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


METHODS
Young 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).


RESULTS
The 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.


CONCLUSIONS
These 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.
Sarton
E
E
Departments of Anesthesiology, Clinical Pharmacy and Toxicology, and Physiology, Leiden University Medical Center, Leiden, The Netherlands.
Olofsen
E
E
Romberg
R
R
den Hartigh
J
J
Kest
B
B
Nieuwenhuijs
D
D
Burm
A
A
Teppema
L
L
Dahan
A
A
D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D009022:Morphine Derivatives / Q000097:blood; D017288:Pain Threshold / Q000187:drug effects*; D011446:Prospective Studies; D012737:Sex Factors
D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; C018108:morphine-3-glucuronide