Multimodal postoperative pain management is advocated to lower the doses of opioids that are needed to achieve adequate postoperative pain relief combined with less adverse effects and a reduced surgical stress response.1 The role of antagonists of the N-methyl-D-aspartate (NMDA) receptor in this multimodal strategy has been the subject of renewed interest during the last two decades. This receptor has an important role in central nervous system function and particularly in pain processing, neuronal plasticity and generation of central sensitisation.2 Of the clinically available compounds that have NMDA receptor-blocking properties, ketamine and magnesium are of particular interest. In 2001, Liu et al.2 observed synergistic effects of a combination of ketamine and magnesium on the NMDA receptor, which might be responsible for less opiate requirements compared with each drug alone. The aim of our study was to investigate whether in a standardised postoperative pain protocol consisting of a patient controlled analgesia (PCA) device with the opioid piritramide, the use of S(+)-ketamine alone or a combination of S(+)-ketamine and magnesium sulphate (MgSO4) would result in a reduction in opioid requirements compared with placebo, and also to examine potential differences in pain experience between the experimental groups. An additional goal was to explore the incidence of adverse effects.
We designed a double-blind randomised controlled trial, approved by the institutional ethics committee of the University Hospital Maastricht on 23 December 2002 (ethical committee No. MEC 02–076.6, chairperson Prof. P. Knipschild). All participants gave informed consent. General anaesthesia was performed following a standardised protocol. In addition, the control group received a placebo (NaCl 0.9%) for 24 h. In the ketamine group, a bolus of S(+)-ketamine of 0.2 mg kg−1 was given, followed by a continuous infusion for 24 h at a rate of 2 μg kg−1 min−1. In the ketamine-magnesium group, boluses of S(+)-ketamine 0.2 mg kg−1 and MgSO4 15 mg kg−1 were given followed by continuous infusions of S(+)-ketamine (2 μg−1 kg−1 min−1) and MgSO4 (5 mg−1 kg−1 h−1) for 24 h. Trial medication was started during induction. At the end of surgery, every patient received an intravenous loading dose of piritramide 0.15 mg kg−1 and after arrival in the postanaesthetic care unit, all patients received a PCA with piritramide (no background infusion, bolus 1 mg, lockout period 5 min). Pain scores were recorded using a 0 to 100 mm visual analogue scale (VAS). We also recorded adverse effects including nausea, vomiting, pruritus, urine retention, sedation, dysphoria or hallucination up to 48 h after the operation. Primary outcome measure was the total amount of piritramide used during the first 48 h following the operation.
Statistical analysis was performed using a Student's t-test for continuous data and a χ2 test or a Fisher's exact test for categorical data. For comparison of the multiple pain measurements, the area under the curve of the serial VAS scores was calculated. Missing data on VAS pain scores were imputed using regression estimates. Comparisons were made separately between the ketamine group and control and between the ketamine-MgSO4 group and control. Baseline characteristics and adverse effects were analysed according to the intention to treat principle. VAS pain and piritramide use were analysed according to the per-protocol principle. Analyses were performed with the Statistical Package for the Social Sciences (SPSS) version 12.0.1.
Between 15 March 2004 and 9 May 2007, 167 patients who were scheduled for lower abdominal open surgery at the University Hospital Maastricht (MUMC+) were screened. Fifty patients were eventually included in the study after having given informed consent: control group, n = 18; ketamine group, n = 17 and ketamine-MgSO4 group, n = 15. During the study, we encountered seven dropouts due to loss of follow-up, adverse effects or unexpected major surgery (Table 1). One patient had hallucinations, which may have been attributed to ketamine.
Average (SD) piritramide use at 48 h was 0.663 mg kg−1 (0.469) in the control group, 0.616 mg kg−1 (0.431) in the ketamine group (P = 0.11 compared with control) and 1.017 mg kg−1 (0.419) in the ketamine-MgSO4 group (P = 0.12 compared with control). The cumulative dose of intravenous piritramide after 48 h was lower in the ketamine group compared with control, but was higher in the ketamine-MgSO4 group compared with control (Fig. 1).
Due to numerous organisational problems, randomisation had to be stopped prematurely, and this may be the reason why none of the results reached statistical significance. The VAS score decreased over time in all groups (Fig. 2). A significant number of patients in all three groups experienced adverse effects such as hallucinations, vivid dreams and also nausea and vomiting but without statistically significant differences between the experimental and control groups (Table 1). In conclusion, our study showed a trend towards less opioid use in the group treated with ketamine compared with control. The group treated with a combination of MgSO4 and ketamine showed a trend towards more opioid use compared with ketamine alone.
Assistance with the letter: none declared.
Financial support and sponsorship: The Department of Anaesthesiology and Pain Management, MUMC+ has received payments from Grünenthal for consultancy activities of MAM. HG has received payments from Beer Advocaten NV for expert testimony and from the Committee for European Education in Anaesthesiology for lectures.
Conflicts of interest: none declared.
1. Kehlet H. Surgical stress: the role of pain and analgesia. Br J Anaesth
2. Liu HT, Hollmann MW, Liu WH, et al. Modulation of NMDA receptor function by ketamine and magnesium: Part I. Anesth Analg