Effect of tramadol on electroencephalographic and auditory-evoked response variables during light anaesthesia

D. J. A. Vaughan*, G. Shinner, C. Thornton and M. D. Brunner

Anaesthetic Research Department, Imperial College of Science, Technology and Medicine, Northwick Park and St. Mark’s NHS Trust, Watford Road, Harrow, Middlesex, UK

Accepted for publication: May 27, 2000


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Tramadol is a centrally acting opioid-like analgesic commonly used for analgesia during surgery. It has been stated that the use of tramadol increases the risk of awareness during anaesthesia. We studied 29 patients under steady state anaesthesia, ventilated via a laryngeal mask airway with 0.6 MAC isoflurane in 50% nitrous oxide, and with no surgical stimulus. The electroencephalogram (EEG) and auditory-evoked response (AER) were recorded throughout the study period, as were pulse and arterial pressure. Patients were given randomly a bolus of either saline (S), tramadol 100 mg (T1), or tramadol 200 mg (T2). Significant increases in systolic arterial pressure and decreases in heart rate were seen in the tramadol groups compared to the saline group. Significant, dose-related activation in all EEG variables (median power frequency, spectral edge, Delta Power and Alpha/Delta ratio) but no significant change in Pa or Nb amplitudes or latencies were noted. The EEG changes were not at levels thought to be associated with awareness. This study indicates that tramadol, whilst causing EEG activation, has no effect on depth of anaesthesia as measured by the AER.

Br J Anaesth 2000; 85: 705–7

Keywords: analgesics non-opioid, tramadol; brain, electroencephalograph; brain, evoked potentials


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Tramadol is a centrally acting opioid agonist which, it has been suggested, increases the risk of awareness when used during anaesthesia.13 Indeed, the British National Formulary4 states that it is not recommended during light anaesthesia for this reason, and an editorial in the British Journal of Anaesthesia1 described the perceived risk of tramadol-related awareness as ‘... a major drawback’. A recent study by Coetzee and colleagues2 showed that tramadol caused significant dose-dependant activation of some electroencephalograph (EEG) variables when given as a bolus, although no patients recalled perioperative events or moved on skin incision. Lehmann and colleagues3 have reported an increased incidence of awareness associated with perioperative tramadol usage.

The auditory-evoked response (AER) is a validated measure of depth of anaesthesia, especially amplitude and latency changes in the waves Pa and Nb.5 An advantage that evoked responses have over raw or processed EEG data in measuring depth of anaesthesia is that they represent a measure of central nervous system responsiveness rather than a measure of its resting state. We decided to look for any changes in depth of anaesthesia reflected in the EEG and AER using patients undergoing steady state anaesthesia in response to a bolus dose of tramadol.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The study was approved by Harrow Ethics committee, and written consent was obtained from each subject. Twenty-nine ASA I/II unpremedicated patients attending our hospital for routine surgery were recruited for the study.

On arrival in the anaesthetic room i.v. access was secured and standard monitoring commenced. Anaesthesia was induced with propofol 2 mg kg–1 and neuromuscular blockade obtained with vecuronium 0.1 mg kg–1. A laryngeal mask airway was inserted, and the subjects’ lungs were ventilated to an end tidal carbon dioxide level of 4.0–4.5 kPa. Anaesthesia was maintained with 50% nitrous oxide in oxygen and 0.6 MAC isoflurane (age adjusted).

After 20 min of stable anaesthesia with supplemental doses of vecuronium 0.05 mg kg–1 given as required, the subjects were allocated randomly by draw to one of three groups: an i.v. bolus of tramadol 100 mg or 200 mg (groups T1 and T2), or of saline (group S). The investigator was blinded to the group allocation and drug given during data collection and analysis. All haemodynamic and gas analysis variables were recorded at 5-min intervals. Fifteen minutes after drug injection, analysis was discontinued and the subjects were transferred to the operating theatre.

Data collection and analysis
The EEG signal was recorded via silver–silver chloride electrodes attached to the mastoid and forehead and stored on a PC-based system developed at Northwick Park Hospital.6 The auditory stimulus for the AER was a rarefaction click delivered to the ears via tightly fitting earpieces at a rate of 6 s–1, at 75 dB above the average hearing threshold. For EEG variables the digitized data were analysed using a fast Fourier transformation, and values for Median Frequency (F50), Spectral Edge (F95), Delta Power (DP) and Alpha/Delta ratio (A/D) generated. The EEG signal was analogue filtered at bandwidths of 25–500 Hz to produce the AER recording.

