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Effect of tramadol on bispectral index during intravenous anaesthesia with propofol and remifentanil.


The aim of this study was to investigate the effects of tramadol on the Bispectral Index (BIS) during total intravenous propofol-remifentanil anaesthesia. Forty-four adult ASA Physical status I-II patients, scheduled for elective general surgical procedures were included in a prospective observational randomized study. Doses for anaesthetics and opioids were adjusted to keep the BIS value at 50[+ or -]. After 20 minutes of stable anaesthesia, the subjects were randomly allocated to receive intravenous saline (control group) or tramadol 1.5 mg/kg (tramadol group). BIS values, mean arterial pressure, and heart rate were recorded every five minutes for 20 minutes. Mean BIS values after tramadol administration were not significantly different from those following saline, throughout the observation period (P>0.05). There were no patients in whom BIS values were more than 60 or who presented explicit recall of events under anaesthesia. There were no significant changes in mean arterial pressure, Sp[O.sub.2], or heart rate (P>0.05). The results indicate that the administration of tramadol during stable total intravenous anaesthesia with propofol-remifentanil does not affect BIS values. The clinical relevance is that tramadol can be safely administered pre- and intraoperatively as pre-emptive or preventive analgesia without modification of the depth of anaesthesia.

Key Words: bispectral index, general anesthesia, intravenous, propofol, remifentanil, tramadol


Studies in humans have shown that pre-emptive or preventive analgesia with tramadol may prevent the development of severe postoperative pain and decrease the need for opioid analgesics (1-4). However intraoperative administration of tramadol has been reported to cause dose-dependent activation of the electroencephalogram (EEG) during volatile anaesthesia (5). For this reason, it has been suggested that the use of tramadol could increase the risk of intraoperative awareness (5,6). We have recently demonstrated that tramadol given to prevent postoperative pain during inhalational anaesthesia with sevoflurane-remifentanil does not modify the Bispectral Index value (7). Tramadol may also be used for transitional analgesia following total intravenous anaesthesia (8). The aim of this study was to test the hypothesis that intra-operative administration of tramadol during total intravenous anaesthesia with propofol-remifentanil alters the depth of anaesthesia as determined by the BIS.


After institutional review board approval and written informed consent, 44 adult ASA I-II patients scheduled for minor general surgical procedures were included in a prospective observational study. Exclusion criteria were central nervous system disease, haemodynamic instability, ischaemic heart disease, renal or hepatic failure, or therapies with drugs affecting EEG activity.

On arrival in the anaesthetic room, standard monitoring with continuous electrocardiography, non-invasive arterial blood pressure monitoring, pulse oximetry and capnography was applied. EEG activity was measured by means of a Bispectral Index monitor (BIS XP, software version 3.12, Aspect Medical systems, U.S.A.). The BIS electrode (four-electrode sensor) was positioned on the patient's forehead as recommended by the manufacturer.

All patients were commenced on a remifentanil infusion at 0.4 ?g/kg/min, and 4 minutes later anaesthesia was induced with target-controlled infusion (TCI) of propofol. The initial target in TCI was 2.8-3.2 [micro]g/ml. neuromuscular blockade was obtained with cisatracurium 0.1 mg/kg. A tracheal tube was inserted, and the lungs were ventilated with air/oxygen (Fi[O.sub.2] 0.4). Immediately after intubation, remifentanil was reduced to 0.2-0.25 [micro]g/kg/min. Controlled ventilation was adjusted to maintain normocapnia. Anaesthesia was maintained with propofol and remifentanil. Doses for anaesthetics and opioids were adjusted to keep the BIS value at 50[+ or -]5 (9,10).

After 20 minutes of stable anaesthesia, the subjects were randomly allocated to receive intravenous saline (control group) or tramadol 1.5 mg/kg (tramadol group). Treatment allocations were performed using the random number generator function of stats[TM] (Version 1.1) and concealed in individual opaque envelopes until shortly before the time of administering tramadol. The investigator was blinded to the drugs administered and to the aim of the study. To avoid possible identification, the syringes were prepared in a similar manner, irrespective of the content (saline or tramadol). All haemodynamic and BIS variables were recorded at the following times: before administration of tramadol or saline (0 minutes), and at 5, 10, 15, and 20 minutes after administration of tramadol, as previously described (7,11).

