1Respiratory Medicine Unit, Department of Medical and Radiological Science, University of Edinburgh, Royal Infirmary, Edinburgh, 2Department of Pharmacology, University of Edinburgh, 3Department of Medical Physics, Western General Hospital, Edinburgh and 4Department of Anaesthetics, University of Edinburgh, Royal Infirmary, Edinburgh, UK
Accepted for publication: March 1, 2000
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Abstract |
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Br J Anaesth 2000; 85: 2116
Keywords: pharmacology, tramadol; ventilation, hypoxic response
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Introduction |
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We have therefore studied the effect of oral tramadol on the ventilatory response to acute isocapnic hypoxia in normal subjects. The hypoxic ventilatory response was measured on a background of mild hypercapnia to mimic the postoperative situation.8 In addition, we studied both men and women as sex-related differences have been found in the effect of morphine on ventilatory control in humans.6
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Subjects and methods |
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Each subject attended the laboratory on three occasions. The first visit was for familiarization. A medical history was obtained and the FEV1 and FVC measured to confirm normal lung function. Subjects were then allowed to become accustomed to breathing through the facemask under normoxic, hypercapnic and hypoxic conditions. The second and third visits were study days and subjects were requested to fast for 3 h and to refrain from taking substances known to affect ventilation (e.g. caffeine) for a minimum of 8 h prior to study. On each study day the ventilatory response to hypoxia was measured before and 1 h after taking either tramadol 100 mg (ZYDOL, Searle) or matched placebo tablets. Drug and placebo study days were in random order and neither the subject nor assessor of ventilatory variable was aware of the treatment given. Subjects sat and read during the 1-h period between studies. Experimental studies were scheduled for the same time of day in any individual subject to minimize the effects of diurnal variation on the hypoxic ventilatory response. Females were studied within the first 10 days of a normal menses to ensure that they were not pregnant and to avoid the effect of increasing levels of progesterone in the luteal phase of the menstrual cycle.
Subjects were studied in a semi-recumbent position in a well-lit room and listened to music via headphones. They were instructed to stay awake and were roused if they appeared to fall asleep. Subjects breathed through a facemask (Hans Rudolf, series 8930) which enclosed both nose and mouth, was sealed to the face with gel (Aqua Gel, Adams Healthcare, UK), and was connected to a low-resistance two-way valve. Inspiratory gas mixtures prepared from primary gases (oxygen, nitrogen, carbon dioxide) were delivered to the subject through a T-piece attached to the inspiratory port of the two-way valve.
Ventilatory variables were recorded using methods described previously.9 Expiratory gas passed via a heated pneumotachograph (Fleisch No. 2) through mixing and drying chambers to a Parkinson Cowan CD4 dry gas meter modified to give a digital signal. The integrated expiratory flow signal, which gave breath-by-breath tidal volume, was calibrated against the output of the CD4 gas meter every 10 litres to correct the flow signal. A mass spectrometer (VG Spectralab M), calibrated with four gas mixtures of known oxygen, carbon dioxide, nitrogen and argon concentration, measured inspiratory and end-tidal oxygen (PE'o2; kPa) and carbon dioxide (PE'co2; kPa) partial pressures at the lips. Pulse oximetry (SpO2, %; Ohmeda Biox 3700, set to a fast averaging time of 2 s), and electrocardiogram (Hewlett-Packard 78351A) were measured continuously throughout the study.
Breath-by-breath values of inspiratory time (TI, s), expiratory time (TE, s), total breath time (TTOT=TI + TE, s), ventilatory frequency (f=60/TTOT, b.p.m.), tidal volume (VT, litres BTPS), instantaneous minute ventilation (VEinst=f x VT, litres min1 BTPS), mean inspiratory flow (VT : TI, litres s1), and inspired and end-tidal partial pressures were digitized using an Olivetti PCS 286 computer and stored on disk for off-line analysis.
Oxygen consumption (litres min1 STPD) and carbon dioxide output (litres min1 STPD) were measured from collections of mixed expired gas made over a 2-min period, and the gas exchange ratio calculated. Concentrations of oxygen and carbon dioxide were measured using a Servomex oxygen analyser (Servomex model 570A) calibrated with air and 100% nitrogen, and a Gould capnograph (Mark IV) calibrated with four gas mixtures of known carbon dioxide concentrations, respectively.
