REVIEW ARTICLE

Recent Management Advances in Acute

Postoperative Pain

Charles E. Argoff, MD
Albany Medical College Neurology Group, Albany, New York, U.S.A.

& Abstract adol) or opioid formulations (morphine–oxycodone), and

patient-controlled analgesia.
Introduction: Acute postoperative pain remains a major
Conclusion: New, targeted, analgesic medications and tech-
problem, with both undertreatment and overtreatment
niques may provide a safer and more effective approach to
leading to serious consequences, including increased risk of
the management of acute postoperative pain than tradi-
persistent postoperative pain, impaired rehabilitation,
tional approaches such as postoperative oral analgesics. &
increased length of stay and/or hospital readmission, and
adverse events related to excessive analgesic use, such as
Key Words: acute pain, analgesia, preoperative, intraop-
oversedation. New analgesic medications and techniques
erative, postoperative, perioperative, review
have been introduced that target the preoperative, intraop-
erative, and postoperative periods to better manage acute
postoperative pain, with improvements in analgesic efficacy INTRODUCTION
and safety over more traditional pain management
approaches. This review provides an overview of these new An estimated 25 million inpatient surgeries and an
analgesic medications and techniques. Specific topics that are additional 35 million ambulatory surgeries are per-
discussed include the use of preoperative nonsteroidal anti- formed annually in the USA.1,2 Greater than 80% of
inflammatory drugs, anxiolytics, and anticonvulsants; intra-
surgical patients experience postoperative pain, and
operative approaches such as neuraxial analgesia, continuous
39% experience “severe” to “extreme” postoperative
local anesthetic wound infusion, transversus abdominis plane
block, extended-release epidural morphine, intravenous pain.3 The mismanagement of postoperative pain,
acetaminophen, and intravenous ketamine; and postopera- whether undertreatment or overtreatment, is associated
tive use of intravenous ibuprofen, new opioids (eg, tapent- with a variety of negative consequences, including
cardiac alterations and increased risk of myocardial
ischemia or infarction, thromboembolic and pulmonary
Address correspondence and reprint requests to: Charles E. Argoff, complications, immune alterations, increased risk of
MD, Albany Medical College, 47 New Scotland Avenue, MC 70, Physicians persistent postoperative pain, impaired rehabilitation,
Pavilion, 1st Floor, Albany, NY 12208, U.S.A. E-mail: argoffc@mail.amc.edu.
Disclosures: Dr. Argoff has worked in an advisory/speaker’s bureau/ increased length of stay and/or hospital readmission,
investigator capacity and received honoraria or grants from Endo Phar- decreased quality of life, and adverse events related to
maceuticals Inc, Pfizer Inc, Eli Lilly and Company, Forest Laboratories Inc,
and NeurogesX. He has also worked as an advisor for King Pharmaceu-
excessive analgesic use.4–8
ticals, sanofi-aventis, Boehringer Ingelheim GmbH, Nuvo Research Inc, and The consequences of overtreatment are often
Jazz Pharmaceuticals plc, and has received honoraria from these compa-
nies for his expertise. Dr. Argoff has additionally served in the PriCara
overlooked but can be life-threatening. Indeed, an
speakers’ bureau and has received honorarium monies for his participa- observational study of surgical patients found high rates
tion.
of analgesic-induced oversedation in the first 12 post-
Submitted: February 06, 2013; Revision accepted: July 09, 2013
DOI. 10.1111/papr.12108 operative hours, with dangerous levels of sedation
occurring in 72.7% of patients on patient-controlled
© 2013 World Institute of Pain, 1530-7085/13/$15.00
analgesia (PCA).4 A chart review of trauma center site
Pain Practice, Volume 14, Issue 5, 2014 477–487 surveys reported to the American College of Surgeons
478  ARGOFF
Committee on Trauma as part of their verification process
identified excessive use of analgesics as a direct factor in
13 of 1,655 deaths (0.7%) from 1994 through 1998 and
in 32 of 867 deaths (3.6%) from 2000 through 2004.5
A variety of new analgesic medications and tech-
niques have been introduced to more effectively manage
acute postoperative pain during the preoperative, intra-
operative, and postoperative periods, all of which may
contribute to the development of acute postoperative
pain. This review will focus on new analgesic medica-
tions and techniques targeted for use during these
periods for the management of acute postoperative pain.
