Pharmacology of

Acetaminophen,
N o n s t e ro i d a l A n t i i n f l a m m a t o r y
D r u g s , a n d S t e ro i d M e d i c a t i o n s :
Implications for Anesthesia or
Unique Associated Risks
Kenneth D. Candido, MDa,b,c,*, Oscar J. Perozo, MD
a
,
Nebojsa Nick Knezevic, MD, PhDa,b,c

KEYWORDS
 Analgesia  NSAIDs  Perioperative  Intraoperative  Steroids  Anesthesia
 Acetaminophen

KEY POINTS
 Acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDS) and corticosteroids have
useful perioperative and intraoperative indications.
 Acetaminophen has shown to be effective to decrease opioid consumption and the inci-
dence of postoperative nausea and vomiting (PONV). Coadministration with NSAIDs re-
sults in superior analgesia.
 NSAIDs significantly decrease postoperative pain and the need for opioids. The use of
NSAIDs does not increase the risk of bleeding. Their effect on PONV is unclear.
 Corticosteroids can be used for analgesia, PONV, and prolonged duration of sensory and
motor block when added to the local anesthetics in peripheral nerve blockade.
 No increased incidence of side effects is noted with short-term use.

Providing analgesia is fundamental for health care providers when treating patients
undergoing different surgical procedures. Preventing pain, instead of treating the
pain once it has started, is a challenging goal in everyday anesthesiology practice.
Whether providing analgesia before (preemptive analgesia1), during, or after surgery,

Disclosure Statement: None.

a
Department of Anesthesiology, Advocate Illinois Masonic Medical Center, 836 West
Wellington Avenue, Suite 4815, Chicago, IL 60657, USA; b Department of Anesthesiology,
University of Illinois, 1740 W. Taylor Street, Chicago, IL 60612, USA; c Department of Surgery,
University of Illinois, 840 S. Wood Street, Chicago, IL 60612, USA
* Corresponding author.
E-mail address: kdcandido1@gmail.com

Anesthesiology Clin 35 (2017) e145e162

http://dx.doi.org/10.1016/j.anclin.2017.01.020 anesthesiology.theclinics.com
1932-2275/17/ 2017 Elsevier Inc. All rights reserved.
e146 Candido et al

it is particularly important to know which drug to choose, considering not only its indi-
cation and effectiveness, but also the pharmacologic profile, dosing, route, and poten-
tial side effects, as well as patients comorbidities.
Acetaminophen, nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids,
and opioids are 4 major types of nonopioid drugs considered in perioperative pain
management. Intraoperatively, nonopioid analgesics have been used to decrease
anesthetic and opioids requirements and to reduce the hemodynamic changes related
to painful stimuli.2
We conducted a literature review regarding the main nonopioid analgesics used in
anesthesiology practice beginning with a review of their pharmacologic characteris-
tics. We are reporting their efficacy in the perioperative setting, essentially based on
published systematic reviews and metaanalyses.
The use of analgesics has historically proven to decrease the risks related to
severe pain,3 such as myocardial ischemia, thrombosis, and thromboembolisms
associated with immobilization, atelectasis, and pulmonary complications correlated
with decreased tidal volume and shallow breathing, impaired wound healing and reha-
bilitation.4,5 However, opioids have been linked to numerous adverse effects, espe-
cially when used alone. These effects include nausea, vomiting, pruritus, urinary
retention, constipation, and respiratory depression. The risks of adverse effects can
be lowered by the use of multimodal analgesia. Multimodal analgesia involves the
use of different medications and techniques to produce analgesia through different
mechanisms.3 It has been proposed since the 1990s, so that the dose of opioids
can be restricted or even avoided.47 Nevertheless, multimodal pain management
also includes approaches to regional anesthesia, peripheral nerve blocks and local
infiltration techniques, and neuraxial analgesia,3,5 discussions of which are outside
of the scope of this review.

ACETAMINOPHEN

Acetaminophen (also known as paracetamol) has been clinically used since 1887 and
was not marketed worldwide until the 1950s owing to concerns regarding toxicity.8
Acetaminophen is the active metabolite of phenacetin. It has analgesic and antipyretic
effects similar to those of aspirin. However, its antiinflammatory properties are weak,
presumably owing to poor effectiveness when the concentration of peroxides is high
(at the inflammatory site). The analgesia provided by acetaminophen is induced by an
inhibition of the cyclooxygenase (COX) pathway, decreasing the production of prosta-
glandins. Other recently described possible mechanisms of action include an endo-
cannabinoid effect9 and a modulatory effect on the descending serotoninergic
inhibitory pathways.10
Acetaminophen can be administered orally or per rectum and, since 2010, an intra-
venous form was approved in the United States. Oral and rectal administrations have
excellent bioavailability but undergo first-pass hepatic metabolism. Oral plasma peak
concentration is noticed within 1 hour, and in approximately 30 minutes with the intra-
venous formulation.8 The therapeutic dose in adults is up to 1000 mg every 6 hours,
with a maximum of 4 g/d. Conjugation with glucuronic and sulfuric acid are the prin-
cipal pathways of its metabolism. However, a small proportion of acetaminophen is
metabolized to NADPI, a product related to the toxic effect of overdose. This byprod-
uct is highly reactive and hepatotoxic, and can lead to a potentially fatal hepatic failure,
renal tubular acidosis, and hypoglycemia with very high doses of acetaminophen.
It can be detoxified with the use of N-acetylcysteine therapy. The elimination half-
life of acetaminophen is 2 to 3 hours and the analgesic effect is 4 to 6 hours.2,11
 Pharmacology of Opioid-Sparing Medications e147

