Erik Olofsen

Sex differences in morphine analgesia: an experimental study in healthy volunteers.

BackgroundAnimal and human studies indicate the existence of important sex-related differences in opioid-mediated behavior. In this study the authors examined the influence of morphine on experimentally induced pain in healthy male and female volunteers. MethodsYoung healthy men and women (10 of each sex) received intravenous morphine (bolus 0.1-mg/kg dose followed by an infusion of 0.030 mg · kg−1 · h−1 for 1 h). Pain threshold and pain tolerance in response to a gradual increase in transcutaneous electrical stimulation, as well as plasma concentrations of morphine and its major metabolites (morphine-6-glucuronide and morphine-3-glucuronide) were determined at regular intervals up to 7 h after the start of morphine infusion. A population pharmacodynamic model was used to analyze the morphine-induced changes in stimulus intensity. The improvement of the model fits by inclusion of covariates (sex, age, weight, lean body mass) was tested for significance. The model is characterized by baseline current, a rate constant for equilibrium between plasma and effect-site morphine concentrations (ke0), and analgesic potency (AC50, or the morphine concentration causing a 100% increase in stimulus intensity for response). ResultsThe inclusion of the covariates age, weight, and lean body mass did not improve the model fits for any of the model parameters. For both pain threshold and tolerance, a significant dependency on sex was observed for the parameters ke0 (pain threshold: 0.0070 ± 0.0013 (± SE) min−1 in men vs. 0.0030 ± 0.0005 min−1 in women; pain tolerance: 0.0073 ± 0.0012 min−1 in men vs. 0.0024 ± 0.0005 min−1 in women) and AC50 (pain threshold: 71.2 ± 10.5 nm in men vs. 41.7 ± 8.4 nm in women; pain tolerance: 76.5 ± 7.4 nm in men vs. 32.9 ± 7.9 nm in women). Baseline currents were similar for both sexes: 21.4 ± 1.6 mA for pain threshold and 39.1 ± 2.3 mA for pain tolerance. Concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide did not differ between men and women. ConclusionsThese data show sex differences in morphine analgesia, with greater morphine potency but slower speed of onset and offset in women. The data are in agreement with observations of sex differences in morphine-induced respiratory depression and may explain higher postoperative opioid consumption in men relative to women.

Permutation entropy of the electroencephalogram: a measure of anaesthetic drug effect

BACKGROUND It would be useful to have an open-source electroencephalographic (EEG) index of gamma-amino-butyric acid (GABA)-ergic anaesthetic drug effect that is resistant to eye-blink artifact, responds rapidly to changes in EEG pattern, and can be linked to underlying neurophysiological and neuropharmacological mechanisms that control the conscious state. METHODS The EEG waveform can be described as a sequence of ordinal patterns. The permutation entropy (PE) describes the relative occurrence of each of these patterns. It is high ( approximately 1.0) when the signal has predominantly high frequencies and low ( approximately 0.4) when the signal consists of only low frequencies. The response of the PE to various computer-generated EEG-like waveforms was assessed. A composite PE index (CPEI) was developed, which was the sum of two simple PEs and included a small measurement-noise threshold (0.5 microV). We also applied the CPEI to two small pilot EEG data sets from patients receiving sevoflurane (n=21) or propofol (n=9) anaesthesia. RESULTS With minimal pre-processing or artifact rejection, the CPEI reliably tracked the anaesthetic-related EEG changes, namely loss of high frequencies, spindle-like waves, and delta waves. Using NONMEM, it was possible to construct adequate pharmacokinetic-pharmacodynamic models from the data. The CPEI was comparable with models derived using the bispectral index [BIS R(2)=0.88 (0.08) vs CPEI R(2)=0.91 (0.06) for the propofol data] and M-entropy indices [M-entropy R(2)=0.91 (0.06) vs CPEI R(2)=0.87 (0.09) for the sevoflurane data]. CONCLUSIONS PE of the EEG shows promise as a simple measure of GABAergic anaesthetic drug effect.

