1 Medeval Ltd, Skelton House, Manchester Science Park, Lloyd Street North, Manchester M15 6SH, UK. 2 MICU, UZ Gasthuisberg, Leuven, Belgium. 3 ICU, Leeds General Infirmary, Leeds, UK. 4 ICU, Royal Hallamshire Hospital, Sheffield, UK. 5 ICU, Hilleroed Syngehus, Hilleroed, Denmark. 6 ICU, Amtssygehuset i Herlev, Herlev, Denmark. 7 ICU, J-W Goethe Universitat Zentrum der Anaesthesiologie und Wiederbelebung, Frankfurt, Germany. 8 ICU, Universitat Erlangen-Nurnberg.Klinik fur Anaesthesiologie, Erlangen, Germany. 9 GlaxoSmithKline R&D, Greenford, UK
*Corresponding author. E-mail: m.pitsiu@medeval.com Declaration of interest. This study (USA30212) was supported by a research grant from GlaxoSmithKline, UK.
Accepted for publication: November 12, 2003
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Abstract |
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Methods. Forty adult ICU patients with normal/mildly impaired renal function (creatinine clearance [CLcr] 62.9 (SD) 14.5 ml min1; n=10) or moderate/severe renal impairment (CLcr 14.7 (15.7) ml min1; n=30) were included. Remifentanil was infused for up to 72 h, at a starting rate of 69 µg kg1 h1 titrated to achieve a target sedation level, with additional propofol (0.5 mg kg1 h1) if required. Intensive arterial sampling was performed for up to 72 h after infusion. Pharmacokinetic parameters obtained by simultaneous modelling of remifentanil and RA data were statistically compared between the two groups.
Results. Remifentanil pharmacokinetics were not significantly affected by renal status. RA clearance in the moderate/severe group was reduced to about 25% that of the normal/mild group (41 (29) vs 176 (49) ml kg1 h1, P<0.0001). Metabolic ratio, a predictor of the ratio of RA to remifentanil concentrations at steady state, was approximately eight-fold higher in the moderate/severe group relative to the normal/mild group (116 (110) vs 15 (4), P<0.0001). Maximum RA levels approached 700 ng ml1 in the moderate/severe group.
Conclusions. Although RA accumulates in patients with moderate/severe renal impairment, pharmacokinetic modelling predicts that RA concentrations during a 9 µg kg1 h1 remifentanil infusion for up to 15 days would not exceed those reported in the present study, for which no associated prolongation of µ-opioid effects was observed.
Br J Anaesth 2004; 92: 493503
Keywords: analgesics opioid, remifentanil; intensive care, renal; pharmacology, drug metabolism; pharmacology, pharmacokinetics
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Introduction |
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Remifentanil (remifentanil hydrochloride) is an opioid with a rapid onset of action of about 1 min which quickly achieves steady state. It has a context-sensitive half-life of 23 min, which is independent of the duration of infusion.3 Remifentanil is not a substrate for plasma cholinesterase and therefore its metabolism is not subject to genetic variance. Unlike existing opioids, remifentanil exhibits a predictable, rapid metabolism by non-specific esterases in the blood and tissues, principally to a carboxylic acid derivative, remifentanil acid (RA).4 This organ-independent elimination of remifentanil makes it a useful agent in the ICU setting, where patients commonly have some degree of organ dysfunction.5 These features of remifentanil combine to make it easy to titrate to the desired analgesic effect and allow it to be administered for long periods and at higher doses than are normally used with traditional opioids, without the risk of significant accumulation. A number of studies have looked at the potential role and use of remifentanil in the critically ill.613
Whilst remifentanil elimination is essentially independent of renal and liver function, RA is eliminated via the kidneys, and its elimination is prolonged in patients with severe renal impairment (predicted creatinine clearance (CLcr) <10 ml min1).14 RA therefore accumulates in these patients. Since RA has never been administered to man, the concentration at which µ-agonist effects are likely to be seen has not been ascertained. A remifentanil infusion of 0.2 µg kg1 min1 results in respiratory depression and, according to simulations by Minto and colleagues,15 that equates to a remifentanil blood concentration of approximately 5 ng ml1 in volunteers. RA has been demonstrated to be much less potent (1/4600) a µ-opioid agonist than the parent molecule in dogs,16 and assuming the same potency ratio applies to man, it is therefore thought not to result in any clinically relevant effects at concentrations below 900 ng ml1. A clinical trial was designed primarily to determine any potential safety issues that might arise as a result of the accumulation of RA in renally impaired ICU patients given a continuous remifentanil infusion for up to 72 h. This length of infusion was chosen as a cautious approach, which would on average allow steady-state concentrations of RA to be approached and also complied with the 72 h restriction in the propofol data sheet in some countries. In addition to the pharmacodynamic effect, adverse events and haemodynamic profiles, the pharmacokinetic profiles of remifentanil and RA were assessed. The specific objectives of the analysis were to characterize the pharmacokinetics of remifentanil and RA using both model-independent and compartmental modelling methods, and to correlate the pharmacokinetic parameters obtained to the degree of renal impairment.