A summary of the included most relevant studies regarding the perioperative use of
acetaminophen is depicted in Table 1.
The effects of acetaminophen, COX 2 selective inhibitors (coxibs) and dexametha-
sone on postoperative pain, has been studied by Tiippana and colleagues17 random-
izing a total of 160 postcholecystectomy patients in several groups, and then
evaluating postoperative pain. The results showed that dexamethasone reduced the
need for opioids in phase 2 post anesthetic care unit (decreasing by an average of
2 mg the need of oxycodone [7.0 mg vs 9.1 mg; P<.001]); patients in the groups
receiving coxibs needed more rescue opioid medications compared with those
receiving acetaminophen (P<.001). The authors concluded that acetaminophen could
be recommended for the treatment of pain after laparoscopic cholecystectomy over
NSAIDs, owing to the superior safety profile of acetaminophen.
In a metaanalysis, Doleman and colleagues12 included 7 articles containing a total of
544 patients older than 16 years, aiming to determine the effect of prophylactic intra-
venous (IV) acetaminophen use on postoperative pain, opioid consumption, and vom-
iting. The results were cautiously analyzed owing to potential bias and heterogeneity
(I2 5 33%82%). It was found that there was a statistically significant lower 24-hour
opioid consumption (standardized mean difference [SMD], -0.52 [95% confidence in-
terval [CI], -0.98 to -0.06]), delayed time of first analgesic request (mean difference
[MD], -0.34 [95% CI, -0.67 to, -0.01]) and decreased incidence of postoperative vom-
iting (risk ratio, 0.50 [95% CI, 0.31083]); the incidence of nausea was not affected.
De Oliveira and colleagues13 similarly analyzed 11 prospective randomized clinical
trials evaluating 740 patients who received a single 1000 mg dose of IV acetamino-
phen before or during surgery compared with patients who did not receive
this drug. Results showed decreased pain at rest (weighted mean difference
[WMD], -1.1 [95% CI, -2.0 to -0.2]), decreased pain at movement during the first
4 hours after surgery (WMD, 1.9 [95% CI, -2.8 to -1.0]) and decreased opioid con-
sumption in the first 24 hours (WMD, 9.7 [95% CI, -13 to -6.4]). Both authors showed
a correlation between the use of acetaminophen and decreased opioid use and post-
operative pain, but the effect on PONV was not clear. This metaanalysis analyzed
studies with different types of anesthesia, surgical procedures, postoperative anal-
gesia, and timing for the dose of acetaminophen given, supposing a high level of het-
erogeneity (I2 >50%), potential for bias, for which the data have to be cautiously
interpreted.
In a systematic review with 1909 analyzed patients from 21 different studies, Ong
and colleagues15 primarily compared pain scores and the need for analgesic supple-
mentation between patients receiving a combination of an NSAID and acetaminophen
and patients receiving only 1 of these 2 drugs. Results, as expected, showed that the
combination was more effective: 17 of 20 studies (85%) comparing acetaminophen
alone versus the combination found a reduction of pain intensity standard deviation
(SD) of 35% (vs 10%) and a decreased need for analgesic supplementation of
SD 5 38.8% (vs 13%). Nine out of 14 studies (64%) comparing the combination versus
the use of NSAID alone, indicated a reduction in pain intensity (38% vs 26%) and anal-
gesic supplementation (31% vs 13%).
Even when acetaminophen is compared with weak opioids like tramadol,18 which
has a potency of approximately 10% that of morphine,19 as studied in several ran-
domized clinical trials,18,2022 measuring postoperative pain relief and PONV; acet-
aminophen use showed less PONV20 with similar analgesia21,22 based on the visual
analog scale (P<.001).18
Regarding the effect on PONV, Apfel and associates14 conducted a metaanalysis
based on 30 studies and 2364 patients to determine what the relationship was
 e148
Candido et al
Table 1
Summary of the included most relevant studies regarding perioperative use of acetaminophen

Author and Number Number of Main Subject Statistically Relevant Reported Outcomes of
Year of Studies Patients of Research Interest to the Metaanalysis I2 Range (%)
Doleman 7 544 Effect of the use of preventive  Preventive acetaminophen decreased: overall 3382
et al,12 2015 IV acetaminophen after opioid consumption, pain during the 2 firsts
surgery postoperative hours, incidence of PONV
De Oliveira 11 740 Effect of systemic acetaminophen  Decreased pain at rest during the first 4 h 097
et al,13 2015 to prevent postoperative pain postoperative
 Decreased pain at movement during the
first 4 h postoperative
 Decreased postoperative opioid consumption
Apfel 30 2364 Relationship between use of  Use of prophylactic acetaminophen reduced the 046
et al,14 2013 acetaminophen and incidence incidence of PONV
of PONV  Decreased incidence of PONV was more significant
when acetaminophen was given preoperatively
or intraoperatively
 Reduction of PONV with prophylactic IV
acetaminophen was not related with opioid
consumption
Ong 21 1909 Efficacy of acetaminophen plus  85% of the compared studies (17/20) showed that Not reported
et al,15 2010 NSAIDs in the treatment of the coadministration was more effective than
postoperative pain vs either receiving only acetaminophen
drug alone  64% of the compared studies (9/14) showed that
the coadministration was more effective than
receiving NSAIDs alone
Remy 7 490 Effect of acetaminophen on PCA  Use of acetaminophen did not show reduction in 079
et al,16 2005 morphine consumption and side PCA morphine side effects
effects  Use of acetaminophen reduced the consumption
of 20% PCA morphine

Abbreviations: I2, index of heterogeneity of the analysis; IV, intravenous; NSAIDS, nonsteroidal antiinflammatory drugs; PCA, patient-controlled analgesia; PONV,
postoperative nausea and vomiting.
 Pharmacology of Opioid-Sparing Medications e149

between the use of acetaminophen and the decrease of PONV. They found that, when
acetaminophen was given prophylactically (either before surgery, intraoperatively, or
immediately after surgery), there was a statistically significant reduction of PONV
(RR [risk ratio] 0.63 [95% CI 0.540.75]) not related to the amount of postoperative
opioid consumption; this reduction was more significant if the dose of acetaminophen
was given preoperatively or intraoperatively rather than postoperatively. Similarly,
Remy and colleagues16 conducted a metaanalysis, wherein morphine consumption
and side effects were compared in patients either receiving only patient-controlled
analgesia with morphine (226 patients), or patients receiving patient-controlled
analgesia with morphine plus oral or IV acetaminophen (265 patients). An
acetaminophen-related morphine-sparing effect was statistically significant ( 9 mg
[95% CI, -15 to -3]; P 5 .003). However, Remy and colleagues failed to show a
decrease in morphine side effects when acetaminophen was used. It is important to
mention that in the former metaanalysis, neither the route of administration nor the
moment when acetaminophen was administered were standardized, leading to
possible bias and elevated heterogeneity.

NONSTEROIDAL ANTIINFLAMMATORY DRUGS

NSAIDs are very versatile antiinflammatory, antipyretic, and analgesic drugs, with a
wide therapeutic index, and few noteworthy adverse effects when used in appropriate
dosing. However, a boxed warning was issued for all prescription NSAIDs by the US
Food and Drug Administration on April 6, 2005, which indicated that NSAIDs can
cause gastrointestinal (GI) side effects (obstruction, perforation, bleeding) and cardio-
vascular side effects (thrombosis, myocardial infarction, stroke), even in standardized
doses. Furthermore, this warning is applicable to all prescription NSAIDs without
regard to COX selectivity (COX 1 selective; COX 2 selective; or nonselective). They
are useful in perioperative analgesia and are usually prescribed for the management
of immediate postoperative pain. However, the pharmacologic profile can vary among
different NSAIDs, for which a brief, evidence-based description is provided in this
review.
Even though NSAIDs have been used for centuries, their mechanism of action was
elucidated in 1971 and was found to include an inhibition of the synthesis of prosta-
glandins. NSAIDs block the action of the enzyme responsible for this effect, COX.
COX has 2 main isoforms: COX-1, expressed constitutively in almost every cell, and
COX-2, which is upregulated by cytokines, growth factors, and shear stress. There
is evidence that whenever the cell is damaged there is release of prostaglandins,
which is what triggers an inflammatory cascade response. At high doses of NSAIDs,
other mechanisms have been implied in their effects. However, the main mechanism
involved seems to be the COX inhibition. Aspirin differs from NSAIDs because aspirin
irreversibly acetylates the enzyme.23,24
NSAIDs include a variety of drugs with interindividual and intraindividual differences
in their clinical effects and pharmacokinetics. In general, they have high bioavailability,
with peak concentrations occurring within the first 4 hours when administered orally.
IV ibuprofen and IV ketorolac are available in the United States. Most NSAIDs are
bound to plasma proteins in more than 90%, and undergo hepatic metabolism and
renal excretion. Thus, this should be taken into consideration for patients with severe
hepatic or renal disease.24
Most NSAIDs inhibit both COX isoenzymes with little selectivity, although some
(coxibs, meloxicam, nimesulide) have been shown to mainly block COX-2. A compar-
ison of 2 of the COX-2selective NSAIDs (meloxicam vs celecoxib) did not show
e150 Candido et al

