1 Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands. 2 Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratory, Leiden, The Netherlands
* Corresponding author: Anesthesia and Pain Research Unit, Department of Anesthesiology, Leiden University Medical Center (LUMC, P5-Q), PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail: a.dahan{at}lumc.nl
Accepted for publication December 31, 2004.
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Abstract |
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Methods. In healthy volunteers, the opioids were infused i.v. over 90 s and measurements of minute ventilation at a fixed end-tidal of 7 kPa were obtained for 7 h. Buprenorphine doses were 0.7, 1.4, 4.3 and 8.6 µg kg1 (n=20 subjects) and fentanyl doses 1.1, 2.1, 2.9, 4.3 and 7.1 µg kg1 (n=21). Seven subjects received placebo. In rats, both opioids were infused i.v. over 20 min, and arterial
was measured 5, 10, 15 and 20 min after the start of fentanyl infusion and 30, 150, 270 and 390 min after the start of buprenorphine infusion. Doses tested were buprenorphine 0, 100, 300, 1000 and 3000 µg kg1 and fentanyl 0, 50, 68 and 90 µg kg1.
Results. In humans, fentanyl produced a dose-dependent depression of minute ventilation with apnoea at doses 2.9 µg kg1; buprenorphine caused depression of minute ventilation which levelled off at doses
3.0 µg kg1 to about 50% of baseline. In rats, the relationship of arterial
and fentanyl dose was linear, with maximum respiratory depression at 20 min (maximum
8.0 kPa). Irrespective of the time at which measurements were obtained, buprenorphine showed a non-linear effect on
, with a ceiling effect at doses >1.4 µg kg1. The effect on
was modest (maximum value measured, 5.5 kPa).
Conclusions. Our data confirm a ceiling effect of buprenorphine but not fentanyl with respect to respiratory depression.
Keywords: analgesics, opioid ; complications, opioid-induced respiratory depression ; complications, respiratory depression ; receptors, µ-opioid ; ventilation, analgesics, effects of respiration
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Introduction |
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In this study we assessed whether there is an apparent maximum in opioid-induced respiratory depression for buprenorphine. We measured the respiratory responses to buprenorphine and compared them with responses to fentanyl, a µ-opioid receptor agonist for which no ceiling has been observed.10
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Methods |
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To study ventilation we used the dynamic end-tidal forcing technique.11 This technique enables the investigator to force end-tidal (
) and end-tidal
(
) to follow a specific pattern in time. We clamped the
and
to 7 and 14.5 kPa respectively throughout the studies. The subjects were comfortably positioned in a hospital bed and breathed through a face mask positioned over the nose and mouth (a noseclip was not used). The face mask received fresh gas (45 litre min1) from a gas-mixing system consisting of three mass flow controllers (Bronkhorst High Tec, Veenendaal, The Netherlands) for oxygen, carbon dioxide and nitrogen. A personal computer running ACQ software (Erik Kruyt, Leiden University Medical Center, Leiden, The Netherlands) provided control signals to the mass flow controllers, allowing adjustment of the inspired gas concentrations to obtain the desired end-tidal concentrations. The inspired and expired gas flows were measured at the mouth using a pneumotachograph connected to a pressure transducer (Hans Rudolf, Myandotta, MI, USA) and electronically integrated to yield a volume signal. The volume signal was calibrated with a motor-driven piston pump. The oxygen and carbon dioxide concentrations were measured using a gas monitor (Datex Multicap, Helsinki, Sweden); a pulse oximeter (Massimo, Irvine, CA, USA) continuously measured the oxygen saturation (
) of arterial haemoglobin with a finger probe. All relevant variables (minute ventilation,
,
and
) were available for on-line analysis (using RRDP software; Erik Olofsen, Leiden University Medical Center) and stored on a breath-to-breath basis for further analysis. The Bispectral Index (BIS®) of the EEG was monitored with a BIS XP machine (Aspect Medical Systems, Newton, MA, USA; release 2002) using a four-lead electrode placed on the forehead as specified by the manufacturer. BIS values were collected at 1-min intervals.
