ANESTHETIC PHARMACOLOGY

INTERNATIONAL SOCIETY

FOR

ANAESTHETIC PHARMACOLOGY

SECTION EDITOR
JAMES G. BOVILL

EDITORIAL

Opiate-Induced Nausea and Vomiting: What Is

the Challenge?
Martin Redmond,

MD

and Peter Glass,

MBChB

Department of Anesthesiology, SUNY at Stony Brook, Stony Brook, New York

ostoperative pain management is an everchanging and challenging conundrum.

The Agency for Healthcare Research and Quality

(previously known as the Agency for Health Care
Policy and Research) was created by Congress in 1989
was charged with the development of practice guidelines. In 1992, they released the publication Acute
Pain Management in Operative or Medical Procedures
and Trauma, which stated, Opioid analgesics are the
cornerstone of pharmacological postoperative pain
management, especially for more extensive surgical
procedures that cause moderate to severe pain. (1)
This was followed by the Joint Commission on Accreditation of Healthcare Organizations emphasis on
pain management and the recognition of pain as the
fifth vital sign. These aggressive efforts to enhance
postoperative pain management led to increasing opiate administration. Opioid use was further increased
by the availability of newer, simpler, and more effective drug delivery systems, including central neuraxial
administration, patient-controlled analgesia pumps,
drug patches, and slow release oral formulations. Although the practice of increasing opiate administration has resulted in more effective pain therapy and
patient satisfaction, it has also come at a price of
increased opiate side effects (2,3) including sedation,
respiratory depression, urinary retention, pruritus,
constipation, and nausea and vomiting. Certainly the
incidence and severity of sedation and respiratory
depression are dose-related phenomenon, but is the
incidence of these other adverse events dichotomous
(all or none), or are they also dose-dependent? This is
an important question because if these adverse events
occur independent of dose, then the many efforts to
Accepted for publication July 11, 2005.
Address correspondence to Peter S. Glass, MB.ChB., FFA (S.A.),
University Medical Center at Stony Brook, Department of Anesthesiology, Nicolls Rd - HSC Level 4, Rm 060, Stony Brook, NY 11794
8480. Address e-mail to Peter.Glass@stonybrook.edu.
DOI: 10.1213/01.ANE.0000181329.07214.D8
2005 by the International Anesthesia Research Society
0003-2999/05

provide opiate sparing have limited value. Unfortunately, although numerous studies have demonstrated that a variety of interventions or therapies can
result in opiate sparing, they are generally underpowered to demonstrate an improvement in outcomes (4).
Several recent articles have, at least in general, evaluated if opiate sparing reduces the incidence or severity of opiate side effects or what the authors have
termed clinically meaningful events (CMEs) (5,6).
This work resulted from the development of cyclooxygenase (COX)-2 analgesics for perioperative pain. In
the control group, the incidence of a CME and the
number of CMEs was related to the dose of opiate
analgesic administered. Interestingly, the authors also
found that below a morphine equivalent threshold of
approximately 10 mg, opiate-related symptoms did
not occur. In another study, Gan et al. (6) found after
a cholecystectomy and using the same symptom distress questionnaire that the opiate sparing produced
by the coadministration of a COX-2 similarly reduced
the incidence of CMEs proportional to the reduction in
opiate administration. The authors, however, were unable to discriminate the effect of dose on individual
adverse events produced by opiates. These studies
confirmed that opiate-related side effects, in general,
were reduced by decreasing opiate administration,
but they could not confirm if the incidence of specific
adverse events were decreased by reduced opiate administration. More recently, Marret et al. (7) performed a meta-analysis of studies investigating the
opiate-sparing effects of nonsteroidal antiinflammatory drugs (NSAIDs). By combining these studies,
they demonstrate that the approximately 30% opiatesparing effect that these drugs provided also resulted
in a decreased relative risk of nausea and vomiting.
More importantly, their analysis showed there was a
dose-response relationship between the amount of
opiate administered and the incidence of both nausea
and vomiting. They found a linear relationship, with
each reduction of 10 mg of morphine decreasing the
incidence of nausea by 9%. Being a retrospective metaanalysis, these data required verification by a prospective study.
Anesth Analg 2005;101:13412

1341

1342

EDITORIAL

In this issue of Anesthesia & Analgesia, Roberts et al.

