Elise Sarton

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.

Melanocortin-1 receptor gene variants affect pain and μ-opioid analgesia in mice and humans

Background: A recent genetic study in mice and humans revealed the modulatory effect of MC1R (melanocortin-1 receptor) gene variants on κ-opioid receptor mediated analgesia. It is unclear whether this gene affects basal pain sensitivity or the efficacy of analgesics acting at the more clinically relevant μ-opioid receptor. Objective: To characterise sensitivity to pain and μ-opioid analgesia in mice and humans with non-functional melanocortin-1 receptors. Methods: Comparisons of spontaneous mutant C57BL/6-Mc1re/e mice to C57BL/6 wildtype mice, followed by a gene dosage study of pain and morphine-6-glucuronide (M6G) analgesia in humans with MC1R variants. Results: C57BL/6-Mc1re/e mutant mice and human redheads—both with non-functional MC1Rs—display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to the μ-opioid selective morphine metabolite, M6G. In both species the differential analgesia is likely due to pharmacodynamic factors, as plasma levels of M6G are similar across genotype. Conclusions: Genotype at MC1R similarly affects pain sensitivity and M6G analgesia in mice and humans. These findings confirm the utility of cross species translational strategies in pharmacogenetics.

Gender differences in opioid-mediated analgesia: animal and human studies.

EXOGENOUSLY administered opioids display marked interindividual differences with respect to their intended (analgesia) and unwanted (e.g., respiratory depression, nausea and vomiting) pharmacologic effects. In addition to the well-documented effects of age or development and genetic background, the contribution of gender and hormonal status as factors in opioid potency is becoming increasingly appreciated. We review recent findings on the interaction of sex and opioid analgesic potency and discuss possible mechanisms. Although most of the literature on sex differences in opioid analgesia comes from work with rodents, the available human data also indicate the presence of sex differences. Because opioids exert their analgesic effects through m-, d-, and k-opioid receptor (OR) subtypes, each with a unique pharmacology and role in pain control, each OR subtype is considered separately. In general, progress in the area has been slow. This may reflect the overwhelming use of male subjects to circumvent controlling for estrous or menstrual status or the failure of some researchers to examine their data for sex differences. The lack of consistent sex differences in opioid analgesia may reflect differences in the methodology (e.g., species, strain and age of subjects, particular nociceptive assay employed, quantification of analgesia) employed by each laboratory. It is beyond the scope of this paper to detail comprehensive methodologic details of all the reports cited in this article. We provide details of some studies in which apparently contradictory or complimentary findings necessitate elaboration. Nonetheless, findings from the increasing number of wellcontrolled animal and human studies directly examining the issue of sex in the potency of opioids show that patient sex may impact on the clinical efficacy of opioids for pain.

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.

Sex-related Differences in the Influence of Morphine on Ventilatory Control in Humans

Background Opiate agonists have different analgesic effects in male and female patients. The authors describe the influence of sex on the respiratory pharmacology of the micro‐receptor agonist morphine. Methods The study was placebo‐controlled, double‐blind, and randomized. Steady‐state ventilatory responses to carbon dioxide and responses to a step into hypoxia (duration, 3 min; oxygen saturation, [approximately] 82%; end‐tidal carbon dioxide tension, 45 mmHg) were obtained before and during intravenous morphine or placebo administration (bolus dose of 100 micro gram/kg, followed by a continuous infusion of 30 micro gram [center dot] kg sup ‐1 [center dot] h sup ‐1) in 12 men and 12 women. Results In women, morphine reduced the slope of the ventilatory response to carbon dioxide from 1.8 +/‐ 0.9 to 1.3 +/‐ 0.7 l [center dot] min sup ‐1 [center dot] mmHg sup ‐1 (mean +/‐ SD; P < 0.05), whereas in men there was no significant effect (control = 2.0 +/‐ 0.4 vs. morphine = 1.8 +/‐ 0.4 l [center dot] min sup ‐1 [center dot] mmHg sup ‐1). Morphine had no effect on the apneic threshold in women (control = 33.8 +/‐ 3.8 vs. morphine = 35.3 +/‐ 5.3 mmHg), but caused an increase in men from 34.5 +/‐ 2.3 to 38.3 +/‐ 3 mmHg, P < 0.05). Morphine decreased hypoxic sensitivity in women from 1.0 +/‐ 0.5 l [center dot] min sup ‐1 [center dot] % sup ‐1 to 0.5 +/‐ 0.4 l [center dot] min sup ‐1 [center dot] % sup ‐1 (P < 0.05) but did not cause a decrease in men (control = 1.0 +/‐ 0.5 l [center dot] min sup ‐1 [center dot] % sup ‐1 vs. morphine = 0.9 +/‐ 0.5 l [center dot] min sup ‐1 [center dot] % sup ‐1). Weight, lean body mass, body surface area, and calculated fat mass differed between the sexes, but their inclusion in the analysis as a covariate revealed no influence on the differences between men and women in morphine‐induced changes. Conclusions In both sexes, morphine affects ventilatory control. However, we observed quantitative and qualitative differences between men and women in the way morphine affected the ventilatory responses to carbon dioxide and oxygen. Possible mechanisms for the observed sex differences in the respiratory pharmacology of morphine are discussed.