significant differences in pain severity.25 A summary of the included most relevant

studies regarding perioperative use of NSAIDs is provided in Table 2.
A systematic review conducted by Straube and colleagues32 included 22 clinical tri-
als and 2246 patients, and focused on the effect of COX-2selective NSAIDs (coxibs)
in postoperative outcomes. Unfortunately, these drugs have shown an increased
number of adverse effects related to thrombosis and myocardial infarction.33 How-
ever, in none of the clinical trials reviewed by Straube and colleagues is there a
mention of serious cardiovascular or renal impairment, or any infections. Even though
this study indicates that coxibs may have a potential use as postoperative analgesia,
there was not enough evidence to support the use of coxibs over nonselective
NSAIDs.30
Michelet and colleagues30 conducted a metaanalysis based on 27 articles, comparing
postoperative outcomes in 567 pediatric patients who received NSAIDs (25 articles
comparing nonselective NSAIDs, and 2 comparing coxibs) either before or during
surgery in 418 patients who did not receive this medication. Although an increased
heterogeneity (I2 5 ranging from 0% to 90%) and possible publication bias were present,
the metaanalysis showed that the use of NSAIDs decreased opioid consumption in the
postanesthetic care unit (SMD, 0.66 [95% CI, -0.84 to -0.48]; P<.00001) as well as dur-
ing the following 24 hours (SMD, 0.83 [95% CI, -1.11 to -0.55]; P<.00001). There
was also a statistically significant reduction in PONV in patients 24 hours after adenoton-
sillectomy (odds ratio, 0.75; P 5 .04). The study failed to show a difference between
nonselective NSAIDs and rofecoxib34,35 on pain severity, opioid consumption and post-
operative nausea and vomiting (PONV) incidence. Subsequently, Bu and colleagues36
confirmed these results through a metaanalysis in pediatric patients assessing the effi-
cacy and safety of parecoxib for acute postoperative pain. The data from 12 trials (994
patients) were analyzed. The results showed an overall reduction of pain scores and
lower PONV compared with placebo.
The data from 31 randomized controlled studies were analyzed by Wong and
colleagues28 to determine the effect of acetaminophen and NSAIDs on opioid con-
sumption in children. To further explain this effect, the studies were classified in 4
groups (AD), based on the type of administration and the distribution of the doses.
In groups A and B, an infusion of IV opioid was controlled by the patient (patient-
controlled analgesia) or the nurse (nurse-controlled analgesia). When NSAIDs or
NSAID plus paracetamol were administered several times perioperatively (group A),
the opioid dose requirements were reduced by 31.6% (95% CI, 16%46%). When
only 1 dose of NSAIDs was given (group B), the mean reduction was 24%. Likewise,
in groups C and D (where the distribution of doses for NSAIDs and acetaminophen
was similar to groups A and B), the opioids were given in bolus doses (instead of as
infusions) and showed significant opioid-sparing effects with a mean reduction for
the amount required for analgesia by 24%. The use of NSAIDs alone or in combination
also resulted in increased patient satisfaction, lower pain scores and a reduced inci-
dence of PONV. No increased risk of bleeding was noted.
In adults, Bainbridge and colleagues31 after a metaanalysis of 20 randomized,
controlled trials (RCTs), with a total of 1065 patients, showed a significant reduction
in pain scores and opioid consumption with NSAID use. The studies included only
postcardiothoracic surgery patients receiving NSAIDs. All-cause mortality, incidence
of atrial fibrillation, bleeding, or any other major side effect did not experience a signif-
icantly different change overall.
Nevertheless, special attention must be paid to aspirin. It has long been established
that it has a potent and irreversible platelet antiaggregation effect. In a metaanalysis
based on 28 studies and more than 20,000 patients, the authors showed that, with
 Table 2
Summary of the included most relevant studies regarding perioperative use of NSAIDs and aspirin

No. of No. Statistically Relevant Reported Outcomes of Interest to the I2 Range

Author and Year Studies Patients Main Subject of Research Metaanalysis (%)
Moore et al,26 41 >10,000 Oral analgesic in postoperative  Efficacy of analgesic (NSAIDs, opioids and acetaminophen) N/A
2015 [Review] pain in adults (single dose) varies with type, dose and combination
 All analgesics provided and significant absolute risk
reduction, with an average NNT between 2 and 3
Ma et al,27 2014 27 >20,000 Safety of preoperative aspirin  Doses <100 mg represent minimal risk of bleeding 088
[Systematic in patients undergoing CABG  Not clear cutoff value for risk of bleeding
review]  Doses >325 mg are related to increased risk of postoperative
bleeding and increased packed red blood cells requirements
Wong et al,28 2013 31 Not Effect of acetaminophen and  Better analgesic effect when NSAIDs are given with N/A
[Systematic review] reported NSAIDs on opioid acetaminophen than when given alone
consumption in children  NSAIDs produce an opioid-sparing effect in both, bolus and

Pharmacology of Opioid-Sparing Medications

infusion
 No increased risk of bleeding or adverse effects overall
De Oliveira 13 RCT 782 Efficacy and dose of ketorolac  Overall postoperative pain intensity decreased with the use of 093
et al,29 2012 in postoperative pain ketorolac 60 mg at rest and with movement in the first 24 h
 Doses of 30 mg did not show reduction in pain
 PO opioid consumption and PONV were decreased
Michelet 27 985 Pediatric use of NSAIDs for  Postoperative: NSAIDs decreased opioid consumption in PACU 090
et al,30 2012 PO pain and during the next 24 h
 Decreased PONV after 24 h adenotonsillectomy
 No general difference between nonselective NSAIDs and coxibs
Bainbridge 20 1065 Analgesia and opioid sparing  Significant pain score reduction 089
et al,31 2006 effect of NSAIDs in  Significantly less need of opioids in the 24 h postoperative
cardiothoracic surgery  No difference on heart, renal and GI functioning
Straube et al,32 2005 22 CT 2246 Effect of coxibs in postoperative  Reduction in postoperative pain, opioid consumption N/A
[Systematic review] outcomes compared with  No significant difference in intraoperative blood loss
placebo  Overall, no significant difference in PONV

Abbreviations: CABG, coronary artery bypass grafting; coxibs, cyclooxygenase inhibitors; CT, controlled trial; I2, index of heterogeneity of the analysis; N/A, not
applicable; NNT, number needed to treat; NSAIDs, nonsteroidal antiinflammatory drugs; PACU, postanesthesia care unit; PONV, postoperative nausea and vom-
iting; RCT, randomized, controlled trial.