Composition of the inspired gas was controlled by three mass-flow controllers (Bronkhorst Hi-Tech Types F-202AC and F-201AC with Bronkhorst E7200-AAA power supply and control unit). These supplied accurately controlled flows in the range 010 litres s1 for carbon dioxide, 050 litres s1 for oxygen and 0100 litres s1 for nitrogen. The gas input pressure for each controller was maintained at 2 bar by means of precision pressure regulator (04 bar, RS components) attached to the inlet to each mass-flow controller. The output of the three controllers was passed through a mixing chamber before being presented to the subject. A computer (Elonex PT-5120/l) was interfaced with the mass-flow controllers via a digital-to-analogue converter (Amplicon PC24) and also with the data-acquisition computer. A custom-written program displayed graded flow scales representing the output of each of the mass-flow controllers and breath-by-breath values of end-tidal oxygen and end-tidal carbon dioxide on the Elonex PC monitor. Adjustment of the graded scales using the computer mouse altered the output of the mass-flow controllers so that the required gas mixture delivered to the subject could be adjusted to achieve rapid, accurate changes in end-tidal partial pressures.
Each hypoxic ventilatory response measurement lasted 37 min. Subjects initially breathed room air for 15 min and duplicate measurements of oxygen consumption and carbon dioxide output were made between 8 and 13 min. The subjects then breathed a 21% oxygen mixture produced from the mass-flow controller system for a further 5 min to obtain a steady baseline. Mild hypercapnia was then induced for 10 min by increasing inspired carbon dioxide so that end-tidal PCO2 was raised by 0.7 kPa above the previous baseline level. Inspired oxygen concentration was then decreased so that SpO2 was reduced to 85% for 7 min. The end-tidal was maintained at 0.7 kPa above the initial baseline level throughout hypoxia.
Mean values for all the ventilatory variables were calculated for each of the last 3 min of the baseline normoxic period, each of the last 3 min of the hypercapnic period, and each minute during hypercapnic hypoxia. In addition, mean values were calculated during the following 3-min periods of each run: normoxia (3 min before the onset of hypercapnia); hypercapnia (3 min before the onset of hypoxia): hypercapnic hypoxia (the last 3 min of hypoxia). The hypoxic ventilatory response was calculated as the ratio of the changes in VEinst and SpO2 occurring between the periods of hypercapnia and hypercapnic hypoxia (VEinst/ SpO2; litres min1 %1).
Group means and SD for imposed ventilatory variables and group means and 95% confidence limits (CL) for studied variables in the three measurement periods were calculated for each run. Students t-test was used to compare anthropometric data in men and women, and a paired t-test for within-run comparison of end-tidal PCO2 during hypercapnia and hypoxia. Comparisons between runs for the group as a whole were made by one-way analysis of variance with post hoc comparisons made using the least significant difference method. Comparisons between runs for males and females considered separately were made using Friedmans non-parametric analysis of variance. Significance was set at P<0.05. Computations were made using SPSS version 9 for Windows.
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Results |
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Discussion |
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Studies were performed on two separate days because the 5-h elimination half-life of tramadol10 meant that the order of the placebo and active drug runs could not be randomized if the studies were performed on the same day. However, the hypoxic ventilatory response is known to vary substantially within and between days.11 Individuals were studied at approximately the same time of day to minimize the effect of diurnal variation. To overcome the between-day variability, a baseline study was performed on each day and the effect of placebo or tramadol compared with the respective baseline measurements.
