1Department of Anesthesiology, Leiden University Medical Center (P5-Q), PO Box 9600, 2300 RC Leiden, The Netherlands. 2Department of Anaesthesia, Critical Care and Pain Medicine, University of Edinburgh, Royal Infirmary, Edinburgh, UK. 3Respiratory Medicine, Department of Medical and Radiological Science, University of Edinburgh, Royal Infirmary, Edinburgh, UK*Corresponding author
Accepted for publication: July 17, 2001
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Abstract |
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Br J Anaesth 2001; 87: 8605
Keywords: analgesics opioid, tramadol; ventilation, control of breathing; ventilation, hypercapnic response
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Introduction |
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We set out to quantify the effect of oral tramadol on ventilatory control in healthy volunteers and to locate its site of action within the ventilatory control system. In order to do so, we used the dynamic end-tidal forcing technique.9 10 This technique measures the steady-state ventilatory carbon dioxide sensitivity and also estimates the relative contributions of the peripheral and central chemoreflex gains.
We applied square-wave changes in end-tidal carbon dioxide concentration and divided the ventilatory response (measured on a breath-to-breath basis) into a fast, peripheral dynamic component and a slow, central component, using an empirical two-compartment model of the ventilatory controller. This mathematical model has been validated in cats.11 It has been used in humans to assess the effect of opioids,12 anaesthetics13 and catecholamines14 on ventilatory control.
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Methods |
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On the study day, after arrival at the laboratory, electrodes for ECG (Hewlett-Packard 78351A) and EEG electrodes (BisSensor; Aspect Medical Systems, Newton, MA, USA) were placed on the thorax and head respectively. Next, the subjects rested for 1020 min. The subjects breathed through a facemask (Vital Signs, Totowa, NJ, USA). Expiratory gas flows were measured with a pneumotachograph (Fleisch no. 2) and a pressure transducer (Furness Micomanometer), and the signal was integrated electronically to obtain volume. The inspired gas mixture was set using mass-flow controllers (Bronkhorst High-Tec, Veenendaal, The Netherlands) controlled by a personal computer (Elonex PT-5120/1). This allows the forcing of end-tidal PO2 (PE'O2) and end-tidal PCO2 (PE'CO2) according to a specified pattern in time. The inspired and expired oxygen and carbon dioxide concentrations were measured near the mouth with a mass spectrometer (VG Spectralab M, Winsford, UK) and the arterial haemoglobin oxygen saturation (SpO2) with a pulse oximeter (Ohmeda Biox 3700, Ohmeda, Helsinki, Finland) set to give a rapid response. End-tidal oxygen and carbon dioxide partial pressures, tidal volume, inspiratory time (Ti), expiratory time (Te), breathing frequency (f=60/[Ti+Te]), expired minute ventilation (V·E=fxVT) and SpO2 were collected and stored on disk for further analysis.
The EEG was recorded using an A-2000 EEG monitor (Aspect Medical Systems; software version 3.3). The monitor computed the bispectral index (BIS) over 5-s epochs. We averaged the BIS values over 1-min intervals.
Oxygen consumption (litre min1 standard temperature and pressure, dry (STPD) and carbon dioxide output (litre min1 STPD) were measured from collections of mixed expired gas made over a 2-min period, and the gas exchange ratio was calculated. Concentrations of oxygen and carbon dioxide were measured using a Servomex oxygen analyser (model 570A, Servomex, Norwood, MA, USA) calibrated with air and 100% nitrogen, and carbon dioxide with a Datex analyser (Normocap 200, Datex, Helsinki, Finland) calibrated with four calibration gas mixtures.
The experiments consisted of normoxic steps into and out of hypercapnia. After a period of steady-state breathing (assessed by stable ventilation) with PE'CO2 raised 0.10.2 kPa above resting values, PE'CO2 was increased by 1 kPa in a stepwise fashion and kept constant for 7 min. Subsequently, PE'CO2 was returned to its original value and kept constant for another 7 min. During the experiment, PE'O2 was kept constant at resting values. In each subject, two control studies and two tramadol studies were performed. Control runs preceded the drug runs. The drug runs were started 30 min after the subject had taken 100 mg tramadol as two 50 mg tablets (Zydol; Searle). Females were studied within the first 10 days of a normal menses to ensure that they were not pregnant and to avoid any effect of progesterone on ventilation.
The data were analysed by fitting the breath-by-breath ventilatory responses to a two-compartment model, as described previously.9 10 In short, the steady-state relationship of V·E to PE'CO2 at constant PE'O2 is described by the expression
V·E=(GP+GC) [PE'CO2B]
where V·E is minute ventilation, GP is the carbon dioxide sensitivity of the peripheral chemoreflex loop, GC is the carbon dioxide sensitivity of the central chemoreflex loop and B is the apnoeic threshold or extrapolated PE'CO2 of the steady-state ventilatory response to carbon dioxide at zero V·E. The sum of GP and GC is the total carbon dioxide sensitivity (GTOT). To describe the delay in effect and dynamics of the peripheral and central ventilatory responses to carbon dioxide, time delays and time constants are incorporated in the model. The deterministic model parameters are B, GC, GP, the time constant of the peripheral chemoreflex loop, the time constant of the central chemoreflex loop and a linear trend term.10 The noise corrupting the data was modelled through an external pathway with first-order dynamics.10 The parameters were estimated with a one-step prediction error method.15
The estimated parameters of control and tramadol experiments were tested by two-way analysis of variance. P-values <0.05 were considered significant. All values are given as mean (SD) and the lower (25%) and upper (75%) quartiles.
