British Journal of Anaesthesia 1996; 76: 415418

Effect of tramadol on depth of anaesthesia

J. F. COETZEE, J. S. MARITZ AND J. C. DU TOIT

Summary
We have studied 51 patients who were anaes-
thetized with propofol and suxamethonium fol-
lowed by 0.7 % isoflurane and 66 % nitrous oxide in
oxygen to see if tramadol caused lightening of
anaesthesia. A two-channel EEG was recorded and
music was played via headphones. Two groups
received tramadol 200 and 100 mg i.v. and the third
group received saline. Tramadol caused significant,
dose-dependent activation of the EEG, evidenced
by increased frequencies and decreased amplitudes,
but these changes were small and probably un-
important. Derived EEG variables did not approach
values known to be associated with near-
awakening during isoflurane anaesthesia. No
patient moved on skin incision and there were no
incidences of free recall. (Br. J. Anaesth. 1996; 76:
415418)
Key words
Analgesics opioid, tramadol. Anaesthetics volatile, isoflurane.
Memory. Anaesthesia, depth.

Tramadol is a relatively new, centrally acting opioid
agonist that modifies spinal pain transmission by
inhibiting monoamine reuptake. It has been sug-
gested that it is unsuitable for intraoperative use
after a 65 % incidence of awareness in 20 patients
who received tramadol infusions during nitrous
oxide anaesthesia supplemented by intermittent
administration of low concentrations of enflurane
[1]. A recent editorial [2] described the possible risk
of awareness associated with intraoperative tramadol
administration as a major drawback and suggested
that the risk of intraoperative awareness may
represent significant disadvantages for tramadol.
The purpose of this study was to determine if single
doses of tramadol administered to patients during
isofluranenitrous oxide anaesthesia resulted in un-
acceptable lightening of anaesthesia.
Patients and methods
Institutional approval and informed consent were
obtained from 51 non-obese, ASA III patients,
1869 yr old, with body weights 42103 kg. All
patients were undergoing orthopaedic and gynae-
cological surgery. Premedication comprised diaze-
pam 10 mg orally. After attachment of ECG elec-
trodes and preoxygenation, anaesthesia was induced
with propofol 1.52.0 mg kg
91
and the trachea intu-
bated after administration of suxamethonium
1.0 mg kg
91
. Patients lungs were ventilated mechan-
ically, maintaining end-expired carbon dioxide con-
centration at 4.24.8 %. Anaesthesia was maintained
with 66 % nitrous oxide in oxygen and the isoflurane
vaporizer was adjusted to maintain an end-expired
isoflurane concentration of 0.7 % (Siemens Sirecust
734G). No additional doses of neuromuscular
blockers were given and recovery from
suxamethonium block was confirmed using a nerve
stimulator with the stimulating electrodes applied to
the skin over the median nerve at the elbow.
The electroencephalogram (EEG) was monitored
with a two-channel monitor (Ceregraph, Somchem
Ltd, Somerset West, South Africa) using bilateral
frontalipsilateral mastoid montages via standard
silversilver chloride ECG electrodes. Good elec-
trical contact was ensured by abrading the skin and
cleansing with ether. Measured electrodeskin impe-
dances were less than 5 k. The Ceregraph monitor
performs power spectral analysis by fast Fourier
transform (FFT) on digitized EEG data and stores
the derived quantitative descriptors of EEG fre-
quency and amplitude on computer disk : these
included 95th percentile power frequency (95 % PF),
median power frequency (MF) [3] delta ratio (DR)
[4], relative delta power (RDP) and root mean square
of the EEG signal voltage (RMS).
After maintaining stable end-expired isoflurane
concentrations of 0.7 % for 20 min, music was played
via earphones. Before being placed on the patient,
the earphones were applied to an investigator who
adjusted the volume control so that the music was
heard clearly without experiencing discomfort. The
music content was applicable to the patients cultural
background. Patients were allocated randomly to one
of three groups (n : 17) who received isotonic saline
4 ml (saline group), tramadol 100 mg (group T100)
or tramadol 200 mg (group T200) i.v. The EEG was
recorded for another 20 min, after which skin
incision was performed. Patient movement within
1 min of incision was recorded. The saline group
received morphine 0.2 mg kg
91
during operation for
postoperative analgesia. A blinded investigator vis-
J. F. COETZEE, BSC, MB, CHB, MMED(ANES), DIPDAT, PHD (Depart-
ment of Anesthesiology); J. S. MARITZ, DSC (University of
Witwatersrand, Department of Statistics) University of
Stellenbosch/Tygerberg Hospital, PO Box 19063, 7505
Tygerberg, Republic of South Africa. J. C. DU TOIT, MB, CHB,
MMED (ANES), Department of Anesthesiology, Tygerberg Hospital,
Private bag, 7505 Tygerberg, Republic of South Africa. Accepted
for publication: October 10, 1995.
416 British Journal of Anaesthesia