We were not able to measure serum tramadol concentrations to ensure that adequate concentrations had been achieved. A single oral dose of tramadol 100 mg given to fasting normal subjects is absorbed rapidly after an initial lag time of 30 min, with serum concentrations reaching the analgesic threshold of 100 ng litre1 after
40 min and reaching peak levels at 2 h.10 However, there is considerable individual variability in bioavailability, with times for peak serum concentration varying between 1 and 4 h.10 In this study, the repeated measurements were started 1 h after drug administration so that the repeated hypoxic challenge occurred after
90 min when serum concentrations would be approaching maximum in most subjects. While this ensured that the hypoxic ventilatory response was unlikely to be depressed as a result of previous hypoxic exposure,12 it is possible that peak serum concentrations had not been reached in some subjects. However, there was a reduction in hypercapnic VEinst of over 1.5 litres in nine out of 14 subjects after tramadol, whereas this only occurred in two subjects after placebo suggesting that active levels of tramadol had been achieved in most subjects. It is therefore unlikely that low drug concentrations account for the lack of depression of the hypoxic ventilatory response. Although 20 subjects were recruited, data were only obtained in 14 for a variety of reasons. Failure to detect a significant effect of tramadol on the hypoxic ventilatory response might therefore be a type 2 statistical error. However, this is unlikely to be the explanation as the study had a power of 0.9 to detect a change in the VEinst/SpO2 ratio of 0.5.
Dahan and colleagues6 found a sex-dependent effect on the hypoxic ventilatory response which was independent of differences in weight, lean body mass, body surface area and calculated fat mass. In their study, morphine significantly reduced the initial ventilatory response to sustained hypoxia in women but not in men. We studied similar numbers of men and women. It was possible, therefore, that an effect in women was being masked by an absence of effect in the men. However, separate analysis of the results in seven men and eight women who completed the study showed no effect of tramadol on the initial hypoxic ventilatory response in either sex.
The O-desmethyltramadol metabolite of the (+) enantiomer of tramadol, produced by hepatic phase I metabolism by cytochrome P-450 2D6 (CYP2D6), has an affinity for the µ-opioid receptor which is 200 times that of the parent compound.13 It is likely, therefore, that the bulk of any ventilatory depression would be mediated by this metabolite. Approximately 10% of the Caucasian population are phenotypically poor metabolizers14 and have a reduced analgesic effect of tramadol.13 If, by chance, most of our subjects were poor metabolizers, then this could explain the absence of effect on the hypoxic ventilatory response. This effect could contribute to our findings but is unlikely to be the only explanation as tramadol suppressed the hypercapnic ventilatory response in nine out of 14 of our subjects.
The lack of suppression by tramadol of the hypoxic ventilatory response contrasts with the 5060% suppression produced by morphine. Unlike morphine, tramadol produces its analgesic effects by a combination of low but preferential activity at µ-opioid receptors,1 by inhibiting both noradrenaline and 5-hydroxytrypamine (5-HT) uptake,1 and by facilitating 5-HT release.15 The effects of these non-opioid actions of tramadol on ventilation are difficult to assess. A recent study showed that the 5-HT reuptake inhibitor fluoxetine caused a slight depression in resting ventilation in goats.16 However, 5-HT can stimulate or depress ventilation depending on the subtype of receptor affected and the type of respiratory neurone activated.17 Catecholamines have a similar dual effect on ventilation depending in part on whether the action is central or peripheral. Catecholamines administered to the respiratory neurones in the medulla usually cause depression,18 whereas systemic administration stimulates breathing19 and increases the ventilatory response to hypercapnia.20 It is possible, therefore, that stimulation by 5-HT and noradrenaline offsets the opioid depressant effects of tramadol. The relative opioid receptor affinity of tramadol may also explain the ventilatory effects. In cats, depression of peripheral chemosensory discharge is mediated via receptors.21 Tramadol has modest affinity for µ-receptors but extremely weak
affinity. Tramadol may therefore suppress the ventilatory response to hypercapnia4 via central µ-receptor activity leaving the peripheral component relatively intact. Studies with selective opioid receptor blockers would be required to confirm this.
In conclusion, we have shown that tramadol, in a standard clinical dose, does not significantly affect the ventilatory response to hypoxia. However, tramadol reduced resting tidal volume and insignificantly reduced ventilation, resembling the effects reported by Vickers and colleagues3 at a dose of 1 mg kg1. Seitz and colleagues4 also showed that tramadol caused a moderate depression of the hypercapnic ventilatory response. The significant reduction in hypercapnic ventilation after tramadol is in keeping with previous observations that tramadol causes a moderate depression of the hypercapnic ventilatory response,4 and suggests that this suppression can be significant even at values which are only just above the normoxic resting level.
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Acknowledgement |
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Footnotes |
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References |
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