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Methods |
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Male or female (of non-child bearing potential or using contraception) post-surgical and medical patients were eligible for entry into the study if they were aged 18 yr or more, weighed 120 kg or less, and if they were expected to require mechanical ventilation for a further 2472 h. Patients should have had a sedationagitation scale (SAS) score in the range 24 at admission to the ICU (score of 2: patient is very sedated, can be roused by physical stimuli but does not communicate or follow commands, may move spontaneously; score of 3: patient is sedated, difficult to rouse, awakens to verbal stimuli or gentle shaking but drifts off again, will follow simple commands; score of 4: patient is calm and cooperative, easily rousable and follows commands).17
During an initial screening period, the patients renal function was measured by estimating CLcr from plasma and urinary creatinine concentrations and urine volumes over a minimum period of 4 h with extrapolation to 24 h.18 Patients with an estimated CLcr of 50 ml min1 or higher were classified as having normal renal function or mild renal impairment; patients with values below 50 ml min1 were classified as having moderate/severe renal impairment.
Remifentanil (lyophilized powder in sterile vials each containing 5 mg of the compound, provided by GlaxoSmithKline UK, reconstituted and diluted to 50 ml using standard diluents) was administered as a continuous i.v. infusion for a maximum of 72 h. The remifentanil infusion started at a dose of 6 or 9 µg kg1 h1, and was then titrated according to a dosing algorithm.19 Propofol (starting dose 0.5 mg kg1 h1) was administered as an additional infusion if required when the remifentanil infusion rate requirements reached 12 µg kg1 h1. During the treatment period, patients were continuously assessed and the remifentanil (and propofol if required) dose regimen was adjusted in order to maintain an SAS score of 24 (as considered clinically appropriate) with no or only mild pain. In addition, scheduled down-titrations of the remifentanil regimen by 25% of the initial rate at 10 min intervals were performed at 8, 24 and 48 h. The infusion rate was reduced until an offset of remifentanils pharmacodynamic effects was observed. If propofol was being infused at the time of a scheduled down-titration, it was maintained at a constant infusion rate. Study treatment was permanently discontinued after a maximum of 72 h, by reducing the remifentanil infusion rate by 25% at 10 min intervals. Any propofol which was infused at this time was maintained at a constant rate until 30 min after the remifentanil had been stopped and then decreased in decrements. After the remifentanil was finally discontinued, the patient was switched to standard therapy of the investigators choice. Although the intention was for patients to complete the 72 h of remifentanil infusion, there was no minimum infusion period for entry into the trial and all patients who received remifentanil and had measurable remifentanil concentrations were included.