PAIN MANAGEMENT APPROACHES TARGETED AT
THE PREOPERATIVE PERIOD
Interventions targeted at the preoperative period are
increasingly common and often are used for “preemp-
tive analgesia” or as part of a “preventive analgesia”
regimen. Preemptive analgesia involves the preoperative
administration of an analgesic so that it is active during
surgery. Administration at this time should reduce the
consequences of afferent nociceptive neurotransmission
arising from the surgery itself, thereby decreasing
postoperative pain.9,10
In contrast, preventive analgesia involves a broader
approach to postoperative pain management, in that the
goal is to prevent central sensitization by blocking the
neural transmission of all noxious perioperative stimuli
arising from the time of incision until wound healing,
which then should decrease postoperative pain and
analgesic use, as well as the risk of persistent postoper-
ative pain. Preventive analgesia aims to minimize central
sensitization by blocking the consequences of all peri-
operative noxious stimuli, not just those arising from the
surgery itself; it is slowly replacing preemptive analgesia
as the more encompassing approach to postoperative
pain management.9,10
Nonsteroidal anti-inflammatory drugs (NSAIDs) (eg,
ketorolac, etoricoxib, celecoxib), anxiolytics (eg, mi-
dazolam), and anticonvulsants (eg, gabapentin, pregab-
alin) have been studied in the preoperative setting. What
follows is a review of the current literature on use of
these classes of drugs before surgery.
NSAIDs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are
widely used analgesics, antipyretics, and anti-inflam-
matory agents that act by inhibiting the enzyme
cyclooxygenase, which is responsible for the biosynthesis
of prostaglandins.11 Inflammation and nerve injury sec-
ondary to surgery may independently trigger postopera-
tive pain and result in central sensitization and persistent
postoperative pain.9,12 A recent, randomized, placebo-
controlled, clinical trial comparing a single preoperative
dose of the selective cyclooxygenase (COX)-2 inhibitors
etoricoxib and celecoxib in patients undergoing arthro-
scopic anterior cruciate ligament reconstruction under
spinal anesthesia found that patients receiving etoricoxib
(but not celecoxib) had significantly less intense pain for
the first 8 hours. However, the 2 treatment groups did not
differ from the placebo group in time to first dose or
amount of postoperative analgesic used (recorded at
48 hours), or in pain intensity from 12 to 48 hours.13
These findings suggest limited efficacy of etoricoxib as a
preemptive analgesic.
A meta-analysis of the effects of a single perioperative
(preoperative or intraoperative) intravenous or intra-
muscular dose of ketorolac (30 mg or 60 mg) for
postoperative pain found that ketorolac reduced pain
at rest in the early (0 to 4 hours) but not late (24 hours)
postoperative period, with a greater analgesic effect
following intramuscular administration than following
intravenous administration. The 60-mg dose of ketoro-
lac also reduced postoperative opioid use and nausea
and vomiting.14 These findings suggest that a single,
intramuscular dose of ketorolac may be effective as a
preemptive analgesic during the preoperative or intra-
operative periods.
Theoretically, NSAIDs with a longer elimination half-
life should be more effective in reducing postoperative
pain when administered preoperatively.15 For individual
patients, the efficacy of NSAIDs should be weighed
against the risk of serious adverse events affecting the
gastrointestinal,16 rensal,17 and cardiovascular18 sys-
tems, although the risk of these adverse events should be
decreased when only a single preoperative dose is
administered. A systematic review of the efficacy and
safety of selective COX-2 inhibitors in the perioperative
setting identified a consistent opioid-sparing effect of
COX-2 inhibitors,19 which should further decrease
analgesic complications by reducing the risk of opioid-
related adverse events such as respiratory depression.20
Although the available data are conflicting, clinicians
should be aware of the potential for NSAIDs to impair
bone healing, and NSAIDs should be avoided in patients
at high risk of impairments in bone healing, particularly
for surgeries that directly involve the bone such as
arthroplasty.21
 Advances in Acute Postoperative Pain  479

Anxiolytics consumption was similar in the two groups.29 Severe

sedation was greater in the gabapentin group, but no
Anxiety is common prior to surgery and is associated
significant group difference was found in the incidence of
with poor outcomes, including severe postoperative
postoperative nausea and vomiting, or in neonatal
pain.22 Researchers have explored the use of anxiolytics
outcomes.29
for managing anxiety and pain, with positive results.