e151
e152 Candido et al

preoperative long-term doses of less than 100 mg/d, the risk of bleeding was not sta-
tistically increased in patients undergoing coronary artery bypass grafting (MD, 103
[95% CI, -65 to 272]; P 5 .23). However, at higher doses, the risks of postoperative
bleeding, PRBC (packed red blood cells) transfusion requirements and reoperation
for rebreeding had a statistically significant increase.27
In a different metaanalysis, comparing NSAIDs with opioids, Mezentsev37 showed
that there was no difference in the analgesia provided by these 2 classes of drugs
during modern shock wave lithotripsy.
Scientific review on the use of ibuprofen indicates that ibuprofen is a racemic
mixture of S- and R-isomers.4 The R-isomer is inactive and the S-isomer is the one
responsible for the therapeutic effects. However, approximately 60% of the R-enan-
tiomer is metabolized to the S-isomer (dexibuprofen), helping in the maintenance of
the pharmacologic effects. Derry and colleagues38 aimed to determine the role
of the oral dexibuprofen on postoperative pain in adults and showed that 400 mg of
racemic ibuprofen was related to a 50% pain relief in 51% of patients, and 70% of
the patients receiving 400 mg dexibuprofen use showed a 50% pain reduction. These
results lacked statistical power owing to the low number of subjects and lack of
convincing evidence available. Koh and colleagues4 mentioned 3 studies on the ther-
apeutic efficacy in postoperative analgesia of ibuprofen compared with placebo, and
the results showed a statistically significant reduction in postoperative pain and opioid
consumption with no significant variance on the incidence of adverse effects even with
a daily dose of 3200 mg of ibuprofen.
De Oliveira and colleagues29 studied the effects of a single dose of systemic (IV
or IM) ketorolac on postsurgical pain. A metaanalysis of 13 randomized clinical
trials including 782 patients showed a statistical significance (WMD, 0.64 [95%
CI, -1.11 to -0.18]) in the first 4 hours for postoperative pain over placebo. Other ben-
efits included decreased opioid consumption (MD, -1.71 [95% CI, -2.83 to -0.60]) and
PONV (odds ratio (OR) 0.57). Differences between the intramuscular or intravenous
routes were difficult to analyze because of a low number of patients in each subgroup.
However, it seems that ketorolac provided a better analgesic effect when the dose is
given IM. Two doses were studied: 30 mg (4 RCTs) and 60 mg (9 RCTs). Doses of
30 mg did not seem to have a clinically important benefit on outcomes.
As expected, oral NSAIDs have also proven to be beneficial for postoperative
analgesia. Oral diclofenac (sodium and potassium) was studied by Derry and col-
leagues,39 who compared the NSAID versus placebo in 18 studies including 3714
subjects. The study showed an increase in the efficacy of the drug, related to the
dose used, of up to 100 mg. The effect was greater for the potassium formulation
of Diclofenac, and the maximum pain relief (for 50 mg) compared with placebo was
evident with a number needed to treat of 2.1 (95% CI, 1.92.5).39 Moore and col-
leagues26 extended this study to general analgesics, with an analysis of 39 reviews.
Forty-one different NSAIDs were studied, and the overall effect was similar to the
one of diclofenac (the average number needed to treat ranged from 1.6 for ibuprofen
200 mg 1 acetaminophen 500 mg; to 3.5 for acetaminophen alone 500 mg). Certain
drugs like etodolac and aspirin had a considerable change in efficacy related to the
different doses.
GI events and renal impairment are two of the most common adverse effect of
NSAIDs and usually become manifest in the first weeks of therapy, even though GI
bleeding can occur much later. Other systems affected include central nervous sys-
tem (headache, vertigo, dizziness, confusion, depression), blood (inhibited platelet
activation, increased risk of bleeding), uterine (tocolysis), vascular (closure of ductus
arteriosus), and hypersensitivity reactions.24
 Pharmacology of Opioid-Sparing Medications e153

Related to the renal impairment, a metaanalysis on the effect of NSAIDs on the post-
operative renal function of 1459 healthy adults found that NSAID use only led to a mild
transient reduction of the creatinine clearance (16 mL/min [95% CI, 528]) 1 day after
surgery, which was insignificant when compared with placebo (difference placebo/
NSAIDs: 0 mL/min).40 Therefore, NSAIDs should not be avoided in healthy individuals
owing to concern for renal side effects.
An increased incidence of gastric or duodenal ulcers and upper GI tract bleeding
varies according to the specific NSAID.41 For instance, the odds ratio for upper GI tract
bleeding for diclofenac is 9.1, ibuprofen 8.2, and meloxicam 13.1. An interesting
exception is metamizole (Dipyrone), which odds ratio is 0.9 (95% CI, 0.71.2) and
has been proposed as the drug to use in patients with GI or renal impairment (odds
ratio, 1.2 [95% CI, 1.01.3]).41 IV coadministration of H2 blockers and proton pump in-
hibitors, 1 hour before surgery, has been proven to decrease gastric volume and in-
crease the pH.42

CORTICOSTEROIDS

The hormonal steroids synthetized in the outer adrenal cortex belong to 1 of 2 classes:
glucocorticoids (cortisol), with effects in the intermediary metabolism, or mineralocor-
ticoids (aldosterone), with mainly salt-retaining activity. Synthetic analogs of glucocor-
ticoids, especially methylprednisolone, betamethasone, and dexamethasone, have
been found to have several uses in perioperative medicine. The differences between
these medications are predominantly based on their antiinflammatory potency,
sodium-retaining potency, and duration of action (ranging from several minutes to
several days).43
The main mechanism of action of glucocorticoids involves interaction with specific
proteins and regulation of gene expression, which usually takes hours to become
apparent. However, receptor-independent mechanisms have been described. Alto-
gether, this affects several metabolic pathways, generating anabolic, catabolic, anti-
inflammatory, immunosuppressive, vascular, endocrine, and many other effects.43,44
Regarding purposeful perioperative use, studies have described several effects. For
instance, decreased nausea and vomiting, relief of inflammation, analgesia, opioid-
sparing effect, cardiovascular uses, positive pulmonary effects, and neuraxial involve-
ment have been the subjects of intensive research. A summary of the included most
relevant studies regarding perioperative use of corticosteroids is shown in Table 3.
The Society of Ambulatory Anesthesiology included the use of steroids in the guide-
lines for the management of PONV, primarily dexamethasone 4 to 5 mg IV at induction
(level of evidence: A1), and methylprednisolone 40 mg IV (level of evidence: A2) among
the first-line therapy of drugs used for prophylaxis.55,56
Similarly, the Society of Ambulatory Anesthesiology states that ondansetron has a
level of evidence of A1. Wang and colleagues48 included 7 studies comparing ondan-
setron with dexamethasone in a metaanalysis and concluded that in the first 6 hours
postoperative, ondansetron was more effective (relative risk [RR], 1.71 [95% CI, 1.05
2.77] but dexamethasone was more effective in the next 24 hours (range, 624 hours;
RR, 0.51 [95% CI, 0.270.93]).
Because PONV and pain are the 2 most common reasons for delaying discharge for
patients undergoing laparoscopic cholecystectomy,57 these could be prevented with
the co-administration of dexamethasone and NSAIDs.
Allen and colleagues50 analyzed 8 RCTs and found that, in patients who received
neuraxial morphine as part of the anesthetic technique, dexamethasone was an effec-
tive drug for prophylaxis of PONV (decreased incidence of PON: RR, 0.57 [95%
 e154
Candido et al
Table 3
Summary of the included most relevant studies regarding perioperative use of corticosteroids