Sample acquisition, handling and processing
Arterial blood samples (5 ml) were collected from all patients into tubes containing citric acid and were frozen for subsequent assay at the following time points: before the start of the remifentanil infusion and at 15 and 30 min, and 1, 2 and 4 h after starting the infusion; at 08:00 h and 20:00 h each day (unless these times were within 4 h of a scheduled down-titration); and at the 8, 24 and 48 h scheduled down-titrations (immediately before the first down-titration step and before the infusion rate was turned up again). If the remifentanil infusion was temporarily discontinued during a scheduled down-titration, a blood sample was obtained immediately before discontinuation and at 5, 10 and 30 min or just before the infusion was restarted, whichever occurred first. At final treatment discontinuation (72 h maximum), blood samples were obtained immediately before the first down-titration, before the infusion was decreased by 25% of the initial rate at 10 min intervals (three samples) and immediately before the infusion was finally discontinued. During the post-treatment period, blood samples were obtained at approximately 5, 10 and 30 min, and at 1, 2, 4, 8, 24, 40, 56 and 72 h after final discontinuation of remifentanil infusion.
On the occasions that renal replacement therapy (RRT) was performed, at the time of starting dialysis and after the system had been stabilized, two blood samples were obtained simultaneously from the line entering the dialysis machine and from the line exiting the dialysis machine.
Assay method
The concentrations of remifentanil and RA in whole blood were determined using validated assay procedures. The method, a specific liquid chromatography tandem mass spectrometry method, was a modification of a previously published method,20 which involved solid-phase extraction with methanol instead of dichloromethane and enables simultaneous quantification of free remifentanil and RA. The lower limit of quantification (LLQ) for both analytes was 0.1 ng ml1. Intra-assay precision values at LLQ were less than 20% and accuracy values were within 100 (20)%, with reference to the nominal value. Overall intra- and inter-assay precision values were less than 15% and accuracy values within 100 (15)% of the nominal value.
Pharmacokinetic analysis
The following parameters were determined for remifentanil and RA using standard model-independent methods in WinNonlinTM professional version 3.121 maximum plasma concentration (Cmax), the first time to reach Cmax (tmax), and area under the plasma concentrationtime curve (AUC) to the last sample time (AUClast). The metabolic ratio was calculated as the ratio of AUClast of RA to that of remifentanil.22 The extraction of remifentanil and RA during RRT was determined as the ratio (%) of the concentration in the samples taken from the lines entering and exiting the dialysis equipment.
Simultaneous pharmacokinetic modelling of the individual remifentanil (parent) and RA data was performed using NONMEM.23 Visual inspection of the data indicated that remifentanil concentrations during the post-infusion period were adequately characterized by a monoexponential decline. However, RA concentrations during the post-infusion period were characterized by either a mono- or a biexponential pattern. Consequently, simultaneous compartmental analysis of parent drug and metabolite involved fitting either a two- or a three-compartment model to the blood concentrationtime data, with one compartment associated with the parent drug and one or two compartments with the metabolite, with a variable zero-order input rate to the parent compartment. The pharmacokinetic model is depicted in Figure 1.
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dR1/dt=k0/V(R1k12)
dM2/dt=(R1k12)(M2k23)+(M3k32)(M2k20)
dM3/dt=(M2k23)(M3k32)
where R1 is the concentration of remifentanil in compartment 1; M2 and M3 are the concentrations of RA in compartments 2 and 3, respectively; k0 is the remifentanil infusion rate, V is the volume of distribution of remifentanil (compartment 1), and k12 is the total elimination rate constant of remifentanil, assuming that all the parent drug is converted into the metabolite.
To facilitate the fitting process, the model was re-parameterized in terms of remifentanil clearance (CL) and volume of distribution (V), and RA clearance (CLm), central compartment volume (Vm1), intercompartmental clearance (Qm) and peripheral compartment volume (Vm2), which were estimated as primary parameters. From these the compartmental rate constants were estimated as follows:
k12=CL/V
k20=CLm/Vm1
k23=Qm/Vm1
k32=Qm/Vm2
The elimination half-life of remifentanil (t1/2)was estimated as t1/2= ln(2)/k12. The half-lives associated with the alpha () and beta (ß) of the exponential form of the model for RA[M(t)=Ae
t+Beßt] were derived from the appropriate rate constants.24 The phase that on average contributed most to the total AUC was termed the elimination phase and the corresponding half-life as the RA elimination half-life.
Since this analysis involved individual data, the variance model in NONMEM represented intra-individual variability (), with different
values estimated for remifentanil (
R) and RA (
M), both assumed to arise from a log-normal distribution.