ited the patients on the first postoperative day to
enquire about intraoperative recall, including hear-
ing music.
DATA ANALYSIS
Every 4 s the Ceregraph monitor calculated the
quantitative EEG descriptors derived from FFT of
the previous 8-s epoch and stored these values in an
ASCII file on computer disk. During subsequent
offline analysis, values for the various EEG descri-
ptors (95 %PF, MF, etc.) were tabulated at the
following times: before administration of tramadol
or saline (0 min), and at 5, 10, 15 and 20 min. Each
value was obtained by calculating the mean of 20
readings from the data in the ASCII file. Preliminary
analysis of the tabulated data included descriptive
statistics (mean, SD, SEM, median) and tests for
normality distribution (KomolgorovSmirnov test).
Plots of the mean values of the various EEG
descriptors over time were inspected to determine
visually if level shifts occurred after administration
of tramadol or saline. Distribution-free methods of
analysis were used to test if level shifts were
significant as follows.
Level shifts within groups
For each EEG descriptor, four successive differences
for each subject were calculated: that is the dif-
ferences in descriptor values between 05, 510,
1015 and 1520 min. The null hypothesis of no
level shift stated that the expected values of these
differences were zero. A permutation test, that is a
distribution-free version of the Hotelling T
2
, was
performed, as described by Maritz [5]. The end-
result of the test is a statistic whose distribution
under the null hypothesis is chi-square with 4
degrees of freedom.
Inter-group comparison of level shifts
For each subject, the value of the EEG descriptor at
time zero was subtracted from the mean of the values
recorded at 5, 10, 15 and 20 min to give a mean
level shift. One-way analysis of variance was
performed between groups on these mean level shift
values. In addition, a t test was performed on the
mean level shift of each group to determine if that
shift differed significantly from zero.
Comparison of trend profiles between the groups
The trend profiles of the EEG descriptors obtained
at 5, 10, 15 and 20 min were considered. In order to
determine if the trend profiles over time differed
between groups, the null hypothesis states that the
expected values of the differences defined above
(510, 1015 and 1520 min) are identical in the
three groups. Pairwise comparisons of group profiles
were made via a trivariate, two-sample permutation
test, that is a distribution-free version of the
Hotelling two-sample T
2
was performed that pro-
duces a statistic whose distribution under the null
hypothesis is chi-square with 3 degrees of freedom.
P : 0.05 was regarded as indicating statistical
significance.
Results
Patient data are presented in table 1: ages and
weights did not differ significantly between groups.
No patient moved on skin incision and there were no
episodes of intraoperative recall or recollection of
music.
EEG CHANGES WITHIN EACH GROUP AFTER TRAMADOL
ADMINISTRATION
There were no significant EEG changes in the saline
group (table 2). In contrast, both tramadol groups
showed significantly increased EEG frequencies and
decreased amplitudes within 5 min of drug adminis-
tration and these appearances were maintained
throughout the measuring period. These changes
were expressed by increased MF, DR and 95 %PF
and decreased RMS and RDP.
INTER-GROUP COMPARISON OF MEAN EEG CHANGES
AFTER TRAMADOL ADMINISTRATION
After tramadol administration, mean EEG changes
in group T200 were significantly different from
those of the saline group but did not differ from
those of group T100. In group T100, mean level
shifts of all EEG descriptors did not differ signi-
ficantly from those of the saline and T200 groups.
INTER-GROUP COMPARISON OF TREND PROFILES AFTER
TRAMADOL ADMINISTRATION
The post-injection trend profiles of all EEG descrip-
tors were similar in the saline and T200 groups. The
95 % PF and left RMS in group T100 differed
significantly from those of the two other groups.
Discussion
Administration of tramadol during stable, light
nitrous oxide isoflurane anaesthesia resulted in
increased EEG frequencies (increased MF, DR and
95 %PF, and decreased RDP) and decreased EEG
amplitude (decreased RMS). These changes were
maintained throughout the 20-min measurement
period. Lightening of anaesthesia usually leads to
increasing EEG frequencies of lower amplitude and
two of the descriptors used in this study have been
shown to indicate near-awakening during isoflurane
nitrous oxide anaesthesia [3, 4]. Schwilden and
Stoeckel [3] concluded that there was an increased
probability of patient awareness if the MF exceeded
56 Hz. Long and colleagues [4] found that near-
Table 1 Patient data for the three groups (mean (SD or range))
Group Age (yr) Weight (kg)
T100 39 (2061) 67.6 (13.1)
T200 34 (1855) 62.8 (15.1)
Saline 40 (1969) 74.3 (16.1)
Tramadol and depth of anaesthesia 417

