Sex differences in opioid analgesia
A Literature Review
Analgesics can be divided into opioid and non-opioid medications. Opioids functionally mimic
endorphins and enkephalins; opiate-like neuropeptides that are naturally present in the body.
These drugs exert their analgesic effect by binding to specialized opiate receptors in cells
located mainly in the brain and spinal cord, hence blocking the transmission of pain signals
(British Medical Association 2012). Opioids are usually divided into two main groups, mu-
agonists and k-agonist-antagonists, based on the predominant receptor subtype that
mediates their analgesic effects (Fillingim & Gear 2004, p.414). Research evidence suggest
that there are marked sex differences not only in pain perception, but in sensitivity to
analgesic agents. The present review aims to provide an overview of sex-based differences in
mu- and kappa-opioid analgesia reported by animal and human studies, and to describe some
of the mechanisms thought to underlie these differences.
1.Sex differences in mu-opioid analgesia
The majority of studies conducted with non-human animals reported that mu-opioid
analgesics provide greater pain relief in males compared with females (Cicero, Nock & Meyer,
1996; Wang, Traub & Murphy, 2006). This sex difference might be attributed to the fact that
an essential neural circuit for opioid analgesia, the midbrain periaqueductal gray (PAG) with
its descending projections to the rostral ventromedial medulla, has been found to be sexually
dimorphic both anatomically and functionally in rats (Loyd & Murphy 2006). Additionally,
Loyd, Wang and Murphy (2008) found that opioid receptor density varied between the sexes,
with males having significantly higher levels of mu-opioid receptors in the ventrolateral PAG
relative to females. However, it must be noted that the analgesic potency of some opioids
differed between subpopulations of a single species, which suggests that the documented sex
differences in opioid-induced pain relief might partly be genotype-dependent (Kest, Wilson,
& Mogil 1999). (More on rat/ mice strains in section 3a).
In contrast, most laboratory studies conducted with humans revealed the opposite trend,
although the results were notably less consistent. Sarton et al. (2000) investigated sex
differences in morphine-induced antinociception on experimentally- induced pain in healthy
1
, human volunteers and found the drug to be more effective and potent in women relative to
men. The researchers proposed that the discrepancy between their findings and those of non-
human animal studies quite possibly results from species differences. They also noted that
the analgesic effect of morphine had slower onset and offset in the female participants, a
finding which led to the speculation that the origin of human sex differences in morphine
analgesia are possibly pharmacodynamic in nature. Considering that times of onset of opioid
analgesics differ in human males and females, the time at which the analgesic effects of
opioids are tested can greatly influence the outcomes of a given study. As Bodnar and Kest
(2010, p. 78) suggested, studies assessing opioid potency only in immediate postoperative
hours would quite possibly yield different results from studies, in which opioid analgesia is
studied over a more extended period of time.
Zacny (2002) used two experimental pain models to investigate human sex differences in
analgesia to three mu-opioids; morphine, hydromorphone and pethidine. Women
experienced greater analgesia for cold pressor pain across all 3 drugs; however, no sex
difference in analgesic responses emerged for pressure pain. These findings strongly suggest
that the analgesic efficacy of mu-opioids between sexes can vary depending on the type of
pain stimuli utilized. Additionally, sex-based analgesic outcomes depend on the specific mu-
opioid drug tested. Researchers failed to report apparent human sex differences in analgesia
induced by alfentanil (Olofsen et al. 2005) and morphine-6-glucuronide (M6G) (Romberg et
al. 2004).
Interestingly, several human studies utilizing clinical pain models paralleled the findings of
non-human animal studies. Cepeda et al. (2003) reported that women experienced greater
post-surgical pain and required 0.03 mg/ kg (about 30%) more morphine than men to achieve
similar level of analgesia. Moreover, Aubrun et al. (2005) also found that female patients
required 0.019 mg/ kg, that is about 11%, more morphine than males to manage
postoperative pain. However, the researchers noted that this sex difference was not evident
in elderly participants, which seem to suggest that there is a link between sex hormones and
sensitivity to morphine analgesia. (More on gonadal hormones in section 3b).