Propofol reduces perioperative remifentanil requirements in a synergistic manner: response surface modeling of perioperative remifentanil-propofol interactions.

Background Remifentanil is often combined with propofol for induction and maintenance of total intravenous anesthesia. The authors studied the effect of propofol on remifentanil requirements for suppression of responses to clinically relevant stimuli and evaluated this in relation to previously published data on propofol and alfentanil. Methods With ethics committee approval and informed consent, 30 unpremedicated female patients with American Society of Anesthesiologists physical status class I or II, aged 18–65 yr, scheduled to undergo lower abdominal surgery, were randomly assigned to receive a target-controlled infusion of propofol with constant target concentrations of 2, 4, or 6 &mgr;g/ml. The target concentration of remifentanil was changed in response to signs of inadequate anesthesia. Arterial blood samples for the determination of remifentanil and propofol concentrations were collected after blood–effect site equilibration. The presence or absence of responses to various perioperative stimuli were related to the propofol and remifentanil concentrations by response surface modeling or logistic regression, followed by regression analysis. Both additive and nonadditive interaction models were explored. Results With blood propofol concentrations increasing from 2 to 7.3 &mgr;g/ml, the C50 of remifentanil decreased from 3.8 ng/ml to 0 ng/ml for laryngoscopy, from 4.4 ng/ml to 1.2 ng/ml for intubation, and from 6.3 ng/ml to 0.4 ng/ml for intraabdominal surgery. With blood remifentanil concentrations increasing from 0 to 7 ng/ml, the C50 of propofol for the return to consciousness decreased from 3.5 &mgr;g/ml to 0.6 &mgr;g/ml. Conclusions Propofol reduces remifentanil requirements for suppression of responses to laryngoscopy, intubation, and intraabdominal surgical stimulation in a synergistic manner. In addition, remifentanil decreases propofol concentrations associated with the return of consciousness in a synergistic manner.

The dynamic relationship between end-tidal sevoflurane and isoflurane concentrations and bispectral index and spectral edge frequency of the electroencephalogram.

BACKGROUND Inhalational anesthetics produce dose-dependent effects on electroencephalogram-derived parameters, such as 95% spectral edge frequency (SEF) and bispectral index (BIS). The authors analyzed the relationship between end-tidal sevoflurane and isoflurane concentrations (FET) and BIS and SEF and determined the speed of onset and offset of effect (t1/2k(e0)). METHODS Twenty-four patients with American Society of Anesthesiologists physical status I or II were randomly assigned to receive anesthesia with sevoflurane or isoflurane. Several transitions between 0.5 and 1.5 minimum alveolar concentration were performed. BIS and SEF data were analyzed with a combination of an effect compartment and an inhibitory sigmoid Emax model, characterized by t1/2k(e0), the concentration at which 50% depression of the electroencephalogram parameters occurred (IC50), and shape parameters. Parameter values estimated are mean +/- SD. RESULTS The model adequately described the FET-BIS relationship. Values for t1/2k(e0), derived from the BIS data, were 3.5 +/- 2.0 and 3.2 +/- 0.7 min for sevoflurane and isoflurane, respectively (NS). Equivalent values derived from SEF were 3.1 +/- 2.4 min (sevoflurane) and 2.3 +/- 1.2 min (isoflurane; NS). Values of t1/2k(e0) derived from the SEF were smaller than those from BIS (P < 0.05). IC50 values derived from the BIS were 1.14 +/- 0.31% (sevoflurane) and 0.60 +/- 0.11% (isoflurane; P < 0.05). CONCLUSIONS The speed of onset and offset of anesthetic effect did not differ between isoflurane and sevoflurane; isoflurane was approximately twice as potent as sevoflurane. The greater values of t1/2k(e0) derived from the BIS data compared with those derived from the SEF data may be related to computational and physiologic delays.

