Raymonda Romberg

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.

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 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.

Naloxone Reversal of Buprenorphine-induced Respiratory Depression

Background:The objective of this investigation was to examine the ability of the opioid antagonist naloxone to reverse respiratory depression produced by the &mgr;-opioid analgesic, buprenorphine, in healthy volunteers. The studies were designed in light of the claims that buprenorphine is relatively resistant to the effects of naloxone. Methods:In a first attempt, the effect of an intravenous bolus dose of 0.8 mg naloxone was assessed on 0.2 mg buprenorphine–induced respiratory depression. Next, the effect of increasing naloxone doses (0.5–7 mg, given over 30 min) on 0.2 mg buprenorphine–induced respiratory depression was tested. Subsequently, continuous naloxone infusions were applied to reverse respiratory depression from 0.2 and 0.4 mg buprenorphine. All doses are per 70 kg. Respiration was measured against a background of constant increased end-tidal carbon dioxide concentration. Results:An intravenous naloxone dose of 0.8 mg had no effect on respiratory depression from buprenorphine. Increasing doses of naloxone given over 30 min produced full reversal of buprenorphine effect in the dose range of 2–4 mg naloxone. Further increasing the naloxone dose (doses of 5 mg or greater) caused a decline in reversal activity. Naloxone bolus doses of 2–3 mg, followed by a continuous infusion of 4 mg/h, caused full reversal within 40–60 min of both 0.2 and 0.4 mg buprenorphine–induced respiratory depression. Conclusions:Reversal of buprenorphine effect is possible but depends on the buprenorphine dose and the correct naloxone dose window. Because respiratory depression from buprenorphine may outlast the effects of naloxone boluses or short infusions, a continuous infusion of naloxone may be required to maintain reversal of respiratory depression.

Simultaneous Measurement and Integrated Analysis of Analgesia and Respiration after an Intravenous Morphine Infusion

Background:To study the influence of morphine on chemical control of breathing relative to the analgesic properties of morphine, the authors quantified morphine-induced analgesia and respiratory depression in a single group of healthy volunteers. Both respiratory and pain measurements were performed over single 24-h time spans. Methods:Eight subjects (four men, four women) received a 90-s intravenous morphine infusion; eight others (four men, four women) received a 90-s placebo infusion. At regular time intervals, respiratory variables (breathing at a fixed end-tidal partial pressure of carbon dioxide of 50 mmHg and the isocapnic acute hypoxic response), pain tolerance (derived from a transcutaneous electrical acute pain model), and arterial blood samples were obtained. Data acquisition continued for 24 h. Population pharmacokinetic (sigmoid Emax)–pharmacodynamic models were applied to the respiratory and pain data. The models are characterized by potency parameters, shape parameters (&ggr;), and blood–effect site equilibration half-lives. All collected data were analyzed simultaneously using the statistical program NONMEM. Results:Placebo had no systematic effect on analgesic or respiratory variables. Morphine potency parameter and blood–effect site equilibration half-life did not differ significantly among the three measured effect parameters (P > 0.01). The integrated NONMEM analysis yielded a potency parameter of 32 ± 1.4 nm (typical value ± SE) and a blood–effect site equilibration half-life of 4.4 ± 0.3 h. Parameter &ggr; was 1 for hypercapnic and hypoxic breathing but 2.4 ± 0.7 for analgesia (P < 0.01). Conclusions:Our data indicate that systems involved in morphine-induced analgesia and respiratory depression share important pharmacodynamic characteristics. This suggests similarities in central &mgr;-opioid analgesic and respiratory pathways (e.g., similarities in &mgr;-opioid receptors and G proteins). The clinical implication of this study is that after morphine administration, despite lack of good pain relief, moderate to severe respiratory depression remains possible.

Alfentanil and placebo analgesia : No sex differences detected in models of experimental pain

Background:To assess whether patient sex contributes to the interindividual variability in alfentanil analgesic sensitivity, the authors compared male and female subjects for pain sensitivity after alfentanil using a pharmacokinetic–pharmacodynamic modeling approach. Methods:Healthy volunteers received a 30-min alfentanil or placebo infusion on two occasions. Analgesia was measured during the subsequent 6 h by assaying tolerance to transcutaneous electrical stimulation (eight men and eight women) of increasing intensity or using visual analog scale scores during treatment with noxious thermal heat (five men and five women). Sedation was concomitantly measured. Population pharmacokinetic–pharmacodynamic models were applied to the analgesia and sedation data using NONMEM. For electrical pain, the placebo and alfentanil models were combined post hoc. Results:Alfentanil and placebo analgesic responses did not differ between sexes. The placebo effect was successfully incorporated into the alfentanil pharmacokinetic–pharmacodynamic model and was responsible for 20% of the potency of alfentanil. However, the placebo effect did not contribute to the analgesic response variability. The pharmacokinetic–pharmacodynamic analysis of the electrical and heat pain data yielded similar values for the potency parameter, but the blood–effect site equilibration half-life was significantly longer for electrical pain (7–9 min) than for heat pain (0.2 min) or sedation (2 min). Conclusions:In contrast to the ample literature demonstrating sex differences in morphine analgesia, neither sex nor subject expectation (i.e., placebo) contributes to the large between-subject response variability with alfentanil analgesia. The difference in alfentanil analgesia onset and offset between pain tests is discussed.