The study was double-blind, randomized and placebo-controlled. Before testing, all subjects received ondansetron 4 mg i.v. The subjects were randomly assigned to receive placebo (NaCl 0.9%), buprenorphine (Reckitt Benckiser Healthcare, Hull, UK) or fentanyl (Janssen-Cilag, Tilburg, The Netherlands). The following doses were given: placebo, 9 ml (n=7); buprenorphine in 9 ml saline, 0.7 µg kg1 (n = 5), 1.4 µg kg1 (n=5), 4.3 µg kg1 (n=5) and 8.6 µg kg1 (n=5); fentanyl in 9 ml saline, 1.1 µg kg1 (n=5), 2.2 µg kg1 (n=5), 2.9 µg kg1 (n=5), 4.3 µg kg1 (n=5) and 7.1 µg kg1 (n=1). The highest fentanyl dose (7.1 µg kg1) was tested only once. After the first subject had been given this dose, the respiratory effects were so severe (apnoea >5 min, and dropped below 70%) that the blinding of this experiment was broken and a decision was made to no longer infuse the highest fentanyl dose. The data of the single subject receiving 7.1 µg kg1 were used in the analysis.
The respiratory studies started after a period of acclimatization to the apparatus and ventilation (at a of 7 kPa) had reached steady state. Next the drug was infused slowly over 90 s. Subsequently, continuous respiratory measurements were obtained for 8090 min, followed by 510 min measurements at 30-min intervals (until 4 h after drug infusion) and then at 60-min intervals. If ventilation returned to baseline values (defined by at least 5 min at or above baseline) before the end of the measurement period, the study was ended. If this did not happen or there was no systematic respiratory depressant effect, the study ended 7 h after drug infusion.
Data analysis
We performed a 1-min average on the ventilation data of individual subjects. From these data we calculated peak ventilatory depression, time to peak effect and time to end of effect (i.e. return to baseline). The dosepeak ventilatory depression data were analysed using the following sigmoid Emax model:
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In order to get an impression of the average drug effect on respiration over the measurement time, we assessed the area between the curves standardized by the length of the study.12 The curves that are involved are those for measured ventilation normalized by predrug baseline (which by definition equals 1; see also Fig. 1). An average drug effect of 40 indicates an average of 40% respiratory depression over the measured time period (i.e. from time of drug infusion to end of effect or end of study if time to end of effect had not been reached within 420 min).
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Animal studies
Male Wistar rats (225250 g, n=63) were housed in groups before surgery and individually after surgery in plastic cages. The animals were housed under laboratory standard conditions at constant room temperature (21°C) and on a 12-h light/12-h dark cycle (lights on at 07.00 a.m.; lights off at 07.00 p.m.). Food (RMH-TM; Hope Farms, Woerden, The Netherlands) and acidified water were allowed ad libitum. The animals were handled and allowed to acclimatize to the experimental environment for 10 days before the start of the experiment. The animal protocol was approved by the University Animal Ethics Committee.
Surgical procedure
Surgery was carried out under anaesthesia with medetomidine hydrochloride (0.1 mg kg1, i.m.; Pfizer, Capelle a/d IJssel, The Netherlands) and ketamine base (1 mg kg1 i.m.; Parke-Davis, Hoofddorp, The Netherlands). Two days before the experiment, two indwelling cannulae were implanted, one in the left femoral artery and one in the right jugular vein. The cannula in the right jugular vein was used for administration of the opioid or vehicle while the cannula in the left femoral artery was used for collection of arterial blood samples. The cannulae are made from pyrogen-free, non-sterile polyethylene tubing. The cannulae were tunnelled subcutaneously and fixed at the back of the neck with a rubber ring. In order to prevent clotting and cannula obstruction the cannulae were filled with a 25% (w/v) polyvinylpyrrolidone solution (PVP; Brocacef, Maarssen, The Netherlands) in pyrogen-free physiological saline (B. Braun Melsungen, Melsungen, Germany) containing heparin 20 IU/ml.
Drugs and dosages
Fentanyl was dissolved in saline; buprenorphine was dissolved in saline with the aid of two drops of polysorbate 80 (Hospital Pharmacy, Leiden University Medical Center). Henceforth, the doses of buprenorphine and fentanyl are expressed as free base.