A meta-analysis of the effects of gabapentin in
Midazolam is a benzodiazepine that is commonly
randomized, controlled, clinical trials found that pre-
administered to decrease preoperative anxiety and
operative gabapentin produced a significant decrease in
produce anesthesia.23 A recent, randomized, double-
postoperative analgesic consumption.30 In this review,
blind, clinical trial compared the efficacy and safety of
preoperative gabapentin was found to produce a signif-
preoperative diclofenac (an NSAID) with or without
icant decrease in vomiting (but not nausea); however, its
midazolam in patients undergoing hernia repair surgery
use was associated with a significant increase in sedation
under general anesthesia.24 The results showed that
and dizziness.30
compared with patients receiving diclofenac alone,
A randomized, double-blind, placebo-controlled,
patients receiving preoperative midazolam in combina-
clinical trial of the effects of 2 perioperative doses of
tion with diclofenac experienced significantly less post-
pregabalin (75 mg each, administered 1 hour before
operative pain in the first 3 postoperative hours (6-point
surgery and 12 hours after the first dose) in patients
Verbal Rating Scale [VRS] score, median [range]: 1.4 [0
undergoing mastectomy under general anesthesia
to 4] vs. 2.4 [1 to 5]; P < 0.001). Thus, preoperative
showed that compared with patients receiving placebo,
midazolam can enhance the analgesic effects of diclofe-
patients receiving pregabalin experienced less pain at
nac. The combination of midazolam and diclofenac also
rest over the first 48 postoperative hours (48-hour 11-
resulted in significantly less nausea/vomiting, but with a
point Verbal Numerical Rating Scale [VNRS] score at
greater degree of sedation and hypotension than that
rest, median [range]: 0 [0 to 4] for pregabalin vs. 2 [1 to
observed with diclofenac alone.24
5] for placebo; P < 0.001) and with arm abduction for
Whether midazolam’s analgesic effect is secondary to
1 week after surgery (1-week VNRS score, median
its anxiolytic effect is unclear, although intrathecal
[range]: 1 [0 to 4] for pregabalin vs. 3 [0 to 5] for
administration of midazolam to rats has been shown to
placebo; P < 0.001), with an exception of the 6-hour
produce analgesic effects by actions on the GABAA
postoperative time point).31 There was no group differ-
receptor complex.25 A randomized case–control study
ence in sedation, postoperative nausea and vomiting, or
of human patients undergoing lower abdominal, gyne-
postoperative analgesic use.31
cological, or orthopedic surgery under spinal anesthesia
A meta-analysis of the effects of pregabalin in
found that intrathecal midazolam significantly increased
randomized, placebo-controlled, clinical trials found
the time to first use of postoperative analgesics and
that perioperative (preoperative or pre/postoperative)
prolonged the duration of sensory blockade, without
administration of pregabalin produced a significant
increasing the incidence of sedation.26
decrease in postoperative pain at rest (Hedges’ g effect
size: –0.31; 95% confidence interval [CI]: –0.50, –0.12)
and with movement (Hedges’ g effect size: –0.27; 95%
Anticonvulsants
CI: –0.50, –0.05), and in postoperative analgesic use
Gabapentin and pregabalin are anticonvulsant drugs (Hedges’ g effect size: –0.32; 95% CI: –0.49, –0.14 for
that act at the a2d subunit of presynaptic, voltage-gated, studies with no group difference in pain scores at rest;
Ca2+ channels.27,28 The efficacy of preoperative gaba- Hedges’ g effect size: –0.98; 95% CI: 1.58, 0.38 for
pentin and pregabalin in decreasing postoperative pain studies with a group difference in pain scores at rest).32
has been investigated in randomized clinical trials and in However, these effects were accompanied by an increase
meta-analyses. in dizziness or lightheadedness and visual disturbances.32
A randomized, placebo-controlled, clinical trial of the
effects of a single preoperative dose (600 mg) of gaba-
PAIN MANAGEMENT APPROACHES TARGETED AT
pentin in patients undergoing cesarean delivery under
THE INTRAOPERATIVE PERIOD
spinal anesthesia found a reduction in pain scores on
movement and at rest in the gabapentin group compared Intraoperative analgesic techniques and formulations
with the placebo group, although postoperative opioid include neuraxial analgesia, continuous local anesthetic
480  ARGOFF
wound infusion, transversus abdominis plane (TAP)
block, extended-release epidural morphine (EREM),
intravenous acetaminophen, and intravenous ketamine.
Neuraxial Analgesia
Neuraxial analgesia involves local administration of an
anesthetic and/or opioids into the neuraxial space of the
spinal cord.