Mechanism-based pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of buprenorphine in healthy volunteers.

Background:The objective of this investigation was to characterize the pharmacokinetic–pharmacodynamic relation of buprenorphine’s antinociceptive effect in healthy volunteers. Methods:Data on the time course of the antinociceptive effect after intravenous administration of 0.05–0.6 mg/70 kg buprenorphine in healthy volunteers was analyzed in conjunction with plasma concentrations by nonlinear mixed-effects analysis. Results:A three-compartment pharmacokinetic model best described the concentration time course. Four structurally different pharmacokinetic–pharmacodynamic models were evaluated for their appropriateness to describe the time course of buprenorphine’s antinociceptive effect: (1) Emax model with an effect compartment model, (2) “power” model with an effect compartment model, (3) receptor association–dissociation model with a linear transduction function, and (4) combined biophase equilibration/receptor association–dissociation model with a linear transduction function. The latter pharmacokinetic–pharmacodynamic model described the time course of effect best and was used to explain time dependencies in buprenorphine’s pharmacodynamics. The model converged, yielding precise estimation of the parameters characterizing hysteresis and the relation between relative receptor occupancy and antinociceptive effect. The rate constant describing biophase equilibration (keo) was 0.00447 min−1 (95% confidence interval, 0.00299–0.00595 min−1). The receptor dissociation rate constant (koff) was 0.0785 min−1 (95% confidence interval, 0.0352–0.122 min−1), and kon was 0.0631 ml · ng−1 · min−1 (95% confidence interval, 0.0390–0.0872 ml · ng−1 · min−1). Conclusion:This is consistent with observations in rats, suggesting that the rate-limiting step in the onset and offset of the antinociceptive effect is biophase distribution rather than slow receptor association–dissociation. In the dose range studied, no saturation of receptor occupancy occurred explaining the lack of a ceiling effect for antinociception.

Response Surface Modeling of Alfentanil-Sevoflurane Interaction on Cardiorespiratory Control and Bispectral Index

Background Respiratory depression is a serious side effect of anesthetics and opioids. The authors examined the influence of the combined administration of sevoflurane and alfentanil on ventilatory control, heart rate (HR), and Bispectral Index (BIS) in healthy volunteers. Methods Step decreases in end-tidal partial pressure of oxygen from normoxia into hypoxia (∼50 mmHg) at constant end-tidal partial pressure of carbon dioxide (∼48 mmHg) were performed in nine male volunteers at various concentrations of alfentanil and sevoflurane, ranging from 0 to 50 ng/ml for alfentanil and from 0 to 0.4 end-tidal concentration (ET%) for sevoflurane, and with various combinations of alfentanil and sevoflurane. The alfentanil–sevoflurane interactions on normoxic resting (hypercapnic) ventilation (&OV0312;i), HR, hypoxic &OV0312;i, and HR responses and BIS were assessed by construction of response surfaces that related alfentanil and sevoflurane to effect using a population analysis. Results Concentration–effect relations were linear for alfentanil and sevoflurane. Synergistic interactions were observed for resting &OV0312;i and resting HR. Depression of &OV0312;i by 25% occurred at 38 ± 11 ng/ml alfentanil (population mean ± SE) and at 0.7 ± 0.4 ET% sevoflurane. One possibility for 25% reduction when alfentanil and sevoflurane are combined is 13.4 ng/ml alfentanil plus 0.12 ET% sevoflurane. Additive interactions were observed for hypoxic &OV0312;i and HR responses and BIS. Depression of the hypoxic &OV0312;i response by 25% occurred at 16 ± 1 ng/ml alfentanil and 0.14 ± 0.05 ET% sevoflurane. The effect of sevoflurane on the BIS (25% reduction of BIS occurred at 0.45 ± 0.08 ET%) was independent of the alfentanil concentration. Conclusions Response surface modeling was used successfully to analyze the effect of interactions between two drugs on respiration. The combination of alfentanil and sevoflurane causes more depression of &OV0312;i and HR than does the summed effect of each drug administered separately. The effects of combining alfentanil and sevoflurane on hypoxic &OV0312;i and HR responses and BIS could be predicted from the separate dose–response curves. Over the dose range tested, the hypoxic response is more sensitive to the effects of anesthetics and opioids relative to resting ventilation.