MEDICAL INTELLIGENCE ARTICLE
Dennis M. Fisher, M.D., Editor
Anesthesiology
2000; 93:539 – 47
© 2000 American Society of Anesthesiologists, Inc.
Lippincott Williams & Wilkins, Inc.
Gender Differences in Opioid-mediated Analgesia
Animal and Human Studies
Benjamin Kest, Ph.D.,* Elise Sarton, M.D.,† Albert Dahan, M.D., Ph.D.‡
EXOGENOUSLY administered opioids display marked in-
terindividual 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 lit-
erature on sex differences in opioid analgesia comes
from work with rodents, the available human data also
indicate the presence of sex differences. Because opi-
oids exert their analgesic effects through -, -, and
-opioid receptor (OR) subtypes, each with a unique
pharmacology and role in pain control,
1
each OR sub-
type 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 method-
ology (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. None-
theless, findings from the increasing number of well-
controlled 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.
Animal Studies
-Opioid Receptor Agonists
In rats and mice, the majority of studies report that the
potency (i.e., ED
50
values) and efficacy (i.e., drug-in-
duced increase in pain response latency) of morphine
administered systemically are higher in male than in
female animals
2–13
(table 1). The enhanced sensitivity to
morphine analgesia displayed by male animals has been
documented with several pain assays, including those
assessing thermal (hot-plate tests
2,6,9,10,13
), somatic (tail-
flick–withdrawal tests
2,3,5,14
), chemical (abdominal
writhing after acetic acid
2
), visceral (hypertonic saline
4
),
and electric shock (jump test
14
) nociception. Studies
utilizing central routes of administration suggest that sex
differences in opioid analgesia are probably mediated, at
* Assistant Professor, Department of Psychology, The College of
Staten Island—City University of New York.
† Resident, Department of Anesthesiology, Leiden University Medi-
cal Center.
‡ Associate Professor, Department of Anesthesiology, Leiden Univer-
sity Medical Center.
Received from Department of Psychology, The College of Staten
Island—City University of New York, Staten Island, New York; and
Department of Anesthesiology, Leiden University Medical Center, Lei-
den, The Netherlands. Submitted for publication August 26, 1999.
Accepted for publication March 23, 2000. Supported solely by institu-
tional and/or departmental sources.
Address reprint requests to Dr. Kest: Department of Psychology
(4S-223), The College of Staten Island—City University of New York,
Staten Island, New York 10314. Address electronic mail to:
kest@postbox.csi.cuny.edu
Individual article reprints may be purchased through the Journal
Web site, www.anesthesiology.org
Key words: Antinociception; gender; hormones; morphine; pain.
539
Anesthesiology, V 93, No 2, Aug 2000
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