Opioids are widely used in the postoperative period owing to their profound analgesic effect. However, some recent experimental and clinical data point to the development of two phenomena following acute exposure to large dose of opioids: acute opioid tolerance and hyperalgesia [1-4]. Beside the classical central sensitization provoked by the injury itself, opioid treatment is believed to induce an enhancement of postoperative hyperalgesia. The occurrence of these effects may lead to an increase in opioid requirement in the postoperative period.
Activation of N-methyl-D-aspartate (NMDA) receptors in the spinal cord has been shown to play a pivotal role in the development of central neuron sensitization . Ketamine, an analgesic that has been used for many years, is a non-competitive antagonist of the phencyclidine site of the NMDA receptor. Whereas sub-anaesthetic doses of ketamine have been proposed to exert a pre-emptive effect on injury-induced hyperalgesia, low sub-analgesic doses have been proposed to prevent opioid-induced tolerance and hyperalgesia . Therefore, numerous clinical studies have tried to prevent the occurrence of acute tolerance and hyperalgesia by co-administration of ketamine and opioids. Some of those were conclusive [6-8], whereas others failed to demonstrate any effect of ketamine [9,10]. All these clinical trials have been recently examined in two systematic reviews; they both concluded that small-dose ketamine was safe and potentially useful adjuvant to opioid analgesia , but that its role remained unclear . The morphine sparing effect may be of particular interest in patients who are prone to the harmful effects of opioids, such as ventilatory depression. Patients presenting for ear, nose and throat (ENT) surgery for cancer could benefit from this morphine sparing effect as they often have a medical history of chronic obstructive pulmonary disease. The purpose of this randomized, placebo-controlled, doubled-blinded study was to test the hypothesis that low-dose ketamine added to remifentanil during ENT surgery decreased the requirements of opioids in the postoperative period. It was hypothesized that any decrease in postoperative morphine consumption was an indirect measure of a decrease in opioid-induced hyperalgesia.
Patients and methods
After approval by the Ethics Committee of our institution we prospectively studied 62 patients undergoing elective ENT surgery for cancer. This approval required that written, informed consent be obtained from each patient. Exclusion criteria included a history of chronic pain, psychiatric disease, the administration of an opioid within the 48 h before surgery or the inability to understand the use of a patient controlled analgesia (PCA) device. Inclusion in the study was confirmed several days before surgery after anaesthesia consultation, and after having explained the use of the PCA. Blocked random allocation using a computer-generated random table number was performed on the day before surgery. Treatment allocation was kept concealed in a sealed envelope. The hospital pharmacist provided products, ketamine or placebo, in an identical 50 mL syringe ready for use.
All patients underwent the same anaesthetic protocol. They were premedicated with hydroxyzine (100 mg) and alprazolam (0.25 mg) 1 h before anaesthesia. After a bolus dose of remifentanil (0.5 μg kg−1) followed by a continuous infusion that was initially set at 0.25 μg kg−1 min−1, anaesthesia was induced with propofol administered by a target-controlled device. The initial target was set at 6 μg mL−1, and then adjusted to allow laryngoscopy and tracheal intubation after topical anaesthesia of the vocal cords and the trachea. The remifentanil infusion was adapted by the anaesthesiologist in steps of 0.05 μg kg−1 min−1 according to the variations of heart rate (HR) and arterial systolic pressure. HR and systolic blood pressure (BP) were kept within 20% of pre-induction values. The i.v. fluid infusion was left to the anaesthetist's discretion. All patients received prophylactic antibiotics according to institutional guidelines. The intervention group received i.v. ketamine just before induction (0.15 mg kg−1) followed by a continuous infusion during anaesthesia (2 μg kg−1 min−1). The control group received the same bolus and continuous infusion of saline.