Each animal was tested once. For buprenorphine the following doses were tested: 0 (vehicle), 100, 300, 1000 and 3000 µg kg1. For fentanyl the doses were 0 (vehicle), 50, 68 and 90 µg kg1. Fentanyl and buprenorphine were infused i.v. over 20 min by constant-rate infusion using an infusion pump (BAS Bioanalytical Systems, West Lafayette, IN, USA). Animals were randomly assigned to the treatment groups with seven animals in each treatment level.
Measurement of arterial PCO2
Arterial blood samples were obtained at fixed times for measurement of using a Bayer 278 Blood gas analyser (Bayer, Mijdrecht, The Netherlands). For buprenorphine these times were: baseline (510 min before drug infusion), 0, 30, 60, 120, 270 and 390 min after drug administration. For fentanyl the times were: baseline, 5, 10, 15 and 20 min after drug administration. Each blood sample withdrawn was replaced by an equal volume of heparinized saline 0.9% (20 IU heparin/ml). The difference in sampling schedule is related to the difference in speed of onset of the two tested opioids, with immediate changes in
observed after fentanyl but not after buprenorphine infusion. During the experiments body temperature was maintained at 37.5°C with a CMA/150 Temperature Controller (BAS Bioanalytical Systems).
Statistical analysis
The buprenorphine and fentanyl studies were analysed separately. One-way analysis of variance was performed to assess the effect of drug dose for each time point, with post hoc Bonferroni correction for multiple comparisons. P-values <0.05 were considered significant.
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Results |
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Placebo
Placebo had no systematic effect on ventilation over the 420-min measurement period. Predrug ventilation was 22.7 (6.1) litre min1. The lowest ventilation after drug infusion was at 180 min: 19.6 (4.6) litre min1. The mean average drug effect was 0.1 (0.1).
Fentanyl and buprenorphine time profiles
The individual ventilatory responses of the subjects are given in Figures 2 and 3. For both drugs, predrug ventilation did not differ among the doses: fentanyl 24.1 (6.0) litre min1, buprenorphine 24.5 (4.1) litre min1. After fentanyl, four subjects developed a period of apnoea shortly after the infusion, one after 2.9 µg kg1 (duration <3 min, lowest measured 92%), two after 4.3 µg kg1 (duration <3 min, lowest
measured 91 and 93%) and one after 7.1 µg kg1 (8 min). Time to fentanyl peak effect did not differ among the doses tested: 4.8 (2.2) min. After buprenorphine, none of the subjects receiving buprenorphine developed apnoea. Time to buprenorphine peak effect was dose-independent and averaged 117 (58) min.
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Rat studies
The effects of both opioids on are shown in Figures 6 and 7. As predicted, the increase in
after the infusion of fentanyl was rapid, with significant effects apparent just 5 min after the initiation of the fentanyl infusion.
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Irrespective of the time at which measurements were obtained and dose, buprenorphine showed a relatively small increase in of 11.5 kPa (buprenorphine vs vehicle, P<0.05; no significant differences among the buprenorphine doses were observed). This indicates that a plateau in respiratory depression occurred at a dose of buprenorphine 0.1 mg kg1, causing an increase in
of about 50% of the maximum increase in
observed after fentanyl.
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Discussion |
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The end-tidal CO2 was controlled within 0.1 kPa (mean SD of fluctuations). In some cases, deviations from target
greater than 0.4 kPa did occur related to the short periods of relative hyperventilation following apnoea (Fig. 2). While these deviations from target
may have influenced the time profile of individual curves and underestimated the average drug effect, we do not believe that the final conclusions of the study were influenced significantly. In instances when apnoea did occur, we coached the subjects to take deep breaths. Coaching may have activated behavioural control of breathing and consequently may have influenced the study results (average drug effect).13 However, the influence of 38 min of coaching during apnoea on a 7-h experiment was minimal.
We were able to successfully coach the subjects through the episode of apnoea after fentanyl 2.9 and 4.3 µg kg1. However, we felt that the prolonged period of apnoea with low observed in the first subject dosed with fentanyl 7.1 µg kg1 was unacceptable and so we decided to restrict our study to a maximum fentanyl dose of 4.3 µg kg1. Similarly, in rats, we had observed in a pilot study that short-term infusions of fentanyl but not buprenorphine caused the death of several of our animals. To overcome this problem, we infused both tested drugs over 20 min in the rats. The different method of drug administration between humans and rats resulted in evident differences in plasma drugtime profiles.