awakening occurred at DR values of approximately
2. The EEG changes caused by administration of
tramadol in our patients, although statistically signi-
ficant, were subtle and small, the values not ap-
proaching those that have been found to occur
during near-awakening. The EEG changes may
therefore be clinically insignificant.
It is possible that the effects of tramadol may be
dose-dependent, as indicated by the tendency
towards different post-injection profiles in group
T100 (95 %PF and RMS) and by the observation
that the mean level shifts of group T100 were not
different from the two other groups, whereas the
mean level shift in group T200 differed significantly
from that of the saline group.
All patients in the study remained sufficiently
anaesthetized so that they did not move during skin
incision and the initial stages of the operative
procedures. Furthermore, there was no evidence of
intraoperative conscious recall, either spontaneously
or on enquiry. It may be argued that inability to
recall music and lack of movement on surgical
stimulation are insensitive indicators of awareness
during anaesthesia. Lehmann, Horrichs and Hoeckle
[1] found free recall of conscious awareness by
playing music to their patients and similarly we
endeavoured to seek conscious awareness without
amnesia in our patients. This should be disting-
uished from the more subtle manifestations of
wakefulness during anaesthesia, namely conscious
awareness with amnesia and subconscious awareness
with amnesia [6], which would have required
detection by different methods, such as the isolated
forearm technique [7, 8] or cued word lists [9].
Movement on skin incision is not concerned
directly with consciousness but is a generally
accepted sign of inadequate anaesthesia. If the
groups who had received tramadol had demonstrated
a greater incidence of movement on skin incision
than the saline group, this may have suggested that
tramadol antagonized anaesthesia. The absence of
this sign was also an important monitor of the ethics
of the study, because a high incidence of movement
on skin incision in the tramadol groups may have
necessitated termination of the study.
The three methods of monitoring depth of an-
aesthesia, that is minor EEG changes, lack of
movement on skin incision and absence of spon-
taneous conscious recall, suggest that tramadol, in
doses up to 200 mg i.v., given to adults during stable,
light isofluranenitrous oxide anaesthesia, did not
lead to clinically significant lightening of anaesthesia
in this study.
Acknowledgement
The work was supported by a grant from Grunenthal GmbH,
Stolberg, Germany.
References
1. Lehmann KA, Horrichs G, Hoeckle W. Tramadol as an intra-
operative analgesic. A randomized double blind study with
placebo. Anaesthesist 1985; 34: 1119.
2. Eggers KA, Power I. Tramadol. British Journal of Anaesthesia
1995; 74: 247248.
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418 British Journal of Anaesthesia
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