Although the AER was recorded throughout the study, averaged responses to clicks representing 1024 sweeps (2 min, 40 s) of EEG data were analysed corresponding to the period immediately before, and at 5, 10 and 15 min after the injection of saline or tramadol. Pa amplitude (Paa) and latency (Pal), and Nb amplitude (Nba) and latency (Nbl) were measured from printouts of these AER waveforms by an investigator, who was blinded to the drug or dose given. These variables were log transformed and analysis of variance was performed, looking for significant changes in each variable pre- to post-drug injection and, if these were present, whether this effect was dose related. A probability value P<0.05 was taken as significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient data are displayed in Table 1: the groups were similar in terms of age, sex and weight. No patients had explicit recall of events under anaesthesia.


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Table 1 Subject characteristics by group
 
Haemodynamic variables
Our data showed significant changes in systolic arterial pressure and heart rate after tramadol injection (BP: P<0.001; HR: P<0.001), and a significant linear trend between the saline, 100 mg and 200 mg groups (BP: P<0.01; HR: P<0.05).

EEG variables
There were no significant changes in the saline group. In contrast, both tramadol groups showed significant changes from pre- to post-injection in all variables (P<0.001 in all cases) bar delta power, in which the change was only significant with a 200 mg dose (P<0.05) (see Table 2). These changes were dose graduated in all cases, with a significant linear trend in each variable (S->T1->T2; P<0.001).


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Table 2 Mean baseline values for haemodynamic, EEG and AER variables by treatment group and the mean percentage change after drug injection. Significant changes pre- to post-dose are marked: #P<0.05; *P<0.001
 
AER variables
There were no significant differences in pre- to post-dose values for any of the AER variables (Table 2).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Our results clearly show the alpha-adrenergic effects associated with tramadol administration at clinically used doses. They are similar to those of Coetzee et al.2 in that tramadol produces evidence of activation in all the derived EEG variables. These changes are not clinically indicative of awakening or awareness.7

Interestingly, no significant changes in the AER variables measured were seen. Previous studies8 in our unit have shown Pa amplitude increases of 53% with succinylcholine, 36% with laryngoscopy and 60% with intubation. This study would have been sensitive enough to detect an increase in Pa amplitude of 21% at the 5% significance level with a power of 80%. These patients were not undergoing surgery, nor were they intubated. These potent and variable stimuli tend to lighten anaesthesia5 and this study excludes any AER changes due to these stimuli from the analysis.

Reviewing the papers mentioned in the introduction, we note that Coetzee and colleagues2 thought that the EEG changes seen, although statistically significant, were not clinically significant. Lehmann’s paper3 states that 65% of patients had recall of music played to them, as opposed to none in the placebo group. It should be noted, however, that the only other analgesic/anaesthetic used in Lehmann’s study was fentanyl and droperidol premedication, and ventilation with 79% nitrous oxide in oxygen. We do not feel this in any way represents standard or ‘normal’ anaesthetic practice for healthy patients undergoing elective orthopaedic or abdominal surgery. A more recent paper9 shows no increased speed of awakening or orientation in patients given tramadol at the end of a procedure as opposed to those given morphine.

In conclusion, our work does not support lightening of anaesthesia due to tramadol and it agrees with the work of others using different techniques.


    Footnotes
 
* Corresponding author Back


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 Eggers KA, Power I. Tramadol. Br J Anaesth 1995; 74: 247–8[Free Full Text]

2 Coetzee JF, Maritz JS, du Toit JC. Effect of tramadol on depth of anaesthesia. Br J Anaesth 1996; 76: 415–8[Abstract/Free Full Text]

3 Lehmann KA, Horrichs G, Hoeckle W. The significance of tramadol as an intraoperative analgesic. A randomised double blind study in comparison with placebo. Anaesthetist 1985; 34: 11–9[ISI][Medline]

4 British National Formulary. September 1999; 38: 210

5 Thornton C. Evoked potentials in anaesthesia. Eur J Anaesth 1991; 8: 89–107[ISI][Medline]

6 Jordan C, Weller C, Thornton C, Newton DEF. Monitoring evoked potentials during surgery to assess the level of anaesthesia. J Med Eng Tech 1995; 19: 77–9[ISI][Medline]

7 Thornton C, Sharpe RM. Evoked responses in anaesthesia. Br J Anaesth 1998; 81: 771–81[Free Full Text]

8 McGregor RR, Allan LG, Sharpe RM, Thornton C, Newton DEF. Effect of remifentanil on the auditory evoked response and haemodynamic changes after intubation and surgical incision. Br J Anaesth 1998; 81: 785–6[Abstract/Free Full Text]

9 Coetzee JF, van Loggereberg H. Tramadol or morphine administered during operation: a study of immediate post operative effects after abdominal hysterectomy. Br J Anaesth 1998; 81: 737–41[Abstract/Free Full Text]