Acta Anaesthesiol Scand 2010; 54: 129–131
Printed in Singapore. All rights reserved
Can central antiemetic effects of opioids counter-balance
opioid-induced nausea and vomiting?
C. C. APFEL and L. JALOTA
Perioperative Clinical Research Core, Department of Anesthesia, UCSF Medical Center at Mt. Zion, University of California San Francisco,
San Francisco, CA
D ESPITEsignificant advances in our understand-
ing of post-operative nausea and vomiting
(PONV) as outlined in the landmark review from
Watcha and White, the incidence is still estimated
to be between 25% and 30%.1,2 And, based on
multivariate analyses of large prospective cohort
studies, we now know that PONV is mainly trig-
gered by inhalational anesthetics and opioids.3,4
Although not widely recognized, serotonin antago-
nists are quite effective in reducing opioid-induced
nausea and vomiting (OINV),5,6 but it is even less
known that opioids have antiemetic properties,
which is the focus of the comprehensive review
by Johnston7 in this issue.
Opioid receptors have been found in the chemo-
receptor trigger zone (CRTZ) on the floor of the
fourth ventricle and in the vomiting center that is
located within the nucleus tractus solitarius (NTS)
in the brain stem.8 Because of the fenestrated
structure of the capillaries in the CRTZ, it is
functionally outside the blood–brain barrier and
therefore physiologically peripheral. At low doses,
opioids have consistently been shown to be emeto-
genic. This effect is achieved through opioid sti-
mulation of the CRTZ because ablating its
connection to the vomiting center in the NTS
eliminates emesis.9 Interestingly, increased opioid
receptor stimulation in the vomiting center located
in the NTS, which may be achieved through higher
doses of morphine or moderate doses of the more
lipophilic fentanyl, will eventually eliminate emesis,
leading to a bell-shaped dose–response curve.8,9
Furthermore, the antiemetic effect of fentanyl to
inhibit morphine-, apomorphine-, copper sulfate-,
and cisplatin-induced emesis can be reversed with
naloxone,8 as well as with a more selective m2 opioid
r 2010 The Authors
Journal compilation r 2010 The Acta Anaesthesiologica Scandinavica Foundation
ACTA ANAESTHESIOLOGICA SCANDINAVICA
doi: 10.1111/j.1399-6576.2009.02133.x
Editorial
receptor antagonist, which suggests that the antie-
metic effects may primarily be mediated through
central m2 opioid receptors.10 The ability of opioids
to affect involuntary processes regulated by the
brain stem is not entirely unfamiliar, given that
opioids are known to suppress the respiratory
system in the NTS.11 For this reason, Johnston’s
review in this issue hypothesized that stimulation of
m1 receptors of the CRTZ outside the blood–brain
barrier is emetogenic, while stimulation of m2 re-
ceptors of the vomiting center inside the blood
barrier is antiemetic, which can lead to a bell-
shaped dose–response curve as reported by Barnes
et al.8 (Fig. 1). As a result, lipophilic opioids such as
fentanyl, which cross the blood–brain barrier faster
than more hydrophilic opioids such as morphine,
might therefore have greater antiemetic potential to
counteract the peripheral emetogenic effects.7 OINV
may thus be a function of the lipophilicity of the
type of opioid used in clinical practice.
However, the functional domains of m1 and m2
opioid receptors may not be mutually exclusive to
either the central vs. peripheral nervous systems or
outside vs. inside the blood–brain barrier. For
example, Foss et al.12 demonstrated that m1 recep-
tors mediate supraspinal (i.e., central) analgesia
and Spampinato et al.13 found m2 receptors in the
periphery to be capable of causing antinociception
and inhibiting gastrointestinal transit. Neverthe-
less, it still remains uncertain whether the conclu-
sions drawn from animal studies about the location
and function of the two different m-receptor sub-
types can be extended to humans.
Furthermore, alvimopan, a peripherally acting
opioid antagonist, not only accelerates GI recovery
but may also reduce OINV, which supports the
129
Editorial
6 "central" inhibition of
"periperal" stimulation the vomiting center at
of the CRTZ at the
area postrema
5
4 approach. The interested reader is thus encouraged
Number of Vomits
3 potential that may shape our future practice.
1
0 Its etiology, treatment, and prevention. Anesthesiology
0.025 0.125 0.25 0.5
Morphine (mg/kg)
Fig. 1. Average number of vomits per individual and dose with
standard errors of the mean. CRTZ, chemo-receptor trigger zone,
NTS, nucleus tractus solitarius. Modified after Barnes et al.8 by
Elizabeth George and Samuel Paran Yap.
notion that peripheral opioid receptors (in the
CRTZ or in the gastrointestinal system) may play
an emetogenic role. This is consistent with Foss
et al.,12 who discovered the antiemetic properties of
morphine when given with methylnaltrexone in
dogs. However, the clinical utility of the central
antiemetic effects of opioids is not as clearly de-
fined. Firstly, despite being more lipophilic than
morphine, piritramid is not associated with a lower
incidence of OINV.14 Secondly, while hydromor-
phone has a faster onset and is more lipophilic than
morphine, it is still associated with comparable
incidences of nausea and vomiting.15 Thirdly, one
study described morphine-6-glucuronide, a more
hydrophilic metabolite of morphine, less emeto-
genic than morphine itself.16 Finally, if stimulation
of peripheral m-receptors is emetogenic and central
m-receptors inhibit emesis, why do intrathecal
opioids increase the incidence of nausea and vo-
miting?17,18
Because it remains to be determined whether m1
receptors are found only peripherally and m2 re-
ceptors only centrally, and the clinical data to
support the hypothesis that more lipophilic opioids
may be less emetogenic are equivocal, a quantita-
tive systematic review and meta-analysis may be
needed to shed more light on this exciting and
promising topic. If the hypothesis of Johnston’s
130
review can be confirmed in such a systematic
review and/or by future clinical trials, the allure
the NTS
of reducing the risk of PONV by selectively admin-
istering certain types of opioids or combining these
with antagonists may become a valuable clinical
to consult the intriguing review by Johnston to gain
a more comprehensive understanding of its clinical
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