2
A Literature Review
Analgesics can be divided into opioid and non-opioid medications. Opioids functionally mimic
endorphins and enkephalins; opiate-like neuropeptides that are naturally present in the body.
These drugs exert their analgesic effect by binding to specialized opiate receptors in cells
located mainly in the brain and spinal cord, hence blocking the transmission of pain signals
(British Medical Association 2012). Opioids are usually divided into two main groups, mu-
agonists and k-agonist-antagonists, based on the predominant receptor subtype that
mediates their analgesic effects (Fillingim & Gear 2004, p.414). Research evidence suggest
that there are marked sex differences not only in pain perception, but in sensitivity to
analgesic agents. The present review aims to provide an overview of sex-based differences in
mu- and kappa-opioid analgesia reported by animal and human studies, and to describe some
of the mechanisms thought to underlie these differences.
1.Sex differences in mu-opioid analgesia
The majority of studies conducted with non-human animals reported that mu-opioid
analgesics provide greater pain relief in males compared with females (Cicero, Nock & Meyer,
1996; Wang, Traub & Murphy, 2006). This sex difference might be attributed to the fact that
an essential neural circuit for opioid analgesia, the midbrain periaqueductal gray (PAG) with
its descending projections to the rostral ventromedial medulla, has been found to be sexually
dimorphic both anatomically and functionally in rats (Loyd & Murphy 2006). Additionally,
Loyd, Wang and Murphy (2008) found that opioid receptor density varied between the sexes,
with males having significantly higher levels of mu-opioid receptors in the ventrolateral PAG
relative to females. However, it must be noted that the analgesic potency of some opioids
differed between subpopulations of a single species, which suggests that the documented sex
differences in opioid-induced pain relief might partly be genotype-dependent (Kest, Wilson,
& Mogil 1999). (More on rat/ mice strains in section 3a).
In contrast, most laboratory studies conducted with humans revealed the opposite trend,
although the results were notably less consistent. Sarton et al. (2000) investigated sex
differences in morphine-induced antinociception on experimentally- induced pain in healthy
1
, human volunteers and found the drug to be more effective and potent in women relative to
men. The researchers proposed that the discrepancy between their findings and those of non-
human animal studies quite possibly results from species differences. They also noted that
the analgesic effect of morphine had slower onset and offset in the female participants, a
finding which led to the speculation that the origin of human sex differences in morphine
analgesia are possibly pharmacodynamic in nature. Considering that times of onset of opioid
analgesics differ in human males and females, the time at which the analgesic effects of
opioids are tested can greatly influence the outcomes of a given study. As Bodnar and Kest
(2010, p. 78) suggested, studies assessing opioid potency only in immediate postoperative
hours would quite possibly yield different results from studies, in which opioid analgesia is
studied over a more extended period of time.
Zacny (2002) used two experimental pain models to investigate human sex differences in
analgesia to three mu-opioids; morphine, hydromorphone and pethidine. Women
experienced greater analgesia for cold pressor pain across all 3 drugs; however, no sex
difference in analgesic responses emerged for pressure pain. These findings strongly suggest
that the analgesic efficacy of mu-opioids between sexes can vary depending on the type of
pain stimuli utilized. Additionally, sex-based analgesic outcomes depend on the specific mu-
opioid drug tested. Researchers failed to report apparent human sex differences in analgesia
induced by alfentanil (Olofsen et al. 2005) and morphine-6-glucuronide (M6G) (Romberg et
al. 2004).
Interestingly, several human studies utilizing clinical pain models paralleled the findings of
non-human animal studies. Cepeda et al. (2003) reported that women experienced greater
post-surgical pain and required 0.03 mg/ kg (about 30%) more morphine than men to achieve
similar level of analgesia. Moreover, Aubrun et al. (2005) also found that female patients
required 0.019 mg/ kg, that is about 11%, more morphine than males to manage
postoperative pain. However, the researchers noted that this sex difference was not evident
in elderly participants, which seem to suggest that there is a link between sex hormones and
sensitivity to morphine analgesia. (More on gonadal hormones in section 3b).
2