Neuraxial analgesia aims to reduce the afferent
transmission of nociceptive signaling and to block the
development of central sensitization. Neuraxial analge-
sic techniques include spinal or epidural analgesia,
regional nerve blocks targeting the surgical field, periph-
eral nerve blocks targeting the nerve innervating the
surgical field, and local nerve blocks targeting local
tissue in the surgical field.6,33 While these techniques are
effective at reducing postoperative pain, they are not
without complications. Nerve injuries, in particular, are
common after neuraxial analgesia, although severe or
disabling neurological complications are rare.33
Ultrasound guidance during peripheral nerve block
has received increased attention as a method to not only
improve the accuracy of nerve localization and needle
placement but also to improve postoperative pain. A
systematic review of randomized, controlled, clinical
trials on the effects of ultrasound guidance during
peripheral nerve block found little evidence of improve-
ment in postoperative pain management, although the
available data were limited to the 23 trials that met the
inclusion criteria for review.34
The conflicting evidence regarding the benefit of
ultrasound guidance might be related, at least in part, to
the level of experience of the anesthetist. Indeed, the use
of ultrasound guidance requires extensive training and
routine practice. Anesthetists must fully understand
ultrasound theory and equipment and the relevant
anatomy. Furthermore, adequate training programs
must be in place to ensure that anesthetists develop
and maintain the competencies required to successfully
perform the technique.35
Continuous Local Anesthetic Wound Infusion
Continuous infusion of local anesthetic into the surgical
field was introduced as a simple alternative to neuraxial
or peripheral nerve blockade for the management of
postoperative pain. When infused into the surgical field,
local anesthetics produce analgesic effects by direct
inhibition of afferent nociceptive signaling and direct
inhibition of the local inflammatory response to surgical
trauma.36 While local anesthetic wound infusion
appears to provide better postoperative pain relief than
placebo infusion,37 it is unclear whether it is superior to
traditional neuraxial or peripheral nerve blockade.
A randomized, controlled, investigator-blind, clinical
trial compared 48-hour continuous wound infusion of
ropivacaine with bolus injections of epidural morphine
administered every 12 hours for up to 48 hours in
patients undergoing elective cesarean delivery and found
that compared with patients receiving epidural mor-
phine, patients receiving the continuous wound infusion
had significantly lower pain scores at rest over the first
48 postoperative hours (48-hour 11-point VNRS score,
median [interquartile range, IQR]: 0 [0 to 0] vs. 2 [0 to
2]; P < 0.001) and with movement over the first 6
postoperative hours (6-hour VNRS score, median
[IQR]: 1 [0 to 4] vs. 5 [4 to 5]; P < 0.001). Although
there was no group difference in the use of rescue
analgesics, the incidence of adverse events was signifi-
cantly reduced in patients receiving the continuous
wound infusion when compared with patients receiving
epidural morphine.38
In contrast, another randomized, placebo-controlled,
clinical trial in patients undergoing elective cesarean
delivery found that pain scores at rest (but not with
walking) were significantly lower among patients receiv-
ing perioperative epidural boluses of levobupivacaine
compared with patients receiving perioperative subfas-
cial boluses of levobupivacaine. However, the group
difference was apparent only for the first 4 postoperative
hours,39 and it was attributed to a greater dose of local
anesthetic administered in the epidural group than in the
subfascial group.39
Given the conflicting results, the available evidence
suggests that wound infusion of local anesthetics may
provide a useful approach to acute pain management
with patients for whom neuraxial analgesia or
peripheral nerve blockade is not an acceptable choice.36
TAP Block
The TAP block was first described by Rafi40 and involves
the injection of local anesthetics into the neurovascular
plane of the abdominal wall. Interest in the use of the
TAP block for acute pain management is growing. A
systematic review and meta-analysis of the literature
identified 7 randomized, double-blind, clinical trials and
found that in 4 of the 7 trials, pain scores at rest and
with motion were significantly decreased in the early

postoperative period (0 to 6 hours) among patients
receiving the TAP block compared with those who did
not.41 In 6 of the 7 trials, patients receiving the TAP
block also consumed less postoperative morphine, and a
meta-analysis confirmed the opioid-sparing effect of the
TAP block.41
Another meta-analysis of 4 randomized, placebo-
controlled, clinical trials found that patients receiving
the TAP block consumed less postoperative morphine
and waited longer to request postoperative analgesia
than patients who did not receive the TAP block.42
Postoperative pain scores measured at 6 and 24 hours
were lower among patients who received the TAP
block.42 However, these findings were not found in the
postanesthesia care unit or at 2 hours. The incidence of
postoperative nausea and vomiting did not differ
between groups.42
EREM
Extended-release epidural morphine (EREM) was
approved in 2004 as a single-dose analgesic adminis-
tered by epidural injection at the lumbar level for the
treatment of pain following major surgery.43 EREM is
administered immediately before surgery or after clamp-
ing the umbilical cord during cesarean delivery. The
efficacy of EREM in the treatment of postoperative pain
has been established, but the safety of EREM has been
questioned.