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Results |
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Mean age of the remaining subjects was 33 (7) (2937) yr, weight 72 (14) (6578.75) kg and height 170 (11) (160.0180.75) cm. All subjects finished the measurements without side-effects.
Examples of a control and a tramadol hypercapnic experiment and model fits of one subject are given in Fig. 1, which shows decreases in the fast and slow components (V·P and V·C) after tramadol.
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Tramadol did not effect the arousal level of the subjects as judged by the BIS of the EEG [control 96.2 (0.6) (95.896.9), tramadol 94.7 (4.1) (91.397) (not significant)].
Two subjects reported side-effects several hours after taking tramadol. One reported dizziness, the other nausea and vomiting.
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Discussion |
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We performed control and drug experiments on one day. For each subject, the order of experiments was the same: first the control and then the tramadol experiment. There are several reasons for this approach. We did not want to perform control and drug experiments on separate days, because day-to-day variability of the ventilatory responses to hypercapnia is more significant than within-day variability.17 18 A randomized cross-over study on one day leads to excessively long sessions and discomfort of the subjects. Furthermore, because tramadol is not eliminated completely within a short time, an influence on subsequent control experiments cannot be excluded.19 Because the differences between treatments could have been small, we opted to use a protocol in which the run-to-run variability was minimal.
Previous studies on the effect of tramadol on ventilatory control give conflicting results, which we relate to the various methods used to measure ventilatory effect and/or to the complexity of protocols. For example, Tarkkila and colleagues3 and Vickers and colleagues6 compared the respiratory effects of tramadol with meperidine or morphine on ventilation in anaesthetized patients breathing 0.31% halothane in 70% nitrous oxide before elective surgery. While meperidine and morphine caused significant respiratory depression, as observed by an increase in end-tidal PCO2, and decreases in minute ventilation and respiratory rate, i.v. tramadol seemed devoid of respiratory effects or had only a minor effect on respiratory rate. Such studies are hard to interpret, taking into account the respiratory effects of halothane (depression of peripheral and central carbon dioxide responses13 20) and nitrous oxide, which can stimulate ventilatory control, probably as a result of its sympathicomimetic properties.21 Interaction of these agents with the opioid and non-opioid actions of tramadol cannot be excluded.
Our observations support those of Seitz and colleagues, who found that the V·ECO2 response was depressed dose-dependently by 1525% by tramadol 1 and 1.5 mg kg1 i.v. in healthy awake volunteers.5 Warren and colleagues tested the effect of oral tramadol on the ventilatory response to short-term (7 min) hypoxia against the background of mild isohypercapnia.4 Whereas hypercapnic ventilation was reduced, an observation in agreement with our findings, tramadol had no effect on the hypoxic V·E response. This is surprising in view of our present observation of a depressant effect of tramadol on respiration, which is probably located in the respiratory integrating centres. The ventilatory response to hypoxia is biphasic: an initial hyperventilatory response, originating in the carotid bodies, is followed after 35 min by a slow decline, which originates centrally (i.e. within the central nervous system).22 The mechanism of this respiratory effect of central hypoxia remains unknown but may involve various neuromodulators. Tramadol may have reduced central hypoxic depression by its non-opioid modes of action, such as central serotonin release (see below), and thus offset the depression of the acute hypoxic response.
Tramadol and the O-desmethyltramadol metabolite of its (+) enantiomer produce analgesia by an agonistic effect on the µ-opioid receptor.23 However, the antinociceptive effect of tramadol in the rat hotplate test is only partially antagonized by naloxone, and activation of opioid receptors appears to be responsible for only 50% of tramadols analgesic effect.1 The remainder of its analgesic action may be by inhibition of norepinephrine and serotonin reuptake and by facilitation of serotonin release in descending neural antinociceptive pathways.1 24 The molecular mechanisms of the respiratory effects of tramadol remain unknown. Whereas the activation of the µ-opioid receptor is associated with respiratory depression,25 the effects of monoamines on respiration are less evident.2628 Central release of serotonin may depress as well as stimulate breathing, depending on the type of respiratory neurone and 5-HT receptor subtype involved.26 Most studies indicate that central release of norepinephrine causes respiratory depression.27 To determine the relative effect of the µ-opioid receptor in tramadol-induced respiratory depression, Teppema and colleagues determined the ability of naloxone to reverse the depression by tramadol of the V·ECO2 response in an anaesthetized cat model.29 Respiratory depression by tramadol was reduced by 7080% after naloxone pretreatment, suggesting that at least 70% of tramadols respiratory effect is related to its action at opioid receptors, while the remainder could be by inhibition of serotonin and norepinephrine reuptake.
Respiration in perioperative patients is related to the balance between stimulation from pain, stress and activated chemoreflexes and depression resulting from sedation and the direct effect of analgesics and anaesthetics on respiratory neurones.30 Our subjects were free of pain or surgical stress, which should be considered before extrapolating our findings to perioperative patients. The respiratory effects in the present study may have been overestimated. The effect observed in this study is equivalent to that found after morphine 0.13 mg kg1 i.v. in healthy volunteers without pain.12
In conclusion, tramadol reduces the hypercapnic ventilatory response. This depression probably acts through the respiratory integrating centres within the brainstem.
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Acknowledgements |
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References |
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