Polymorphism of μ-Opioid Receptor Gene (OPRM1:c.118A>G ) Does Not Protect Against Opioid-induced Respiratory Depression despite Reduced Analgesic Response

Background:The effect of a single nucleotide polymorphism of the &mgr;-opioid receptor at nucleotide position 118 (OPRM1:c.118A>G) was investigated on morphine-6-glucuronide (M6G)–induced analgesia and respiratory depression in a group of healthy volunteers. Methods:Sixteen subjects of either sex received 0.4 mg/kg (n = 8) or 0.6 mg/kg M6G (n = 8). At regular time intervals, the isocapnic acute hypoxic ventilatory response, pain tolerance (derived from a transcutaneous electrical acute pain model), and arterial blood samples were obtained. Data acquisition continued for 14 h after drug infusion. Population pharmacokinetic–pharmacodynamic sigmoid Emax models were applied to the respiratory and pain data. All collected data were analyzed using the statistical program NONMEM (San Francisco, CA). Results:Four of the subjects were OPRM1:c.118GA heterozygotes, and the remainder of the subjects were OPRM1:c.118AA homozygotes. M6G analgesia: In contrast to analgesic responses in OPRM1:c.118AA homozygotes, responses were small and inconsistent in OPRM1:c.118GA heterozygotes and best described by the function Effect(t) = baseline (P < 0.01 vs. OPRM1:c.118AA homozygotes). Emax and C50 values in heterozygotes equaled 0.55 ± 0.18 (or a 55% increase in current above baseline) and 161 ± 42 ng/ml, respectively. M6G-induced respiratory depression: For the acute hypoxic response, neither Emax nor C50 (value = 282 ± 72 ng/ml) differed between genotypes. Conclusions:The data indicate that the OPRM1:c.118A>G polymorphism affects opioid analgesic and respiratory effects differentially. Despite reduced analgesic responses to M6G the OPRM1:c.118A>G single-nucleotide polymorphism does not protect against the toxic effects of the tested opioid. However, some caution in the interpretation of the data is needed because of the small sample size. Further studies are needed to explore the link between this polymorphism and respiratory/analgesic responses beyond the small human sample. In OPRM1:c.118AA homozygotes, the potency parameters differed by a factor of 2 for analgesic versus respiratory effect. In this respect, M6G differs favorably from morphine.

Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: Absence of sex differences

BackgroundMorphine-6-glucuronide (M6G) is a metabolite of morphine and a &mgr;-opioid agonist. To quantify the potency and speed of onset-offset of M6G and explore putative sex dependency, the authors studied the pharmacokinetics and pharmacodynamics of M6G in volunteers using a placebo-controlled, randomized, double-blind study design. MethodsTen men and 10 women received 0.3 mg/kg intravenous M6G and placebo (two thirds of the dose as bolus, one third as a continuous infusion over 1 h) on separate occasions. For 7 h, pain tolerance was measured using gradually increasing transcutaneous electrical stimulation, and blood samples were obtained. A population pharmacokinetic (inhibitory sigmoid Emax)–pharmacodynamic analysis was used to analyze M6G-induced changes in tolerated stimulus intensity. The improvement in model fits by inclusion of covariate sex was tested for significance. P values less than 0.01 were considered significant. Taking into account previous morphine data, a predictive pharmacokinetic-pharmacodynamic model was constructed to determine the contribution of M6G to morphine analgesia. ResultsM6G concentrations did not differ between men and women. M6G caused analgesia significantly greater than that observed with placebo (P < 0.01). The M6G analgesia data were well described by the pharmacokinetic-pharmacodynamic model. The M6G effect site concentration causing a 25% increase in current (C25) was 275 ± 135 nm (population estimate ± SE), the blood effect site equilibration half-life was 6.2 ± 3.3 h, and the steepness parameter was 0.71 ± 0.18. Intersubject variability was 167% for C25 and 218% for the effect half-life. None of the model parameters showed sex dependency. ConclusionsA cumulative dose of 0.3 mg/kg M6G, given over 1 h, produces long-term analgesia greater than that observed with placebo, with equal dynamics (potency and speed of onset–offset) in men and women. Possible causes for the great intersubject response variability, such as genetic polymorphism of the &mgr;-opioid receptor and placebo-related phenomena, are discussed. The predictive pharmacokinetic–pharmacodynamic model was applied successfully and was used to estimate M6G analgesia after morphine in patients with normal and impaired renal function.

Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index.

Background Since propofol and remifentanil are frequently combined for monitored anesthesia care, we examined the influence of the separate and combined administration of these agents on cardiorespiratory control and bispectral index in humans. Methods The effect of steady-state concentrations of remifentanil and propofol was assessed in 22 healthy male volunteer subjects. For each subject, measurements were obtained from experiments using remifentanil alone, propofol alone, and remifentanil plus propofol (measured arterial blood concentration range: propofol studies, 0–2.6 &mgr;g/ml; remifentanil studies, 0–2.0 ng/ml). Respiratory experiments consisted of ventilatory responses to three to eight increases in end-tidal Pco2 (Petco2). Invasive blood pressure, heart rate, and bispectral index were monitored concurrently. The nature of interaction was assessed by response surface modeling using a population approach with NONMEM. Values are population estimate plus or minus standard error. Results A total of 94 responses were obtained at various drug combinations. When given separately, remifentanil and propofol depressed cardiorespiratory variables in a dose-dependent fashion (resting &OV0312;i: 12.6 ± 3.3% and 27.7 ± 3.5% depression at 1 &mgr;g/ml propofol and 1 ng/ml remifentanil, respectively; &OV0312;i at fixed Petco2 of 55 mmHg: 44.3 ± 3.9% and 57.7 ± 3.5% depression at 1 &mgr;g/ml propofol and 1 ng/ml remifentanil, respectively; blood pressure: 9.9 ± 1.8% and 3.7 ± 1.1% depression at 1 &mgr;g/ml propofol and 1 ng/ml remifentanil, respectively). When given in combination, their effect on respiration was synergistic (greatest synergy observed for resting &OV0312;i). The effects of both drugs on heart rate and blood pressure were modest, with additive interactions when combined. Over the dose range studied, remifentanil had no effect on bispectral index even when combined with propofol (inert interaction). Conclusions These data show dose-dependent effects on respiration at relatively low concentrations of propofol and remifentanil. When combined, their effect on respiration is strikingly synergistic, resulting in severe respiratory depression.

Pharmacodynamic interaction between propofol and alfentanil when given for induction of anesthesia

Background Propofol and alfentanil often are combined during induction of anesthesia. However, the interaction between these agents during induction has not been studied in detail. The influence of alfentanil on the propofol concentration-effect relationships was studied for loss of eyelash reflex, loss of consciousness, and hemodynamic function in 20 un-premedicated ASA physical status 1 patients aged 20-55 yr. Methods Patients were randomly divided into four groups to receive a computer-controlled infusion of alfentanil with target concentrations of 0, 50, 200, or 400 ng/ml (groups A, B, C, and D, respectively). While the target concentration of alfentanil was maintained constant, patients received a computer-controlled infusion of propofol, with an initial target concentration of 0.5-1 micro gram/ml, that was increased every 12 min by 0.5-1 micro gram/ml. Every 3 min, the eyelash reflex and state of consciousness were tested and an arterial blood sample was taken for blood propofol and plasma alfentanil determination. The propofol-affentanil concentration-response relationships for loss of eyelash reflex and loss of consciousness were determined by nonlinear regression, and for the percentage of change in systolic blood pressure and heart rate by logistic regression. Results The patient characteristics did not differ significantly among the four groups. The patients in groups A and B continued to breathe adequately, whereas all patients in groups C and D required assisted ventilation. End-tidal carbon dioxide partial pressure remained less than 46 mmHg in all patients. With plasma alfentanil concentrations increasing from 0 to 500 ng/ml, the EC50 of propofol decreased from 2.07 to 0.83 micro gram/ml for loss of eyelash reflex and from 3.62 to 1.55 micro gram/ml for loss of consciousness. With plasma alfentanil concentrations increasing from 0 to 500 ng/ml, the blood propofol concentrations associated with a 10% decrease in systolic blood pressure and heart rate decreased from 1.68 to 0.17 micro gram/ml and from 2.36 to 0.04 micro gram/ml, respectively. Conclusions Alfentanil significantly reduces blood propofol concentrations required for loss of eyelash reflex and loss of consciousness. In addition, alfentanil enhances the depressant effects of propofol on systolic blood pressure and heart rate. Hemodynamic stability, therefore, does not increase in patients receiving propofol in combination with alfentanil compared to those receiving propofol as the sole agent for induction of anesthesia.