No. of Statistically Relevant Reported Outcomes

Author and Year Studies No. Patients Main Subject of Research of Interest to the Metaanalysis I2 Range (%)
Jebaraj et al, 45
2016 5 RCT Not reported Epidural local analgesia using  Decreased demand for rescue analgesia, Not reported
dexamethasone and local anesthetics decreased amount of morphine needed
Knezevic et al,46 2015 14 1022 Dose-related perineural dexamethasone  Better PO analgesia at 24 and 48 h for doses N/A
[Systematic review] effect in brachial plexus block between 4 and 10 mg
 Increased latency for sensory and motor block
 Longer duration of motor block
 No effect in the incidence of complications
Huynh et al,47 2015 12 1054 Effect of dexamethasone in the  26 min longer analgesia in average Not reported
combination of local anesthetics on  76 min longer motor blockade in average
peripheral blockade in adults  Lower incidence of PONV (9% vs 27% in control
group)
 No difference on pain intensity
Wang et al,48 2015 7 608 Dexamethasone vs ondansetron for  Comparable effectiveness for PONV 065
PONV after laparoscopic surgery  Postoperative, in the first 6 h, ondansetron
was more effective (RR, 1.71)
 Postoperative, 624 h dexamethasone was
more effective (RR, 0.51)
 Ondansetron has higher cost benefit ratio
 Overall PONV: dexamethasone 33.3%,
ondansetron 36.7%
Viviano et al,49 2013 70 >5000 Perioperative corticosteroids for  Hydrocortisone (100 mg/d) shows an ARR 18% N/A
[Systematic review] prevention of postoperative atrial (48%30%)
fibrillation  Methylprednisolone 1 dexamethasone: ARR:
30% (51%21%)
 Dexamethasone 50-210 mg risk difference, 0.12
 Allen et al,50 2012 8 RCT 768 Dexamethasone vs placebo in PONV in  Dexamethasone reduced the incidence of PONV, 072
patients undergoing neuraxial the use of rescue antiemetic therapy, pain scores,
anesthesia and rescue analgesics
Waldron 45 5796 Effect of dexamethasone (1.2520 mg)  Lower pain scores, decreased opioids use and 097
et al,51 2012 in PO pain and adverse effects rescue analgesia within 24 h
 Shorter PACU stay
 No effect on wound healing or risk of infections
 Glucose levels were higher in the first 24 h
De Oliveira 24 RCT 2751 Efficacy and dose of dexamethasone in  Overall postoperative pain intensity decreased 092
et al,52 2011 PO pain with the use of dexamethasone at rest and with
movement in the first 24 h
 Low doses of dexamethasone on pain <1 h
postoperative at rest did not show reduction
in pain
 Postoperative opioid consumption was lower
with dexamethasone

Pharmacology of Opioid-Sparing Medications

Baker et al,53 2007 9 990 Corticosteroids in postcardiothoracic  Doses of corticosteroids reduced atrial fibrillation Not reported
surgery atrial fibrillation (OR, 055)
Sauerland 51 1696 Risk-benefit analysis of the use of high  No increase in incidence of complications Not reported
et al,54 2000 dose of methylprednisolone  Reduction of pulmonary complication, mainly in
(1530 mg/kg) in surgical patients trauma patients

Abbreviations: ARR, absolute risk reduction; I2, index of heterogeneity of the analysis; N/A, not applicable; OR, odds ratio; PACU, postanesthesia care unit; PONV,
postoperative nausea and vomiting; RCT, randomized control trials; RR, relative risk.

e155
e156 Candido et al

CI, 0.450.72]; POV: RR, 0.56 [95% CI, 0.430.72] and the use of rescue antiemetic
drugs (RR, 0.47 [95% CI, 0.360.61]). There was also a statistically significant effect
on 24-hour pain scores and the use of recue analgesics.
Dexamethasone has also shown an effect on pain scores and need for rescue medi-
cation.50,52 In 2011, De Oliveira52 performed a metaanalysis using 24 randomized
clinical trials, studying the effect of 3 different single doses of IV dexamethasone
(<0.1 mg/kg; 0.110.2 mg/kg; >0.21 mg/kg), given in a range from 2 hours preopera-
tively to use during surgery. The outcomes studied were the effects on postoperative
pain and the incidence of adverse events. Results, comparing SD, indicated
that dexamethasone decreased the overall postoperative opioid consumption
(SD, 0.41 [95% CI, -0.58 to -0.24]) and postoperative pain during the first 24 hours,
either at rest (SD, 0.49 [95% CI, -0.67 to -0.31]) or with movement (SD, 0.47 [95%
CI, 0.71 to -0.24]). No change was evident at low doses on either early pain at rest
(<4 hours; SD, 0.33 [95% CI, -0.7 to 0.04]) or postoperative opioid consumption
(SD, 0.17 [95% CI, -0.380.03]). Nor was there evidence of a dose-dependent
increased risk of adverse effects, but, according to the authors, this may not apply
for patients with a high risk of wound infections. In a larger metaanalysis involving
45 studies and 5796 patients, Waldron and colleagues51 reached similar conclusions.
Nevertheless, heterogeneity was high, ranging from 0% to 97%.
A recent metaanalysis has reported an effect of combining dexamethasone
(410 mg) to the local anesthetics used for peripheral nerve block.4547 Jebaraj
and colleagues45 found that the need of postoperative analgesia rescues (RR, 0.51
[95% CI, 0.410.63]) and the consumption of morphine (MD, 7.89 mg [95%
CI, -11.66 to -3.71]), significantly decreased when epidural dexamethasone was
administered combined with local anesthetic.
Similarly, Huynh and colleagues47 based a metaanalysis on 12 trials including 1054
patients, and identified several results of combinations of steroids and local anes-
thetics. A longer duration of analgesia and faster onset of analgesic action were found
to be statistically significant; patients receiving the combination had analgesia for
around 351 minutes (WSD, 351 [95% CI, 288413]), versus control patients who
had analgesia lasting around 325 minutes (range, 98888). However, there was no dif-
ference on pain intensity. Time of motor blockade also increased (WSD, 276 minutes
[95% CI, 167387]) approximately 76 minutes more than the control group. PONV was
reduced with the use of the combination, resulting in an absolute risk reduction of 18%
(PONV 9% vs 27%).
Knezevic and colleagues,46 after a systematic review of 14 studies and a total of
1022 patients, concluded that adding dexamethasone to the local anesthetics used
for brachial plexus blocks was related to longer postoperative analgesia at 24 hours
(SMD, 1.46 [95% CI, -2.43 to -0.50]) and 48 hours (SMD, 1.20 [95% CI, -2.26
to -0.13]); longer postoperative analgesia with dose between 4 and 5 mg
(SMD, 2.41 [95% CI, 1.473.35]) and doses of 8 to 10 mg (SMD, 4.46 [95% CI,
3.545.38]) of dexamethasone; increased duration of sensory and motor block
(SMD, 0.56 [95% CI, 1.13 to 0.00]), increased latency for the block, and no effect
in the incidence of complications.
Corticosteroids have been shown to improve the respiratory dynamics by different
mechanisms, including an antiinflammatory effect linked to cytokine production, cell
recruitment, and decreased bronchial hyperactivity. Along with anticholinergic agents
and beta2 agonists, parenteral corticosteroids are used for acute control of reactive
airways in asthmatic patients.58 In a systematic review of 51 randomized clinical trials
with a total of 1696 patients, Sauerland and colleagues54 showed that the use of high
dose methylprednisolone (>15 mg/kg), used no more than 3 days after surgery and
 Pharmacology of Opioid-Sparing Medications e157