Propofol and remifentanil doses were not modified during this period. During data collection, the investigator was not aware of the group allocation of the patient. Patients were interviewed post-operatively using the modified Brice interview (12), which aims to evaluate the possible occurrence of intraoperative awareness.


Demographic data were expressed as mean[+ or -]SD. The BIS values, heart rate, and mean arterial pressure were compared between groups using t-tests for independent groups. P<0.05 was considered statistically significant.


The two groups were similar in relation to age, sex, weight, duration of surgery, and baseline Bispectral Index (Table 1). There were no differences in the total amounts or infusion rate of remifentanil or propofol in the two groups. Mean BIS values after tramadol administration were not significantly different from those collected in patients receiving saline, throughout the observation period (P>0.05, Figure 1). The mean arterial pressure and heart rate were recorded after 10, 15 and 20 minutes were slightly lower in the tramadol group (Figure 2a and 2b), but these differences were not significant when compared to control group (P>0.05). no patients had explicit recall of events under anaesthesia as determined by the Brice interview.



The administration of tramadol during stable intravenous anaesthesia with propofol and remifentanil did not affect BIS values. In addition, none of the patients reported intraoperative awareness.

The effects of tramadol on EEG activity during anaesthesia have been previously investigated. In a volatile isoflurane-nitrous oxide anaesthetic, tramadol caused significant, dose-dependent activation of the EEG, evidenced by increased frequencies and decreased amplitudes (11). nevertheless, derived EEG variables did not approach values known to be associated with near-awakening, and there were no incidences of free recall (11).

Subsequently it was stated that tramadol may cause EEG activation during anaesthesia, although it does not appear to antagonize the hypnotic effects of volatile anaesthetics (6).


Other studies confirmed a dose-related activation in all EEG variables during isoflurane-nitrous oxide anaesthesia. nevertheless the EEG changes were not at levels thought to be associated with awareness, indicating that tramadol, whilst causing EEG activation, had no effect on depth of anaesthesia (5).

In contrast to these studies, our findings do not support any evidence of EEG activation as determined by BIS monitoring when tramadol is given at clinical doses during anaesthesia with propofol and remifentanil. These results are in accordance with another recent study which found that tramadol, given with ketorolac to prevent postoperative pain during anaesthesia with sevoflurane and remifentanil, did not modify the BIS value (7).

The implications of the previous findings of EEG activation by tramadol during anaesthesia are not known. It is likely that the EEG activating effect of tramadol may depend on the concentration of anaesthetic agents used, since in the previous studies, low concentrations of volatile anaesthetics were administered (5,11). It should be noted that the British national Formulary did not recommend the use of tramadol during light anaesthesia (13).

Another factor might be the use of nitrous oxide in previous studies. An increase in EEG activity has been reported in animals when nitrous oxide is added to low concentrations of isoflurane (13). It is possible that the excitatory properties of tramadol might interact with those of nitrous oxide. However, a different effect on EEG and cortical somatosensory evoked potentials was seen when nitrous oxide is added to isoflurane anaesthesia (15).

In addition, different anaesthetic drugs can produce different EEG patterns. Increases in delta activity are interpreted as signs of modification of anaesthesia depth. These EEG patterns are sometimes also found in frontal leads after surgical stimulation during isoflurane anaesthesia, which leads to the conclusion that to avoid incorrect anaesthetic management under EEG monitoring, this phenomenon of "paradoxical arousal" must be taken into consideration (16).

Finally, the dosage of tramadol could also have played a role, since we administered clinical doses of the drug. This hypothesis is consistent with previous studies in which excitatory effects in the central nervous system were observed only when tramadol is given at doses exceeding the therapeutic range (17).