Pharmacodynamic Effect of Morphine-6-glucuronide versus Morphine on Hypoxic and Hypercapnic Breathing in Healthy Volunteers

Background Morphine-6-glucuronide (M6G) is an active metabolite of morphine that is generally associated with less respiratory depression than morphine. Because M6G will be on the market in the near future, the authors assessed the time profile and relative potency of M6Gs effect versus morphines effect on carbon dioxide–driven and hypoxic breathing. Methods In nine healthy female volunteers, the effects of 0.2 mg/kg intravenous M6G, 0.13 mg/kg intravenous morphine, and intravenous placebo were tested on ventilation at a fixed end-tidal pressure of carbon dioxide (Petco2) of 45 mmHg (Vi45) and on the acute hypoxic ventilatory response (AHR). All subjects participated in all three arms of the study. Respiratory studies were performed at 1-h intervals for 7 h after drug infusion. The data were analyzed using a population dose-driven approach, which uses a dose rate in function of time as input function driving the pharmacodynamics, and a population pharmacokinetic–pharmacodynamic (PK/PD) approach in which fixed pharmacokinetic parameter values from the literature were used as input function to the respiratory model. From the latter analysis, the authors obtained the blood effect-site equilibration half-life (t1/2ke0) and the effect-site concentration producing 25% depression of Vi45 and AHR (C25). Values reported are mean ± SE. Results Placebo had no effect on Vi45 or AHR over time. Both analysis approaches yielded good descriptions of the data with comparable model parameters. M6G PK/PD model parameters for Vi45 were t1/2ke0 2.1 ± 0.2 h and C25 528 ± 88 nm and for AHR were t1/2ke0 1.0 ± 0.1 h and C25 873 ± 81 nm. Morphine PK/PD model parameters for Vi45 were t1/2ke0 3.8 ± 0.9 h and C25 28 ± 6 nm and for AHR were t1/2ke0 4.3 ± 0.6 h and C25 16 ± 2 nm. Conclusions Morphine is more potent in affecting hypoxic ventilatory control than M6G, with a potency ratio ranging from 1:19 for Vi45 to 1:50 for AHR. At drug concentrations causing 25% depression of Vi45, M6G caused only 15% depression of AHR, whereas morphine caused greater than 50% depression of AHR. Furthermore, the speed of onset/offset of M6G is faster than morphine by a factor of approximately 2. The authors discuss some of the possible mechanisms for the observed differences in opioid behavior.

Mixed-model regression analysis and dealing with interindividual differences.

Publisher Summary This chapter considers mixed-model regression analysis, which is a specific technique for analyzing longitudinal data that properly deals with within- and between-subjects variance. The term ‘‘mixed model’’ refers to the inclusion of both fixed effects, which are model components used to define systematic relationships such as overall changes over time and/ or experimentally induced group differences; and random effects, which account for variability among subjects around the systematic relationships captured by the fixed effects. To illustrate how the mixed-model regression approach can help analyze longitudinal data with large inter-individual differences, the psychomotor vigilance data is considered from an experiment involving 88 h of total sleep deprivation, during which subjects received either sustained low-dose caffeine or placebo. The traditional repeated-measures analysis of variance (ANOVA) is applied, and it is shown that that this method is not robust against systematic interindividual variability. The data are then reanalyzed using linear mixed-model regression analysis in order to properly take into account the interindividual differences. The study concludes with an application of nonlinear mixed-model regression analysis of the data at hand, to demonstrate the considerable potential of this relatively novel statistical approach.