(8) have confirmed, in a prospective study, that the
incidence of nausea and vomiting are both increased
in a dose-dependent manner by the amount of opiate
administered. This study included epidural, IV, and
oral opiate administration for patients after either orthopedic or abdominal surgery, thereby covering a
wide spectrum of opiate requirements. They found an
exponential relationship between opiate dose and
nausea, with each halving of the opiate dose reducing
the incidence of vomiting by 6% (and a little more for
nausea). Although there are several design problems
in the study by Roberts et al. (which are well discussed
by the authors) and although the percentage reduction
in postoperative nausea and vomiting for each milligram of opiate is not identical between the two studies, they together provide credence to the notion that
opiate-induced nausea and vomiting is dosedependent and that measures to provide opiate sparing are likely to reduce their incidence. One caveat of
the Roberts et al. study is that pain itself may induce
nausea and vomiting (9). This makes it difficult to
determine if pain or the opiate is causing the nausea
and vomiting. The meta-analysis by Marret et al. (7)
would support that this is opiate-induced, as patients
in the various studies analyzed generally had equal
pain relief whether this was provided primarily by the
opiate or the NSAID plus reduced opiate.
In many instances, the use of large-dose opiates is
unavoidable. In these incidences, administering prophylactic antiemetics is clearly indicated. The choices
for first-line antiemetics are multiple and controversial. With the knowledge that reducing opiate requirements decreases nausea and vomiting, it makes sense
to choose an antiemetic that is effective in opiateinduced nausea and vomiting and also enhances analgesic efficacy. Dexamethasone (10), small-dose
promethazine (11), and droperidol (12) have demonstrated, at least in some models of pain, both opiatesparing activity and efficacy in opiate-induced nausea
and vomiting. All of these antiemetics are relatively
inexpensive, effective, and can be used alone or in
combination. When used at appropriate doses they
also have limited side effects.
The articles by Roberts et al. and Marret et al. have
confirmed the notion that opiate-induced nausea and

ANESTH ANALG
2005;101:13412

vomiting is dose dependent. Based on this information

we should consider moving away from the concept
that opiate analgesics are the cornerstone of moderateto-severe pain management but are rather simply one
component of multimodel pain therapy. Unfortunately, all therapies used for pain management are
fraught with adverse events. The challenge for the
clinician today is to minimize the opiate component of
their pain management (thereby reducing the incidence of side effects) while still insuring optimal pain
relief.

References
1. Research AfHCPa. Acute Pain Management Guideline Panel:
Acute Pain Management: Operative or Medical Procedures and
Trauma Clinical Practice Guideline Rockville, MD: US Department of Health and Human Services, Public Health Service,
1992.
2. Wheeler M, Oderda GM, Ashburn MA, Lipman AG. Adverse
events associated with postoperative opioid analgesia: a systematic review. J Pain 2002;3:159 80.
3. Smetzer JL, Cohen MR. Pain scales dont weigh every risk. J
Pain Palliat Care Pharmacother 2003;17:6770.
4. Romsing J, Moiniche S, Mathiesen O, Dahl JB. Reduction of
opioid-related adverse events using opioid-sparing analgesia
with COX-2 inhibitors lacks documentation: a systematic review. Acta Anaesthesiol Scand 2005;49:133 42.
5. Zhao SZ, Chung F, Hanna DB, et al. Dose-response relationship
between opioid use and adverse effects after ambulatory surgery. J Pain Symptom Manage 2004;28:35 46.
6. Gan TJ, Joshi GP, Zhao SZ, et al. Presurgical intravenous parecoxib sodium and follow-up oral valdecoxib for pain management after laparoscopic cholecystectomy surgery reduces opioid
requirements and opioid-related adverse effects. Acta Anaesthesiol Scand 2004;48:1194 207.
7. Marret E, Kurdi O, Zufferey P, Bonnet F. Effects of nonsteroidal
antiinflammatory drugs on patient-controlled analgesia morphine side effects: meta-analysis of randomized controlled trials. Anesthesiology 2005;102:1249 60.
8. Roberts GW, Becker TB, Carlsen HH, et al. Postoperative nausea
and vomiting is strongly influenced by postoperative opioid use
in a dose related manner. Anesth Analg 2005;101:1343 8.
9. Andersen R, Krohg K. Pain as a major cause of postoperative
nausea. Can Anaesth Soc J 1976;23:366 9.
10. Baxendale BR, Vater M, Lavery KM. Dexamethasone reduces
pain and swelling following extraction of third molar teeth.
Anaesthesia 1993;48:961 4.
11. Chia YY, Lo Y, Liu K, et al. The effect of promethazine on
postoperative pain: a comparison of preoperative, postoperative, and placebo administration in patients following total abdominal hysterectomy. Acta Anaesthesiol Scand 2004;48:62530.
12. Lo Y, Chia YY, Liu K, Ko NH. Morphine sparing with droperidol in patient-controlled analgesia. J Clin Anesth 2005;17:2715.