discontinued afterward, did not increase significantly the complication rates and was
actually related to better outcomes on lung function associated with reduction of pul-
monary complications (risk difference of 3.5 [95% CI, -6.1 to -1.0]). Unfortunately, no
metaanalysis was found regarding the dose and use of corticosteroids in intraopera-
tive bronchospasm or used to reduce airway edema.
One double-blind clinical trial59 comparing the effects of methylprednisolone 1 day
after surgery on pain and opioid consumption in the first postoperative hours in 75
patients showed that the methylprednisolone pain-relieving effect was similar
to that of ketorolac, and was statistically significantly (P<.05) better than placebo. In
contrast, a more recent clinical trial60 comparing the effects of ketorolac (30 mg)
versus betamethasone (12 mg) and dexamethasone (4 mg) showed that patients
receiving ketorolac had less pain (88% of patients) and an earlier discharge (165 mi-
nutes) than did patients receiving dexamethasone (74%/192 minutes) and betametha-
sone (67%/203 minutes).
As mentioned, corticosteroids have not only proven to be useful in the prevention of
PONV and reduction of postoperative pain after anesthesia, but also have other salu-
brious effects on physiology. Moderate doses of corticosteroids have proven to
reduce the incidence of postoperative atrial fibrillation in several RCTs and metaanal-
yses.49 Baker and colleagues53 reported that corticosteroids (dexamethasone 50
210 mg or equivalent) in patients postcardiothoracic surgery, significantly reduced
the risk of atrial fibrillation by 45% (OR, 0.55 [95% CI, 0.390.78]).
Corticosteroids have also been shown to decrease the needs for reintubation and
the incidence of stridor in patients at risk in the intensive care unit, which was shown
by Jaber and colleagues61 in a metaanalysis of 7 trials that included 1946 patients, and
confirmed by Malhotra62 and colleagues in a pediatric population. This is related to
their potent antiinflammatory effects on the airway. Similarly, steroids have been
used to decrease the incidence of postoperative sore throat, found by prophylactically
using dexamethasone 10 mg before tracheal intubation,63 or by adding betametha-
sone gel applied over the endotracheal tube.64
Multiple side effects have been described with the use of corticosteroids. Most are
related to discontinuation of chronic therapy or resulting from continuous use at supra-
physiologic doses.43 Some of these side effects include suppression of the adrenal
hormonal axis, hydroelectrolyte imbalances, hyperglycemia, susceptibility to infec-
tions, myopathy, and osteoporosis. However, glucocorticoids are usually used perio-
peratively for only short periods of time, and it is unusual for patients to develop
serious adverse side effects, limiting them primarily to behavioral changes (insomnia,
nervousness, changes in the mood, etc) and GI disturbances.43,44
Additionally, a systematic review of 51 studies concluded that a single high dose
of methylprednisolone was safe for use and was associated with nonsignificant
increased risks, including infections and wound healing problems.54
Likewise, the literature review has shown no relationship between the use of single
dose steroids and an increased risk of wound infections and urinary tract infec-
tions.65,66 However, dexamethasone, as used for prophylaxis, increases glycemic
levels for short periods of time, for which it is important to consider the glycemic profile
individually,67 especially in patients with morbid obesity and poorly controlled dia-
betes mellitus.68

SUMMARY

In this review, we have focused on systematic reviews and metaanalyses that included
randomized, controlled studies regarding the perioperative use of acetaminophen,
e158 Candido et al

NSAIDs, and steroids. IV acetaminophen used perioperatively reduces opioid con-

sumption in the first 24 hours after surgery and some of the metaanalyses confirmed
its effect on the reduction of PONV. NSAIDs showed significant pain reduction and
opioid consumption when used perioperatively, both in adults and the pediatric pop-
ulation, when used alone or in combination with acetaminophen. However, there is a
concern regarding the safety profile on NSAIDs when used perioperatively with an
increased risk of GI events and renal impairment in nonhealthy individuals. Dexameth-
asone showed an effect on reducing postoperative pain and the need for opioids be-
sides its effect on prophylaxes of PONV. Dexamethasone is useful in the prolongation
of peripheral nerve blocks when added to local anesthetics. Corticosteroids decrease
the need for reintubation and the incidence of stridor in intensive care unit patients.
Studies showed that even a high dose of corticosteroids used perioperatively does
not increase the risk of infection wound healing. However, precaution is required in
morbidly obese patients and patients with poorly controlled diabetes. Nevertheless,
the indications and safety of some of these drugs are still controversial and the infor-
mation provided should be analyzed with caution. Anesthesiologists should always
use their clinical judgment when making decisions for the management of these drugs.

REFERENCES

1. Woolf CJ, Chong MS. Preemptive analgesiatreating postoperative pain by

preventing the establishment of central sensitization. Anesth Analg 1993;77:
36279.
2. Evers A, Crowder M, Balser J. General anesthetics. In: Goodman LS, Gilman A,
Brunton LL, et al, editors. Goodman & Gilmans the pharmacological basis of ther-
apeutics. 11th edition. New York: McGraw-Hill; 2006. p. xxiii, 2021 p.
3. Crews JC. Multimodal pain management strategies for office-based and ambula-
tory procedures. JAMA 2002;288:62932.
4. Koh W, Nguyen KP, Jahr JS. Intravenous non-opioid analgesia for peri- and post-
operative pain management: a scientific review of intravenous acetaminophen
and ibuprofen. Korean J Anesthesiol 2015;68:312.
5. Kehlet H. Multimodal approach to postoperative recovery. Curr Opin Crit Care
2009;15:3558.
6. Chandrakantan A, Glass PS. Multimodal therapies for postoperative nausea and
vomiting, and pain. Br J Anaesth 2011;107(Suppl 1):i2740.
7. Rafiq S, Steinbruchel DA, Wanscher MJ, et al. Multimodal analgesia versus tradi-
tional opiate based analgesia after cardiac surgery, a randomized controlled trial.
J Cardiothorac Surg 2014;9:52.
8. Jahr JS, Lee VK. Intravenous acetaminophen. Anesthesiol Clin 2010;28:61945.
9. Mallet C, Barriere DA, Ermund A, et al. TRPV1 in brain is involved in acetaminophen-
induced antinociception. PLoS One 2010;5:e12748.
10. Pickering G, Esteve V, Loriot MA, et al. Acetaminophen reinforces descending
inhibitory pain pathways. Clin Pharmacol Ther 2008;84:4751.
11. Furst D, Munster T. Nonsteroidal anti-inflammatory drugs, disease-modifying anti-
rheumatic drugs, nonopioid analgesics, & drugs used in gout. In: Katzung BG,
Masters SB, Trevor AJ, editors. Basic & clinical pharmacology. 8th edition. New
York: McGraw-Hill Education LLC; 2001. p. xiii, 1,217 p.
12. Doleman B, Read D, Lund JN, et al. Preventive acetaminophen reduces postop-
erative opioid consumption, vomiting, and pain scores after surgery: systematic
review and meta-analysis. Reg Anesth Pain Med 2015;40:70612.
 Pharmacology of Opioid-Sparing Medications e159