In the human study we focused our data analysis on two measures of respiratory outcome: peak effect and the average drug effect. Average drug effect divided by the duration of effect is considered a weighted average of a response12 and allows comparisons among drug doses when no pharmacokinetic data are available. Although both measures (peak effect and average drug effect) are related to the pharmacokinetics and pharmacodynamics of the infused drug, they represent two distinct features of the drug which complement each other. Peak effect is related to the rise in opioid concentration in the brain compartment, subsequent attachment to the opioid receptor and neuronal dynamics. The average drug effect is related to the accumulation of the drug within the brain compartment, receptor kinetics (association and, more importantly, dissociation) and neuronal dynamics and gives an indication of the opioid's respiratory efficacy. Both indices showed great variability (see the standard deviations in Figs 4 and 5). The early effects were especially variable, which may be due to variability in the central volume of distribution, transit and uptake of the drug in the lungs (fentanyl)14 and passage across the bloodbrain barrier.
In humans, the relationships between buprenorphine dose and peak effect and average drug effect were non-linear. These findings are in contrast with the observations that the relationships of peak effect and average drug effect and dose of fentanyl were linear over the dose range from 0 to 4.3 µg kg1. We remain uninformed on the effect of fentanyl at doses >4.3 µg kg1, with only data from one subject at 7.1 µg kg1. However, when we take into account the data from this one subject together with the animal data, it is evident that also at the higher fentanyl doses the human doseresponse curve will have linear characteristics. Few studies have systematically addressed the issue of buprenorphine-induced respiratory depression in humans. Comparison of our data with these studies is difficult. In our studies we used isocapnia (constant end-tidal ) and measured ventilation. Other studies used either no control for carbon dioxide, a constant inspired carbon dioxide concentration or less informative measures, such as respiratory rate. In two studies, Walsh and colleagues assessed the effect of buprenorphine 0.532 mg sublingually on respiratory rate and oxygen saturation.15 16 They observed a non-linear doseresponse curve with a plateau arising between 0.4 and 0.8 mg. Despite the fact that neither respiratory rate nor oxygen saturation is a valid marker of respiration, the results of the studies of Walsh and colleagues do give a qualitative suggestion of buprenorphine's behaviour in humans. Our data, obtained at isocapnia, give a quantitative indication of the occurrence of a ceiling in buprenorphine-induced respiratory depression at i.v. doses of
2.9 µg kg1.
Despite the overt differences in methodology between the human and animal studies, the results of the studies were similar. In the animal studies, we used arterial as a surrogate measure of minute ventilation. The measured
in our studies is not only determined by the respiratory depression per se, but also by its complex interaction with ventilation. The increase in
has a drug-dependent stimulatory effect on breathing causing the (drug-dependent) elimination of carbon dioxide from the lung. We may therefore have underestimated any respiratory depression observed in the animals. An example of the underestimation of respiratory depression in human studies performed under poikilocapnic conditions (i.e. end-tidal
not kept constant) is the observation by Mildh and colleagues of a very high EC50 value (drug concentration causing 50% effect) for fentanyl-induced respiratory depression (6.1 ng ml1).10 In that study ventilation was measured and fentanyl was infused slowly, allowing the accumulation of carbon dioxide, which prevented the occurrence of severe respiratory depression and apnoea. Bouillon and colleagues addressed this issue by using indirectresponse models to calculate the EC50 and taking into account both drug and carbon dioxide effects.17 Although calculation of the EC50 is not directly possible from our study, using pharmacokinetic data from the literature we were able to estimate a value of 1.5 ng ml1, which is a factor of 4 smaller than the value obtained by Mildh and colleagues.
Considering all of the above, we do not believe that our animal data lack importance. Like the studies of Walsh and colleagues, these data give qualitative proof of the behaviour of both opioids. In humans, the occurrence of apnoea shortly after the 90-s infusion of high-dose fentanyl (200 µg or greater) is related to the rapid increase in blood fentanyl concentration, its rapid passage across the bloodbrain barrier (the fentanyl bloodeffect site equilibration half-life is about 5 min),18 with consequently high brain concentrations and almost immediate attachment to the µ-receptor. This caused rapid depression of respiratory neurons expressing the µ-opioid receptor (peak respiratory effect after fentanyl occurred at 4.8 min). Buprenorphine, like fentanyl, is highly lipophilic and shows relatively rapid passage across the bloodbrain barrier. However, in contrast to fentanyl, buprenorphine displays slow opioid-receptor association and dissociation kinetics.19 This may have prevented rapid changes in ventilation in our population despite relatively high brain concentrations (peak respiratory effect after buprenorphine occurred at 117 min).