The reduced structural pharmacokinetic model (one compartment for remifentanil and one compartment for RA, i.e. excluding compartment 3 in Figure 1) and variants of the variance model were also tested. The same parameterization in terms of CL and V for remifentanil and CLm and Vm1 for RA was applied and the compartmental rate constants were estimated as follows:
k12=CL/V
k20=CLm/Vm1
For this model, the elimination half-life of RA was estimated as t1/2,m,k20 = ln(2)/k20.
In both models, it was assumed that all remifentanil was converted to RA. Since 9598% of a remifentanil dose is recovered in urine as RA,14 this assumption was not expected to have led to any significant bias in the parameter estimates.
Model discrimination was based on the NONMEM objective function, taking into account the estimation error and the degree of correlation between the parameters. Residual plots were inspected for goodness of fit and lack of bias. The likelihood ratio was used to assess whether the difference in the NONMEM objective function between the model with a biexponential decline for the RA data (more complex) and that with a monoexponential decline (base model) indicated an improved fit of the model to the data, as follows. A change in the NONMEM objective function of more than 3.84 (based on the likelihood ratio, which is approximately 2 distributed for one degree of freedom) when compared with the base model was considered significant (P<0.05). A superior model was also expected to reduce residual error terms.
Finally, any association between covariates likely to affect the pharmacokinetic parameters of remifentanil and RA (e.g. CLcr, body weight, age) was explored graphically.
Statistical analysis
Descriptive statistics were used to summarize the pharmacokinetic parameters of remifentanil and RA in the two groups and for the following three subgroups in the moderate/severe group: patients who had no RRT (subgroup A); patients having intermittent RRT (i.e. RRT starting or ending within the period of the pharmacokinetic sampling) (subgroup B); patients who had continuous RRT for the duration of pharmacokinetic sampling (subgroup C). As patients in this study received individualized remifentanil regimens for different lengths of time, only the ranges of maximum concentrations and AUC values are reported.
Appropriate statistical methods (ANOVA by group) were employed to test for differences in the pharmacokinetic parameters of remifentanil and RA between the renal function groups. P<0.05 was considered statistically significant. To elucidate any differences, an exploratory ANOVA and contrast analyses between the normal/mild group and the three moderate/severe subgroups were also performed. All statistical analyses were performed in SAS® System version 8.
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Results |
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More patients with moderate/severe renal impairment had higher simplified acute physiology score II values25 (associated with higher hospital mortality rate) than those in the normal/mild group.
Of the 30 patients in the moderate/severe group, five patients underwent continuous RRT, nine underwent intermittent RRT, and 16 patients required no RRT. Four different methods of RRT were used: haemodialysis (n=3), continuous venovenous haemodialysis (n=2), continuous venovenous haemofiltration (n=4) and continuous venovenous haemodiafiltration (n=5). There was no evidence for remifentanil being extracted during RRT; RA appeared to be extracted by approximately 60% in the three cases of haemodialysis. None of the patients in the normal/mild group needed RRT.
The duration of the remifentanil infusion ranged from 45.4 to 72.8 h in the normal/mild group and from 4.8 to 72.5 h in the moderate/severe group; on average it was shorter for the moderate/severe group (mean 43.1 h) than for the normal/mild group (mean 70.4 h). The weighted mean remifentanil infusion rate requirement was slightly lower in the moderate/severe group (10.1 µg kg1 h1) than in the normal/mild group (13.1 µg kg1 h1). Requirement for supplementary propofol infusions was also lower in the moderate/severe group (53%) than in the normal/mild group (70%), with mean propofol infusion rates in the two groups being 0.7 and 1.3 mg kg1 h1, respectively. These differences in remifentanil and propofol requirements between the moderate/severe and the normal/mild group were not statistically significant, and within each group, remifentanil and propofol requirements did not change with time.
Pharmacokinetics
Remifentanil concentrations in both renal function groups rose immediately after starting the i.v. infusion and declined rapidly during the down-titration phase and after discontinuation of the remifentanil infusion. For more than half of the patients, there were fewer than three quantifiable concentrations in the post-infusion samples. Maximum levels of remifentanil were observed at various times during the infusion period, reflecting fluctuations in the remifentanil dosing rate (Fig. 2).