A study using pooled data from 5 randomized clinical
trials conducted between 1998 and 2003 compared the
use of intravenous PCA with fentanyl or morphine in
combination with epidural placebo, epidural morphine
sulfate (5 mg), or EREM (5 to 30 mg) on postoperative
pain after total hip arthroplasty, lower abdominal
surgery, or cesarean delivery. The results showed that
both epidural morphine and EREM decreased postop-
erative pain intensity at rest, and that a 10-mg dose of
EREM produced a greater decrease in postoperative pain
intensity with movement when compared with a 5-mg
dose of epidural morphine, but the effect was limited to
the first postoperative day.44 Postoperative PCA opioid
use was lower with both epidural morphine and EREM,
but a 10-mg dose of EREM produced a greater effect
than a 5-mg dose of epidural morphine on postoperative
day 2.44 There were no significant differences among the
treatment groups in the incidence of respiratory depres-
sion, nausea, vomiting, pruritus, or urinary retention,
except for a tendency for a greater incidence of adverse
events with higher doses of EREM.44
Advances in Acute Postoperative Pain  481
In contrast to the study discussed above, a meta-
analysis of the effects of EREM (10 to 30 mg) versus
intravenous PCA with opioids focused on postoperative
respiratory depression and found that EREM, while
effective at providing postoperative analgesia for up to
48 hours, was associated with a significantly higher risk
of respiratory depression (odds ratio [OR]: 5.80, 95%
CI: 1.05, 31.93; P = 0.04).45
In response to concerns related to respiratory depres-
sion after neuraxial opioid administration, the American
Society of Anesthesiologists (ASA) developed practice
guidelines for the use of neuraxial opioids in the
perioperative setting. With regard to EREM, the guide-
lines recommend periodic monitoring for a minimum of
48 postoperative hours, with increased monitoring for
patients at high risk of respiratory depression (eg, obese,
pediatric, and geriatric patients).46 The ASA also noted
that they are “equivocal regarding whether extended-
release epidural morphine increases the occurrence of
respiratory depression compared with either parenteral
opioids or conventional (immediate release) epidural
morphine.”46
Intravenous Acetaminophen
An intravenous formulation of acetaminophen was
approved in 2010 for the management of fever, mild to
moderate pain, or moderate to severe pain with adjunc-
tive opioids.47,48 A systematic review of randomized,
placebo-controlled, clinical trials of the safety and efficacy
of perioperative (primarily intraoperative) intravenous
acetaminophen for the management of postoperative pain
found that patients receiving perioperative intravenous
acetaminophen had lower pain scores in 12 of 14 trials
and less postoperative opioid use in 10 of 14 trials.49
Another systematic review and meta-analysis found
that patients receiving perioperative (intraoperative or
postoperative) intravenous acetaminophen were more
likely than patients receiving placebo to experience 50%
pain relief and to have less opioid use over the first 4 to 6
postoperative hours, with no group difference in the
overall incidence of adverse events.50
Intravenous Ketamine
Ketamine is a hypnotic drug that is commonly used for
induction of anesthesia, especially in pediatric patients,
and acts by antagonizing the N-methyl-D-aspartate
receptor.51 Ketamine has received increased interest in
recent years as an analgesic for acute pain management.
482  ARGOFF
A randomized, double-blind, placebo-controlled,
clinical trial evaluated the effects of intravenous or
subcutaneous infiltration of ketamine administered
15 minutes before incision in patients undergoing
appendectomy under general anesthesia.52 The results
showed that treatment with ketamine by either route of
administration resulted in significantly lower pain scores
in the postanesthesia care unit than with placebo,52 but
that intravenous administration of ketamine provided
greater long-term postoperative pain relief than subcu-
taneous administration of ketamine, with significantly
lower pain scores up to 24 postoperative hours (24-hour
10-cm visual analog scale [VAS] score, mean  SD:
1.7  0.9 for intravenous ketamine, 4.0  1.5 for
subcutaneous ketamine, and 4.4  0.7 for placebo;
P < 0.001).52 The incidence of adverse events (nausea,
vomiting, or dizziness) did not differ between the three
groups.52
A systematic review and meta-analysis of the effects
of perioperative (intraoperative or postoperative) intra-
venous ketamine on postoperative pain and analgesic
use identified an opioid-sparing effect of ketamine, with
the greatest effects observed with surgeries associated
with greater postoperative pain, such as abdominal
surgery, thoracic surgery, and orthopedic limb or spine
surgery.53 Ketamine was associated with a decrease in
postoperative pain scores in 37.5% of studies at early
time points (30 minutes to 4 hours) and 25% of studies
at later time points (24 to 72 hours).53 In terms of
adverse events, ketamine increased the incidence of
neuropsychiatric effects (eg, hallucinations) and
decreased the incidence of postoperative nausea and
vomiting, but did not alter the incidence of sedation or
other side effects.53
PAIN MANAGEMENT APPROACHES TARGETED AT
THE POSTOPERATIVE PERIOD
Traditional pharmacological approaches to pain man-
agement in the postoperative period include oral or
intravenous administration of opioids and oral admin-
istration of acetaminophen or NSAIDs. These
approaches are associated with a variety of adverse
events, including respiratory depression,20 nausea and
vomiting,54 pruritus,55 and constipation56 with opioids,
and gastrointestinal injury,16 myocardial infarction or
stroke,18 and acute renal failure17 with NSAIDs. Acci-
dental overdose and death also is not uncommon after
opioid use.57 New opioids, drug delivery approaches
and systems, and PCA techniques have been developed
to enhance the analgesic effects of NSAIDs and opioids
and to minimize the risk of adverse events.