It is generally believed that both fentanyl and buprenorphine produce their intended effect (analgesia) via an action at the µ-opioid receptor gene (OPRM1). Using exon 2 Oprm knockout mice, we observed that the µ-opioid receptor is the source of morphine-induced antinociception and respiratory depression.20 21 Involvement of other opioid receptors (-,
- or ORL1-receptors) in morphine-induced respiratory depression seems unlikely. We believe this also holds true for other opioids, such as fentanyl. Hence, we postulate that the effect of fentanyl at the µ-opioid receptor is exclusively responsible for the (almost-linear) doseresponse relationship found in our volunteers and animals (Figs 3
5). In rats, the finding of a maximum effect of fentanyl 20 min after the start of the infusion shows the maximum effect on respiration that is possible in living animals (fentanyl doses >90 µg kg1 are fatal). Our human (average drug effect, Fig. 4) and animal data indicate that fentanyl is a full agonist at the µ-opioid receptor, with high intrinsic activity. The non-linear buprenorphine doseresponse relationship we observed is in agreement with earlier human and animal studies on its respiratory effect.79 Especially in rats, data show a ceiling in buprenorphine-induced respiratory depression at doses above 0.1 mg kg1.7 8 In rhesus monkeys a similar observation was made for doses greater than 1.0 mg kg1.9 This latter study is of interest since it measured steady-state minute ventilation at a fixed inspired carbon dioxide concentration of 5%. Partial agonism of buprenorphine at the µ-opioid receptor is generally held responsible for the ceiling phenomenon.4 7 Partial agonism indicates a partial (respiratory) effect despite full µ-receptor occupancy. Recently, Lutfy and colleagues proposed a different mechanism for the non-linear doseresponse.5 They showed that buprenorphine (but not morphine) given to mice activates ORL1-receptors, compromising antinociception mediated via µ-opioid receptors. Extrapolation of these animal data on antinociception to our respiratory studies would suggest that buprenorphine's action at the ORL1-receptor would cause the reduction of respiratory depression from buprenorphine's action at the µ-receptor. In this respect buprenorphine would act as a respiratory stimulant at the ORL1-receptor. Just one study has addressed the influence of the ORL1-receptor on respiration.22 In an in vitro preparation of the newborn rat brainstem, activation of the ORL1-receptor produced depression of the generation of respiratory rhythm. This observation does not support the hypothesis of involvement of the ORL1-receptor in the development of a ceiling in buprenorphine's respiratory effect. The current data are very scanty and further studies are required to elucidate the involvement of the ORL1-receptor in opioid-induced respiratory depression.
The observation of a ceiling in buprenorphine-induced respiratory depression has contributed to the notion that buprenorphine's respiratory effects are limited.1 (Significant or fatal respiratory depression has only been reported for buprenorphine combined with sedative drugs, such as benzodiazepines.)23 However, buprenorphine's safety profile should be considered against the background of its analgesic profile. For example, if a ceiling in respiratory depression coincided with ceiling in analgesia, then the value of buprenorphine would be limited in clinical practice. While there is evidence from animal data of the occurrence of a ceiling or even a bell-shaped response curve in the analgesic effect of buprenorphine (at doses >1.0 mg kg1),5 7 24 there are no good (placebo-controlled, randomized) human studies available. Our data and those of others obtained in rodents indicate that the ceiling in respiratory effect occurs at a much lower dose (0.1 mg kg1) than the ceiling in analgesic effect (1.0 mg kg1), which indicates the relative safety of buprenorphine combined with its ability to produce effective analgesia in these animals.5 79 24 Before we can extrapolate these claims to humans, we need good clinical studies to determine whether there is a ceiling for analgesia and to assess the dose at which it occurs. Our study cannot address the issue of buprenorphine's efficacy and safety in the light of its analgesic properties.
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Acknowledgments |
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