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Discussion |
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The metabolic ratio is indicative of the ratio of the RA to remifentanil concentrations at steady state.22 The mean metabolic ratio for the normal/mild renal function group in this study (15.1) is consistent with the estimate obtained in a previous study in patients with mild renal impairment (17.0).26 The metabolic ratio increased to 116 in patients with moderate/severe renal impairment and the difference would have been even larger if the complete AUC of the metabolite was estimable. This increase is consistent with previous findings in patients with severe renal failure.14 The differences observed in the metabolic ratio between the moderate/severe subgroups (mean metabolic ratio 70, 132 and 192 for subgroups A, B and C, respectively) inversely correlated with the differences in Clcr in these subgroups (mean CLcr 24.0, 5.3 and 1.8 ml min1 respectively).
One-, two- and three-compartment models have previously been used to describe the pharmacokinetics of remifentanil in humans,4 14 15 while the pharmacokinetics of RA have been previously described by a one-compartment model, reporting a half-life of 1.5 h in healthy patients.14 The present data only supported a one-compartment model for remifentanil. The concentrations of RA in the normal/mild group declined in a biexponential manner, suggesting a two-compartment model, with a much longer terminal half-life, as was also the case in a recent study of similar design using the same assay for analyte determination.26 The ability to observe a slow terminal phase, previously undetected,14 in patients with normal renal function was probably due to the high concentrations of RA, the increased assay sensitivity and the extended sampling period employed in that previous study26 and the present one. This terminal phase, apparently unaffected by renal function, accounted for about 25% of the total AUC and probably represents a slowly equilibrating distribution compartment, which becomes rate limiting at later times. A one-compartment model adequately described RA concentrations in patients in the moderate/severe group. Either a combined three-compartment model (normal/mild group) or a two-compartment model (moderate/severe group) was therefore used for simultaneous modelling of parent and metabolite data.
Mean remifentanil CL was 59.0 (SD 52.9) ml min1 kg1 in the moderate/severe group and 44.3 (14.4) ml min1 kg1 in the normal/mild group; the difference was not statistically significant. V and t1/2 were estimated to be 1.76 (2.34) litre kg1 and 20.5 (17.8) min in the moderate/severe group and 0.737 (0.645) litre kg1 and 11.4 (7.24) min in normal/mild group, respectively. Large variability was observed in both these variables and any apparent differences in the mean estimates were not statistically significant (P=0.0735 and P=0.0824, respectively), and are not expected to have a clinically significant effect on recovery. These observations are also consistent with a previous study in volunteers with renal failure where no significant differences in the pharmacokinetics of remifentanil were observed compared with healthy volunteers,14 although the dosage and duration of remifentanil treatment in that study were much lower. Exploratory contrast analysis between subgroups (results available on request) indicated that the trend in remifentanil volume mainly reflected extremely large differences in the volume estimates of two patients in the moderate/severe group undergoing continuous RRT (subgroup C) compared with all other subgroups. Such differences in volume of distribution might be due to an effect of any concomitant fluid replacement therapy these patients might have undergone and in addition, continuous RRT is known to cause large fluid shifts and hence transient hypervolaemia in such patients. The overall trend in the half-life of remifentanil was again found to mainly reflect differences between subgroup C and the other subgroups, and is attributable to differences in volume of distribution. In a recent study in 13 end-stage renal failure patients undergoing RRT,27 it was reported that remifentanil clearance was significantly reduced and terminal half-life increased relative to matched control patients with normal renal function. As a result, remifentanil blood concentrations were significantly higher in the renal failure group. However, the changes were clinically modest and it was suggested that they may be explained by a reduced volume of distribution in the period following haemodialysis. In the present study, although a (not significant) prolongation of remifentanil half-life was observed, volume of distribution was, if anything, increased in patients undergoing RRT and no consistent effect on remifentanil clearance, or remifentanil concentrations was observed.
