus be not necessary for routine care. Third, NMDA receptor antagonists have not always been found to be associated with analgesic benefit in perioperative care . Some authors were unable to find a significant decrease in morphine consumption when ketamine was used concomitantly . In a meta-analysis, Elia and colleagues  showed no significant difference between ketamine and control groups for any of the main opioid-related adverse effects.
As previously demonstrated , no significant change in mood has been observed in patients receiving ketamine. In the setting of morphine administration in the operating room and on the ward, most trials have not detected any psychomimetic adverse effects. Low-dose ketamine given at an infusion rate lower than 2.5 μg kg−1 min−1 did not cause hallucinations or impairment of cognitive functioning . Ketamine adverse effects are dose-dependent and when ketamine is used below 0.15 mg kg−1, cognitive impairment is negligible . We also assessed cognitive function and memory and no significant variations were observed with ketamine.
Although one patient in the ketamine group developed arrhythmia, the overall incidence of cardiovascular effects was not significantly different between the two groups (Table 3). During ketamine treatment, cardiovascular adverse effects as arrhythmia may occur, notably in patients with a history of chronic antidepressant treatment . In our study, there was no marked incidence of patients who had previously been treated with an antidepressant drug, but the overall numbers studied were low.
In conclusion, we were unable to demonstrate improved analgesia after gynaecological surgery when ketamine was added to a multimodal standard regimen combining morphine and ketoprofen. Ketamine did not significantly alter mood, memory and cognitive functions, did not induce psychomimetic adverse effects, and failed to reduce the amount of morphine consumption or to decrease postoperative pain scores. Although the combination of the three analgesic drugs appears to be safe, we were unable to show any benefit in the use of ketamine. Our study suggests that low-dose ketamine should not be used for routine care after all surgical procedures.
We thank Dr David Baker, DM, FRCA (Staff Anesthesiologist, Department of Anesthesiology, CHU Necker-Enfants Malades, Paris) for reviewing the manuscript. Support was provided solely by departmental sources. No conflict of interest has been declared.
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