One hour before the anticipated end of surgery, patients received i.v. morphine 0.2 mg kg−1. Postoperatively, all patients received a multimodal analgesia regimen for 48 h as is routinely used in our institution. The regimen involved i.v. paracetamol 1 g every 6 h, i.v. methylprednisolone 2 mg kg−1 day−1, and PCA-morphine. The PCA device was programmed to deliver a bolus of 1 mg of morphine on demand, with a lockout interval of 7 min, and without a background infusion. During 48 h, and every 4 h, analgesia was recorded using a visual analogue scale (VAS), ranging from 0 (no pain) to 10 (worst pain imaginable). At the same time points, the cumulative amount of auto-administered morphine and adverse effects were noted. Adverse effect notification was done as a routine monitoring of the patients. No attempt was made to grade postoperative nausea or vomiting. However, dysphoria was especially evaluated through direct questioning. On the ward, nursing staff performed all postoperative evaluations. Patients and staff involved in the study were kept unaware of treatment assignment until the end of the inclusion of all the patients.
Patient characteristic data and clinical variables were compared by using a χ2-test for qualitative data. The effects of ketamine on postoperative pain and cumulative morphine consumption were analysed using a U-test. The total amount of consumed morphine at 24 and 48 h was analysed by the same test. The threshold value of probability to reject the null hypothesis was set at 0.05. All data are expressed as means ± SD. Statistical analysis was performed using Statview software version 5.0. To estimate the sample size required by the study, we chose a power of 80% at an α level of 0.05, and a minimal difference to be detected in postoperative morphine consumption of 30%. The variability of the morphine consumption was estimated from a preliminary study. The calculation yielded 30 patients per groups. The number of patients to be included in the study was thus set at 62.
Sixty-two patients were included in the study; one patient in the ketamine group was excluded due to an error of dosage of morphine administered in the recovery room. The distribution of types of surgery was similar between groups and included radical neck dissection (6 ketamine, 8 control), laryngectomy (14 and 13) and hemimandibulectomy (10 and 10). Patient characteristics data and duration of surgery were similar between groups (Table 1). There was no difference either in the amounts of intra-operative consumption of propofol and remifentanil. In the ketamine group, the mean total amount of administered ketamine was 0.53 mg kg−1.
There was no difference between the groups in the time course of morphine consumption during the first 48 h (Fig. 1). During the same time, pain scores were similar between the two groups. Cumulative doses of morphine including the intra-operative dose and that administered in the recovery room were very similar at 24 h, 33.3 ± 14.9 mg with ketamine and 31.9 ± 15.3 mg with control, and at 48 h, 40.4 ± 20.6 mg with ketamine, and 42.5 ± 25.9 mg with control.
No patient experienced any serious adverse effect. No dysphoria or hallucinations were noted in either group. Five patients in the ketamine group and three in the control group suffered nausea or vomiting. One patient in the ketamine group suffered diplopia and noe nystagmus whereas three patients in the placebo group had nystagmus. There was one case of involuntary movements in the ketamine group and two in the placebo group.
Ketamine failed to decrease the amount of morphine consumed in the postoperative period after a remifentanil-based anaesthetic, and postoperative pain intensities were similar in patients who received ketamine and controls. These data from the ENT cancer surgery setting are in contradiction to the results of previous studies [7,13-16], but confirm findings from clinical studies that have been conducted in other fields of surgery . In a recent systematic review, ketamine was found to improve postoperative opioid analgesia in 20 of 37 trials, and independent of the mode of ketamine administration .