Mean CLm was significantly decreased in the moderate/severe group compared with the normal/mild group: 41.4 (28.9) vs 176 (49.3) ml h1 kg1. The differences between the normal/mild group and all three subgroups of the moderate/severe group were statistically significant and it appears that CLm is linearly related to CLcr (Fig. 6). The mean elimination half-life of RA, as estimated by t1/2,m, for the three-compartment combined model in the normal/mild group, was 2.48 (1.03) h, which is similar to that previously reported for patients with mild renal impairment (2 h).26 It was also significantly shorter than the single RA half-life estimated by the two-compartment combined model for the moderate/severe group, 18.5 (13.6) h. In contrast, the half-life of RA associated with the terminal phase in the normal/mild group (t1/2,m,ß, three-compartment model) was 16.6 h, and this was not significantly different from the single half-life estimated for the moderate/severe group. Due to the different compartmental models used, a comparison of these half-lives is not strictly statistically permissible, but the results of the statistical analyses can be used to elucidate underlying mechanisms. In renal impairment, it is the elimination of RA that is affected, as demonstrated by the decrease in CLm in the present study. The shift in the metabolite kinetics from two compartments to one is consistent with a prolongation of RA elimination half-life (which can be assumed to be given by t1/2,m,
in the normal/mild group) with increasing severity of renal impairment. In the study in patients with mild renal impairment,26 a 2-fold increase in t1/2,m,
has been observed relative to normal patients, while the terminal half-life t1/2,m,ß remained unaltered. It can be expected that, if t1/2,m,
is further prolonged in moderate/severe renal impairment, the two phases may no longer be distinguishable, and that would be consistent with the previously reported 20-fold increase of RA half-life in severe renal impairment.14 It can then be safely assumed that the single half-life estimated in the moderate/severe group in the present study reflects this prolongation in RA elimination half-life, as a result of the increased severity of renal impairment. Although this situation called for mixed-effects modelling in order to statistically evaluate covariate effects such as that of renal function and patient characteristics on RA pharmacokinetics, all attempts to estimate population pharmacokinetic parameters and their variability in NONMEM failed to converge.
In exploratory plots of pharmacokinetic parameters vs the covariates age and weight, no obvious trends were observed. It was not possible to illustrate the previously found effect of age15 on remifentanil pharmacokinetics since patients were unevenly distributed (three aged 3140 yr, 37 aged 5481 yr). In addition, the small number of female patients included in the study and their uneven distribution (9/40, one in the normal/mild group and eight in the moderate/severe group) did not permit any gender comparisons.
Pharmacodynamic results of the same clinical trial, presented by Breen and colleagues,28 showed no evidence of any clinically relevant prolongation of µ-opioid effects, as assessed by the time to the offset of the pharmacodynamic effects. The main finding relevant to the discussion of RA pharmacokinetics was that the difference in the mean time to offset between the normal/mild and moderate/severe groups after 72 h of remifentanil administration was only 17 min, even when RA concentrations reach up to 500 times those of remifentanil in individual patients with a significant degree of renal impairment.
In order to assist future study designs in ICU patients who might require remifentanil administration for longer than 72 h, remifentanil and metabolite simulations were performed using mean parameter estimates obtained here, with CLm expressed as a function of CLcr, using the equation given in Figure 6. Simulations for average patients with various degrees of renal impairment receiving a 9 µg kg1 h1 continuous remifentanil infusion for 15 days are presented in Figure 7A.
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In conclusion, the pharmacokinetics of remifentanil were not significantly altered in ICU patients with moderate/severe renal impairment compared with those with normal/mild impaired renal function, even after continuous i.v. administration for up to 3 days. CLm decreased in a linear fashion with decreasing CLcr, and in patients with moderate/severe renal impairment was reduced to 25% that of the normal/mild group. The metabolic ratio increased by 8-fold in the moderate/severe group relative to the normal/mild group, predicting average RA concentrations at steady state more than 100-fold those of remifentanil in patients with moderate/severe renal impairment. Simulations using the pharmacokinetic parameters obtained from the study predict that in patients with renal failure, RA concentrations would reach steady state after 6 days of continuous infusion and, for a remifentanil regimen of 9 µg kg1 h1, these concentrations would not exceed those reported in the present study, for which no associated prolongation of µ-opioid effects was observed.
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