Intravenous Ibuprofen
An intravenous formulation of ibuprofen was approved
in 2009 for use in adults for fever reduction and the
management of mild to moderate pain or moderate to
severe pain with adjunctive opioids.48,58 A randomized,
multicenter, double-blind, placebo-controlled, clinical
trial of intravenous ibuprofen (400 or 800 mg) in
patients undergoing orthopedic or abdominal surgery
found that compared with placebo, the intravenous
administration of 800 mg ibuprofen at wound closure
and every 6 hours thereafter resulted in a significant
decrease in morphine consumption (intent-to-treat [ITT]
population, 24-hour morphine consumption, adjusted
least squares mean  standard error [SE]:
190.6  13.1 mg vs. 223.0  13.8 mg; P = 0.030),
patient-reported pain scores at rest (ITT population,
12- to 24-hour 100-mm VAS score, adjusted least
squares mean  SE: 32.6  2.4 vs. 42.5  2.6;
P < 0.001), and with movement (ITT population, 12-
to 24-hour VAS score, adjusted least squares
mean  SE: 48.6  2.6 vs. 58.8  2.8; P < 0.001)
over the first 24 postoperative hours.59 A 400-mg
intravenous dose of ibuprofen was less effective.59 In
terms of adverse events, nausea and pyrexia were
significantly less common among patients receiving
intravenous ibuprofen than among patients receiving
placebo, but dizziness was significantly more common
among patients receiving the 800-mg dose of intrave-
nous ibuprofen.59
A recent review of clinical trials on the efficacy and
tolerability of intravenous ibuprofen in hospitalized
adult patients concluded that 800 mg of intravenous
ibuprofen every 6 hours after surgery was efficacious as
an adjunct to morphine and as a morphine-sparing
agent.60 The same review further concluded that intra-
venous ibuprofen is generally well tolerated, with the
most common adverse events being dizziness, headache,
nausea, vomiting, flatulence, hemorrhage, and urinary
retention.60
Another review article focused on dosing strategies
related to the pharmacokinetics and pharmacodynamics
of intravenous ibuprofen.61 The authors concluded from
their analysis that a rapid intravenous infusion of
ibuprofen would provide a more rapid and reliable
onset of analgesia than is typically achieved with the
more common 30- to 60-minute infusion protocols.61

New Opioids and Opioid Formulations
New opioids and opioid formulations are being devel-
oped with unique pharmacodynamic profiles that retain
the analgesic effects of opioids but minimize the adverse
events associated with traditional opioids, such as
morphine, hydrocodone, and fentanyl.
Tapentadol is a novel, centrally acting, l-opioid
agonist, and norepinephrine reuptake inhibitor that is
approved for the treatment of moderate to severe
pain.62,63 Two oral formulations are available: tapent-
adol hydrochloride for acute pain, and extended-release
tapentadol for chronic pain.62,63 A review of clinical
trials of the safety and efficacy of tapentadol for the
treatment of pain after bunionectomy found that
tapentadol has similar efficacy to pure l-opioid agonists
but with fewer opioid-related gastrointestinal adverse
events.64 New clinical trials are needed to determine
whether tapentadol is safe and effective in the treatment
of postoperative pain after other types of surgery.
A new drug application (NDA) has been submitted to
the US Food and Drug Administration (FDA) for an oral
dual-opioid formulation containing a fixed ratio (3:2) of
morphine to oxycodone.65 A randomized, double-blind,
placebo-controlled, clinical trial of morphine–oxyco-
done at ascending doses of 3/2, 6/4, 12/8, or 18/12 mg in
patients who experienced moderate to severe pain after
unilateral bunionectomy found that when compared
with placebo, patients who received morphine–oxyco-
done had greater pain relief (responders: 65% for 18/12-
mg morphine–oxycodone vs. 36% for placebo;
P = 0.003) and required less supplemental analgesia
(600-mg ibuprofen tablets per 24 hours, mean  SE:
2.0  0.40 for 18/12-mg morphine–oxycodone vs.