Several methodological considerations deserve to be examined to explain the observed discrepancies between studies. The first concerns the postoperative multimodal analgesic regimen that was used by us. These agents may have contributed to a decrease in postoperative nociception and, therefore, to a decrease in hyperalgesia. By lowering the pain score, this regimen might have hidden any modest effect of ketamine. However, we may expect that ketamine would have induced a decrease in morphine consumption. In our study, morphine consumption at 24 h across all patients was on average 32.0 mg (standard deviation (SD) 15.7). This was slightly lower [7,15] or similar  to previous studies that used only morphine for postoperative analgesia and it was higher than in studies that used a multimodal analgesic regimen [13,14]. Owing to the sparing effect of co-analgesics included in a multimodal regimen, it could be inferred that the degree of pain was similar to previous studies. As an additional methodological factor to be examined, the co-analgesic agents could have interfered with the phenomenon of acute opioid tolerance. Corticosteroids have been shown to induce a rapid and non-genomic prolongation of NMDA receptor-mediated Ca2+ elevation in central neurons  and to increase the response to excitatory amino acids [18,19]. Finally, the intra-operative doses of remifentanil should be discussed, as we did not directly demonstrate any opioid-induced acute tolerance. Indeed, there was no control group receiving no intra-operative analgesic but this would be ethically unacceptable. In fact, the doses of remifentanil that were administered were higher than that used in studies showing acute tolerance in volunteers [4,19,20], and very close to clinical studies demonstrating acute tolerance . The duration of remifentanil administration was similar to those previous positive studies. Moreover, the amount of remifentanil administered intra-operatively was similar between the two groups and was not likely to have induced a differential effect between them.
The other interpretation of our data could be that remifentanil actually did induce an acute opioid tolerance but that ketamine failed to prevent this effect. Dose and protocol of ketamine administration could be a first limiting factor. Our purpose was to test a low-dose regimen to avoid the potential deleterious effects of ketamine. Indeed, it has been shown that 0.4-0.8 mg kg−1 of ketamine in healthy subjects produced a dose-dependent impairment of episodic and working memory and a slowing of semantic processing . After administration of 0.1 and 0.2 mg kg−1 of ketamine, Hartvig and colleagues observed memory impairment and psychotomimetic effects . However, these effects were minor, and were detected only with specific tests in non-anaesthetized subjects. A recent meta-analysis concluded that in anaesthetized patients, the risk of hallucinations with ketamine was minimal and not dose-dependent with doses up to 1 mg kg−1 . Although the low-dose ketamine that was used by us could have been a limiting factor explaining the lack of its effect, it was very similar to previous publications demonstrating an improvement in postoperative analgesia [7,14,23].
Finally, the lack of efficacy could be related to the mechanisms of postoperative hyperalgesia. A postoperative increase in morphine consumption should not only be ascribed to opioid-induced tolerance and hyperalgesia, but also to injury-induced hyperalgesia. Ketamine is expected to have a preventive effect on the component of injury-induced or opioid-induced hyperalgesia. The NMDA receptors are involved in secondary hyperalgesia resulting from the sensitization of the dorsal horn neurons and as a component of the primary hyperalgesia resulting from sensitization of central neurons . However, this latter hyperalgesia has another component, the sensitization of peripheral receptors. The respective contribution of these two components are not clearly delineated . As NMDA-antagonists are unlikely to prevent sensitization of peripheral receptors, this may explain why ketamine was ineffective in preventing hyperalgesia that was mainly due to peripheral receptors sensitization . In addition, it could be hypothesized that for some surgery, injury-induced hyperalgesia is far more important than opioid-induced hyperalgesia; it has been shown that higher doses of NMDA antagonists are necessary to prevent injury-induced hyperalgesia. The change in postoperative morphine consumption would be, therefore, unable to measure modest opioid-induced hyperalgesia. Therefore, the effect of ketamine could depend on the mechanisms underlying the observed postoperative hyperalgesia. This could explain discrepancies among clinical studies using the same anaesthetic technique but conducted with different types of surgery that involve different kinds of hyperalgesia owing to the respective role of peripheral receptors, central sensitization, injury-induced or opioid-induced hyperalgesia.
In summary, this study has shown that low-dose ketamine, administered during remifentanil-based anaesthesia for ENT surgery, and followed by multimodal postoperative analgesia, failed to have a postoperative morphine sparing effect.
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