Our study has several limitations. Firstly, due to the small number of patients involved we cannot exclude a type II error. The number is certainly too small to make inferences about the incidence of awareness. nevertheless, the number of patients included in each group is higher than those in previous studies evaluating the EEG effects of tramadol during anaesthesia (5,11). Tramadol was also administered during surgery, and not before surgery as in a previous study (5). surgical stimulation plays an important role in the modification of the depth of anaesthesia, and occurrence and recall of intraoperative awakening. our study reflects the clinical conditions in which the anaesthetists commonly give the drugs to prevent postoperative pain. The use of the BIS to monitor EEG modification could also be criticized, compared to previous studies (5,11). nevertheless, electroencephalographic parameters evaluated during nitrous oxide/isoflurane anaesthesia are well correlated at surgical levels with BIS (18), and BIS gives us more information than power spectral-based analysis (19).

The clinical relevance of this study is that tramadol can be administered as pre-emptive or preventive analgesia during intravenous propofol-remifentanil anaesthesia without affecting the depth of anaesthesia, as evaluated by BIS monitoring. This suggests that clinical doses of tramadol do not increase the risk of awareness.

Accepted for publication on October 10, 2005.


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(8.) Cafiero T, Di Minno RM, Sivolella G, Di Iorio C. Immediate postoperative pain management in patients undergoing major abdominal surgery after remifentanil-based anesthesia: sufentanil vs tramadol. Minerva Anestesiol 2004; 70:661-669.

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(13.) British national Formulary. September 1999; 38:210.

(14.) Roald OK, Forsman M, Heier Ms, Steen PA. Cerebral effects of nitrous oxide when added to low and high concentrations of isoflurane in the dog. Anesth Analg 1991; 72:75-79.

(15.) Porkkala T, Jantti V, Kaukinen s, Hakkinen V. nitrous oxide has different effects on the EEG and somatosensory evoked potentials during isoflurane anaesthesia in patients. Acta Anaesthesiol Scand 1997; 41:497-501.

(16.) Litscher G, Schwarz G. Is there paradoxical arousal reaction in the EEG subdelta range in patients during anesthesia? J neurosurg Anesthesiol 1999; 11:49-52.

(17.) Freye E, Latasch L, Von Bredow G, Neruda B. The opioid tramadol demonstrates excitatory properties of non-opioid character--a preclinical study using alfentanil as a comparison. Schmerz 1998; 12:19-24.

(18.) Morimoto Y, Hagihira s, Koizumi Y, Ishida K, Matsumoto M, Sakabe T. The relationship between bispectral index and electroencephalographic parameters during isoflurane anesthesia. Anesth Analg 2004; 98:1336-1340.

(19.) Hagihira s. Bispectral analysis gives us more information than power spectral-based analysis. Br J Anaesth 2004; 92:772- 773.

V. FODALE *, M. TESCIONE ([dagger]), C. ROSCITANO ([dagger]), G. PINO ([section]), A. AMATO ([section]), L. B. SANTAMARIA ([dagger])

Department of Neuroscience, Psychiatric and Anesthesiological Sciences. University of Messina, School of Medicine, Policlinico Universitario "G. Martino", Messina, Italy

* M.D., Research Professor Anesthesia and Intensive Care.

([dagger]) M.D., Resident in Anesthesia and Intensive Care.

([section]) M.D., staff Anesthesiologist.

([dagger]) M.D., Full Professor Anesthesia and Intensive Care.

Address for reprints: Dr V. Fodale, Department of neuroscience, Psychiatric and Anesthesiological sciences, Policlinico Universitario, Via Consolare, Valeria, Messina, Italy 98125.
Table 1
Demographic variables of patients involved in the study, duration
of surgery and baseline Bispectral index values

 Control group Tramadol group

Patients n 22 22

Gender (Male/Female) 12/10 11/11

Age (years) 58[+ or -]8 56[+ or -]11

Weight (kg) 63[+ or -]8 62[+ or -]7

Duration of surgery (min) 72[+ or -]14 69[+ or -]17

Baseline Bispectral index 95[+ or -]2 95[+ or -]3

Values are n, or mean[+ or -]SD.
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Author:Fodale, V.; Tescione, M.; Roscitano, C.; Pino, G.; Amato, A.; Santamaria, L.B.
Publication:Anaesthesia and Intensive Care
Date:Feb 1, 2006
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