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.

Sex-Specific Responses to Opiates : Animal and Human Studies

It is widely reported that analgesic drugs acting at &mgr;, &kgr;, and &dgr; opioid-receptors display quantitative and qualitative differences in effect in males and females. These sex-related differences are not restricted to the analgesic/antinociceptive properties of opioids, but are also present in opioid-induced side effects, such as changes in respiration, locomotor activity, learning/memory, addiction, and changes in the cardiovascular system. An increasing number of well-controlled animal and human studies directly examining the issue of sex in the potency of opioids show that, although sex may affect opioid analgesia, the direction and magnitude of sex differences depend on many interacting variables. These include those specific to the drug itself, such as dose, pharmacology, and route and time of administration, and those particular to the subject, such as species, type of pain, genetics, age, and gonadal/hormonal status. In the current review, we systematically present these animal and human studies and discuss the data in relation to the depending variables. Although the observed sex differences in opioid effect may be clinically relevant, lack of knowledge on other factors involved in the large variability in patient opioid analgesic sensitivity should compel practitioners to customize their dosing regimens based on individual requirements.

Sex Differences in Morphine-induced Ventilatory Depression Reside within the Peripheral Chemoreflex Loop

This study gathers information in humans on the sites of sex-related differences in ventilatory depression caused by the [micro sign]-opioid receptor agonist morphine. Experiments were performed in healthy young men (n = 9) and women (n = 7). Dynamic ventilatory responses to square-wave changes in end-tidal carbon dioxide tension (7.5–15 mmHg) and step decreases in end-tidal oxygen tension (step from 110 to 50 mmHg, duration of hypoxia 15 min) were obtained before and during morphine infusion (intravenous bolus dose 100 [micro sign]g/kg, followed by 30 [micro sign]g [middle dot] kg-1 [middle dot] h-1). Each hypercapnic response was separated into a fast peripheral and slow central component, which yield central (Gc) and peripheral (Gp) carbon dioxide sensitivities. Values are mean +/- SD. In carbon dioxide studies in men, morphine reduced Gc from 1.61 +/- 0.33 to 1.23 +/- 0.12 l [middle dot] mmHg-1 (P < 0.05) without affecting Gp (control, 0.41 +/- 0.16 and morphine, 0.49 +/- 0.12 l [middle dot] [middle dot] min-1 [middle dot] mmHg-1, not significant). In carbon dioxide studies in women, morphine reduced Gc, from 1.51 +/- 0.74 to 1.17 +/- 0.52 l [middle dot] min-1 [middle dot] mmHg-1 (P < 0.05), and Gp, from 0.54 +/- 0.19 to 0.39 +/- 0.22 l [middle dot] min-1 [middle dot] mmHg-1 (P < 0.05). Morphine-induced changes in Gc were equal in men and women; changes in Gp were greater in women. In hypoxic studies, morphine depressed the hyperventilatory response at the initiation of hypoxia more in women than in men (0.54 +/- 0.23 vs. 0.26 +/- 0.34 l [middle dot] min-1 [middle dot] %-1, respectively; P < 0.05). The ventilatory response to sustained hypoxia (i.e., 15 min) did not differ between men and women. The data indicate the existence of sex differences in morphine-induced depression of responses mediated via the peripheral chemoreflex pathway, with more depression in women, but not of responses mediated via the central chemoreflex pathway. In men and women, morphine did not change the translation of the initial hyperventilatory response to short-term hypoxia into the secondary decrease in inspired minute ventilation (Vi) caused by sustained hypoxia.

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.