13. De Oliveira GS Jr, Castro-Alves LJ, McCarthy RJ. Single-dose systemic acet-
aminophen to prevent postoperative pain: a meta-analysis of randomized
controlled trials. Clin J Pain 2015;31:8693.
14. Apfel CC, Turan A, Souza K, et al. Intravenous acetaminophen: the efficacy of
intravenous paracetamol versus tramadol for postoperative analgesia after ad-
enotonsillectomy in children reduces postoperative nausea and vomiting: a sys-
tematic review and meta-analysis. Pain 2013;154:67789.
15. Ong CK, Seymour RA, Lirk P, et al. Combining paracetamol (acetaminophen) with
nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic
efficacy for acute postoperative pain. Anesth Analg 2010;110:11709.
16. Remy C, Marret E, Bonnet F. Effects of acetaminophen on morphine side-effects
and consumption after major surgery: meta-analysis of randomized controlled tri-
als. Br J Anaesth 2005;94:50513.
17. Tiippana E, Bachmann M, Kalso E, et al. Effect of paracetamol and coxib with or
without dexamethasone after laparoscopic cholecystectomy. Acta Anaesthesiol
Scand 2008;52:67380.
18. Shahid M, Manjula BP, Sunil BV. A comparative study of intravenous paracetamol
and intravenous tramadol for postoperative analgesia in laparotomies. Anesth Es-
says Res 2015;9:3149.
19. Ide S, Minami M, Ishihara K, et al. Mu opioid receptor-dependent and indepen-
dent components in effects of tramadol. Neuropharmacology 2006;51:6518.
20. Dejonckheere M, Desjeux L, Deneu S, et al. Intravenous tramadol compared to
propacetamol for postoperative analgesia following thyroidectomy. Acta Anaes-
thesiol Belg 2001;52:2933.
21. Akcali GE, Iskender A, Demiraran Y, et al. Randomized comparison of efficacy of
paracetamol, lornoxicam, and tramadol representing three different groups of an-
algesics for pain control in extracorporeal shockwave lithotripsy. J Endourol 2010;
24:61520.
22. Uysal HY, Takmaz SA, Yaman F, et al. The efficacy of intravenous paracetamol
versus tramadol for postoperative analgesia after adenotonsillectomy in children.
J Clin Anesth 2011;23:537.
23. Smyth E, Burke A, FitzGerald G. Lipid-derived autacoids: eicosanoids and
platelet-activating factor. In: Goodman LS, Gilman A, Brunton LL, et al, editors.
Goodman & Gilmans the pharmacological basis of therapeutics. 11th edition.
New York: McGraw-Hill; 2006. p. xxiii, 2021 p.
24. Burke A, Smyth E, FitzGerald G. Analgesic-antipyretic and antiinflammatory
agents; pharmacotherapy of gout. In: Goodman LS, Gilman A, Brunton LL,
et al, editors. Goodman & Gilmans the pharmacological basis of therapeutics.
11th edition. New York: McGraw-Hill; 2006. p. xxiii, 2021 p.
25. Aghadavoudi O, Saryazdi HH, Shafa A, et al. Comparison of pre-emptive effect of
meloxicam and celecoxcib on post-operative analgesia: a double-blind, random-
ized clinical trial. Middle East J Anaesthesiol 2015;23:28994.
26. Moore RA, Derry S, Aldington D, et al. Single dose oral analgesics for acute post-
operative pain in adults - an overview of Cochrane reviews. Cochrane Database
Syst Rev 2015;(9):CD008659.
27. Ma X, Ma C, Yun Y, et al. Safety and efficacy outcomes of preoperative aspirin in
patients undergoing coronary artery bypass grafting: a systematic review and
meta-analysis. J Cardiovasc Pharmacol Ther 2014;19:97113.
28. Wong I, St John-Green C, Walker SM. Opioid-sparing effects of perioperative
paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) in children. Pae-
diatr Anaesth 2013;23:47595.
e160 Candido et al