3.3  0.31 for placebo; exact P value not reported)
over the first 48 postoperative hours.66 Nausea was the
most common adverse event among patients receiving
morphine–oxycodone, occurring in 38% to 65% of
patients. Somnolence was the least common adverse
event, occurring in 2% to 8% of patients receiving
morphine–oxycodone, but few patients discontinued
study participation due to adverse events.66
Another randomized, double-blind, parallel-treat-
ment, multicenter, clinical trial in patients undergoing
unilateral bunionectomy demonstrated dose-dependent
analgesic effects of morphine–oxycodone that were
comparable to or greater than those achieved with
equivalent doses of morphine or oxycodone alone.67 The
mean (SE) sum of pain intensity difference over the first
24 hours was superior with the morphine–oxycodone
Advances in Acute Postoperative Pain  483
combination product (12/8 mg, 54.3 [7.5]) compared
with each component alone (12 mg morphine, 28.5
[8.1]; P = 0.009; 8 mg oxycodone, 35.7 [7.5];
P = 0.037), and when compared with a lower dosage
strength (6/4 mg, 30.0 [7.8]; P = 0.011). The incidence
of nausea and vomiting (the most common adverse
events) was higher in patients receiving morphine–
oxycodone than in patients receiving morphine or
morphine-equivalent doses of oxycodone alone (nausea,
76.5% vs. 58.6% and 50.0%; vomiting, 52.9% vs.
24.1% and 26.5%; 12/8 mg combination vs. 12 mg
morphine and 8 mg oxycodone, respectively).67
PCA. Patient-controlled analgesia (PCA) is increasingly
recognized as a safe and effective method of postoperative
pain management, with the potential to improve postop-
erative pain management by minimizing the frequency of
analgesic gaps.68 Intravenous PCA with opioids and
patient-controlled epidural analgesia (PCEA) with opi-
oids and/or local anesthetics are the most common
methods of PCA.68 Less common approaches for PCA
include patient-controlled regional anesthesia (PCRA),
patient-controlled intranasal analgesia (PCINA), patient-
controlled transdermal analgesia (PCTA), and patient-
controlled sublingual analgesia (PCSA).
PCRA. Patient-controlled regional anesthesia (PCRA)
typically involves the administration of a local anesthetic
into the surgical incision, intra-articular tissue, or peri-
neural site.68 A number of studies have demonstrated the
safety and efficacy of PCRA, and increased attention has
focused on the use of PCRA for postoperative care after
ambulatory surgery. For instance, a randomized, multi-
center, clinical trial compared perineural PCRA with
ropivacaine (by continuous infusion or basal–bolus) with
intravenous PCA with morphine for home care after
ambulatory orthopedic surgery (acromioplasty or
bunionectomy) under general anesthesia.69 The results
showed that compared with patients receiving intrave-
nous morphine PCA, patients receiving perineural PCRA
with ropivacaine consumed significantly less supplemen-
tal ketoprofen (mean  SD: 200  100 mg for continu-
ous ropivacaine infusion, 100  100 mg for basal–bolus
ropivacaine, and 500  100 mg for intravenous mor-
phine PCA; exact P value not reported) and experienced
fewer drug-related adverse events, including nausea/
vomiting, dizziness, and local vein inflammation, over
72 postoperative hours.69 Additionally, patients receiving
perineural PCRA with ropivacaine (particularly by basal–
bolus infusion) showed greater rehabilitation, including
484  ARGOFF
walking for 10 minutes and participation in daily activ-
ities at home.69
Another randomized, double-blind, placebo-con-
trolled, clinical trial compared the efficacy of perineural
PCRA with ropivacaine, perineural PCRA with saline
(placebo), and oral analgesics (unblinded control) for
postoperative pain relief after ambulatory surgery for
open carpal tunnel release under local anesthesia.70
Patients receiving PCRA with ropivacaine experienced
greater pain relief than patients receiving PCRA with
saline, and fewer patients receiving PCRA with ropiva-
caine required supplemental analgesics than patients
receiving oral analgesics (24% vs. 73%; P = 0.001).70
The 3 groups did not differ in the rate of functional
recovery, however.70 PCRA appears to provide safe and
efficacious postoperative analgesia and may promote
functional recovery after ambulatory surgery.