29. De Oliveira GS Jr, Agarwal D, Benzon HT. Perioperative single dose ketorolac to
prevent postoperative pain: a meta-analysis of randomized trials. Anesth Analg
2012;114:42433.
30. Michelet D, Andreu-Gallien J, Bensalah T, et al. A meta-analysis of the use of
nonsteroidal antiinflammatory drugs for pediatric postoperative pain. Anesth An-
alg 2012;114:393406.
31. Bainbridge D, Cheng DC, Martin JE, et al. NSAID-analgesia, pain control and
morbidity in cardiothoracic surgery. Can J Anaesth 2006;53:4659.
32. Straube S, Derry S, McQuay HJ, et al. Effect of preoperative Cox-II-selective
NSAIDs (coxibs) on postoperative outcomes: a systematic review of randomized
studies. Acta Anaesthesiol Scand 2005;49:60113.
33. Ott E, Nussmeier NA, Duke PC, et al. Efficacy and safety of the cyclooxygenase 2
inhibitors parecoxib and valdecoxib in patients undergoing coronary artery
bypass surgery. J Thorac Cardiovasc Surg 2003;125:148192.
34. Joshi W, Connelly NR, Reuben SS, et al. An evaluation of the safety and efficacy
of administering rofecoxib for postoperative pain management. Anesth Analg
2003;97:358. Table of contents.
35. Sheeran PW, Rose JB, Fazi LM, et al. Rofecoxib administration to paediatric pa-
tients undergoing adenotonsillectomy. Paediatr Anaesth 2004;14:57983.
36. Bu X, Yang L, Zuo Y. Efficacy and safety of perioperative parecoxib for acute
postoperative pain treatment in children: a meta-analysis. Front Med 2015;9:
496507.
37. Mezentsev VA. Meta-analysis of the efficacy of non-steroidal anti-inflammatory
drugs vs. opioids for SWL using modern electromagnetic lithotripters. Int Braz
J Urol 2009;35:2937 [discussion: 298].
38. Derry S, Best J, Moore RA. Single dose oral dexibuprofen [S(1)-ibuprofen] for acute
postoperative pain in adults. Cochrane Database Syst Rev 2013;(10):CD007550.
39. Derry S, Wiffen PJ, Moore RA. Single dose oral diclofenac for acute postoperative
pain in adults. Cochrane Database Syst Rev 2015;(7):CD004768.
40. Lee A, Cooper MC, Craig JC, et al. Effects of nonsteroidal anti-inflammatory
drugs on post-operative renal function in normal adults. Cochrane Database
Syst Rev 2001;(2):CD002765.
41. Konijnenbelt-Peters J, van der Heijden C, Ekhart C, et al. Metamizole (Dipyrone)
as an alternative agent in postoperative analgesia in patients with contraindica-
tions for nonsteroidal anti-inflammatory drugs. Pain Pract 2016. [Epub ahead of
print].
42. Memis D, Turan A, Karamanlioglu B, et al. The effect of intravenous pantoprazole
and ranitidine for improving preoperative gastric fluid properties in adults under-
going elective surgery. Anesth Analg 2003;97:13603.
43. Schimmer B, Parker K. Adrenocorticotropic hormone; adrenocortical steroids and
their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical
hormones. In: Goodman LS, Gilman A, Brunton LL, et al, editors. Goodman &
Gilmans the pharmacological basis of therapeutics. 11th edition. New York:
McGraw-Hill; 2006. p. xxiii, 2021 p.
44. Chrousos G, Margioris A. Adrenocoticosteroids & adrenocortical antagonists. In:
Katzung BG, Masters SB, Trevor AJ, editors. Basic & clinical pharmacology. 8th
edition. New York: McGraw-Hill Education LLC; 2001. p. xiii, 1,217 p.
45. Jebaraj B, Khanna P, Baidya DK, et al. Efficacy of epidural local anesthetic and
dexamethasone in providing postoperative analgesia: a meta-analysis. Saudi J
Anaesth 2016;10:3227.
 Pharmacology of Opioid-Sparing Medications e161

46. Knezevic NN, Anantamongkol U, Candido KD. Perineural dexamethasone added

to local anesthesia for brachial plexus block improves pain but delays block
onset and motor blockade recovery. Pain Physician 2015;18:114.
47. Huynh TM, Marret E, Bonnet F. Combination of dexamethasone and local anaes-
thetic solution in peripheral nerve blocks: a meta-analysis of randomised
controlled trials. Eur J Anaesthesiol 2015;32:7518.
48. Wang XX, Zhou Q, Pan DB, et al. Dexamethasone versus ondansetron in the
prevention of postoperative nausea and vomiting in patients undergoing laparo-
scopic surgery: a meta-analysis of randomized controlled trials. BMC Anesthesiol
2015;15:118.
49. Viviano A, Kanagasabay R, Zakkar M. Is perioperative corticosteroid administra-
tion associated with a reduced incidence of postoperative atrial fibrillation in adult
cardiac surgery? Interact Cardiovasc Thorac Surg 2013;18:2259.
50. Allen TK, Jones CA, Habib AS. Dexamethasone for the prophylaxis of postoper-
ative nausea and vomiting associated with neuraxial morphine administration: a
systematic review and meta-analysis. Anesth Analg 2012;114:81322.
51. Waldron NH, Jones CA, Gan TJ, et al. Impact of perioperative dexamethasone on
postoperative analgesia and side-effects: systematic review and meta-analysis.
Br J Anaesth 2012;110:191200.
52. De Oliveira GS Jr, Almeida MD, Benzon HT, et al. Perioperative single dose sys-
temic dexamethasone for postoperative pain: a meta-analysis of randomized
controlled trials. Anesthesiology 2011;115:57588.
53. Baker WL, White CM, Kluger J, et al. Effect of perioperative corticosteroid use on
the incidence of postcardiothoracic surgery atrial fibrillation and length of stay.
Heart Rhythm 2007;4:4618.
54. Sauerland S, Nagelschmidt M, Mallmann P, et al. Risks and benefits of preoper-
ative high dose methylprednisolone in surgical patients: a systematic review.
Drug Saf 2000;23:44961.
55. Gan TJ, Meyer TA, Apfel CC, et al. Society for Ambulatory Anesthesia guidelines
for the management of postoperative nausea and vomiting. Anesth Analg 2007;
105:161528. Table of contents.
56. Gan TJ, Diemunsch P, Habib AS, et al. Consensus guidelines for the manage-
ment of postoperative nausea and vomiting. Anesth Analg 2014;118:85113.
57. Bisgaard T. Analgesic treatment after laparoscopic cholecystectomy: a critical
assessment of the evidence. Anesthesiology 2006;104:83546.
58. Rajesh MC. Anaesthesia for children with bronchial asthma and respiratory infec-
tions. Indian J Anaesth 2015;59:5848.
59. Romundstad L, Breivik H, Niemi G, et al. Methylprednisolone intravenously 1 day
after surgery has sustained analgesic and opioid-sparing effects. Acta Anaesthe-
siol Scand 2004;48:122331.
60. Thagaard KS, Jensen HH, Raeder J. Analgesic and antiemetic effect of ketorolac
vs. betamethasone or dexamethasone after ambulatory surgery. Acta Anaesthe-
siol Scand 2007;51:2717.
61. Jaber S, Jung B, Chanques G, et al. Effects of steroids on reintubation and post-
extubation stridor in adults: meta-analysis of randomised controlled trials. Crit
Care 2009;13:R49.
62. Malhotra D, Gurcoo S, Qazi S, et al. Randomized comparative efficacy of dexa-
methasone to prevent postextubation upper airway complications in children and
adults in ICU. Indian J Anaesth 2009;53:4429.
63. Park SY, Kim SH, Lee AR, et al. Prophylactic effect of dexamethasone in reducing
postoperative sore throat. Korean J Anesthesiol 2010;58:159.
e162 Candido et al

64. Tabari M, Soltani G, Zirak N, et al. Comparison of effectiveness of betamethasone

gel applied to the tracheal tube and IV dexamethasone on postoperative sore
throat: a randomized controlled trial. Iran J Otorhinolaryngol 2013;25:21520.
65. Assante J, Collins S, Hewer I. Infection associated with single-dose dexametha-
sone for prevention of postoperative nausea and vomiting: a literature review.
AANA J 2015;83:2818.
66. Gali B, Burkle CM, Klingele CJ, et al. Infection after urogynecologic surgery with
the use of dexamethasone for nausea prophylaxis. J Clin Anesth 2012;24:54954.
67. Hans P, Vanthuyne A, Dewandre PY, et al. Blood glucose concentration profile af-
ter 10 mg dexamethasone in non-diabetic and type 2 diabetic patients undergo-
ing abdominal surgery. Br J Anaesth 2006;97:16470.
68. Eberhart LH, Graf J, Morin AM, et al. Randomised controlled trial of the effect of
oral premedication with dexamethasone on hyperglycaemic response to abdom-
inal hysterectomy. Eur J Anaesthesiol 2011;28:195201.