PCINA. A patient-controlled intranasal formulation of
ketorolac tromethamine was approved in 2010 for
short-term (up to 5 days) management of moderate to
moderately severe pain in adults requiring opioids.71 A
randomized, double-blind, placebo-controlled, clinical
trial examined the safety and efficacy of PCINA with
ketorolac (10 or 30 mg) in patients undergoing major
abdominal or orthopedic surgery under general anes-
thesia.72 Compared with patients receiving PCINA with
placebo, patients receiving PCINA with 30-mg ketoro-
lac consumed less morphine over the first 48 postoper-
ative hours (mean  standard error of the mean [SEM]:
61.4  10.8 mg vs. 87.9  9.4 mg; P = 0.0060) and
had greater pain relief at 6 postoperative hours
(Summed Pain Intensity Difference [SPID] score,
mean  SEM: 195.5  12.1 vs. 130.6  14.4;
P = 0.0015).72 The incidence of adverse events was
similar among the 3 groups, although patients receiving
PCINA with 30-mg ketorolac were less likely than those
receiving placebo to experience pyrexia or tachycardia.
Nasal irritation was more common among patients
receiving either dose of ketorolac.72
Similarly, another randomized, double-blind, pla-
cebo-controlled, clinical trial in patients undergoing
major open abdominal surgery under general anesthesia
found that patients receiving PCINA with ketorolac had
greater pain relief over the first 30 postoperative hours
than patients receiving PCINA with placebo (30-hour
100-mm VAS, least squares mean  SE: 24.3  1.5 vs.
29.5  2.2; P = 0.037).73 Patients receiving PCINA
with ketorolac also used less supplemental analgesia
compared with patients receiving PCINA with placebo.73
The overall incidence of adverse events was similar in the
2 groups. Nasal discomfort was more common among
patients receiving PCINA with ketorolac than among
those receiving placebo, but the difference was not
significant.73 Although nasal irritation is common after
PCINA with ketorolac, this approach appears to be useful
in combination pharmacotherapy for postoperative pain.
PCTA. The fentanyl iontophoretic transdermal system
(fentanyl ITS) was approved in 2006 for the treatment of
acute postoperative pain in adult inpatients requiring
postoperative opioids.74 This PCTA system is not yet
marketed in the USA or elsewhere, however, because
new system features are under development.74 Fentanyl
ITS was developed as an alternative to intravenous PCA,
with a lower risk of intravenous PCA–related compli-
cations such as operating errors, mechanical pump
errors, and intravenous catheter infections.74,75
An open-label, multicenter, randomized, active-con-
trolled, parallel-group, clinical trial compared the safety
and efficacy of the fentanyl ITS with that of intravenous
PCA with morphine in patients undergoing abdominal or
pelvic surgery.76 A significantly greater proportion of
patients receiving fentanyl ITS reported “excellent”
postoperative pain control (50.0% vs. 40.2%; P =
0.039). In terms of pain scores, fentanyl ITS was
equivalent to morphine intravenous PCA over the 72-
hour study period.76 Further, patients in both groups
consumed similar amounts of supplemental analgesics
after the first 3 postoperative hours, and the incidence of
opioid-related adverse events was similar in the 2 groups.
While not superior to intravenous PCA with morphine, in
terms of safety or efficacy, patients receiving fentanyl ITS
were more likely to report greater ease-of-care scores,76
suggesting that fentanyl ITS may improve ease of care,
perhaps by reducing the frequency of analgesic gaps.
A secondary subset analysis was conducted on data
from a randomized, multicenter, clinical trial comparing
the safety and efficacy of fentanyl ITS with that of
intravenous PCA with morphine for postoperative pain
relief after major abdominal or orthopedic surgery
under general or spinal anesthesia.77 Although the
analysis was qualitative, in general, the results demon-
strated similar efficacy (evaluated by pain intensity
scores, patient and investigator assessment, and supple-
mental analgesic use) for fentanyl ITS and intravenous
PCA with morphine over the first 24 postoperative
hours, regardless of type of surgery (spine, hip, knee,
lower or upper abdominal, or pelvic), gender, ASA
status (I or II), or type of anesthesia (spinal or general).77

Across all subsets, the incidence of adverse events was
largely similar among the 2 treatment groups. Applica-
tion-site reactions did occur in up to half of patients
receiving fentanyl ITS; however, most of these were mild
or moderate and resolved without treatment.77 Fentanyl
ITS may represent a comparable and potentially safer
alternative to intravenous PCA with morphine for
postoperative pain management.
PCSA. A new, patient-controlled, sublingual, sufentanil
system (ARX-01 Sufentanil NanoTab PCA System;
AcelRx Pharmaceuticals, Inc) is underdevelopment and
designed to overcome the key disadvantages of intrave-
nous PCA; namely, drug-related adverse events, infec-
tions of indwelling intravenous catheters, human
programming errors related to the PCA pump, and
excessive somnolence.75,78 Little published literature is
available on this sufentanil PCSA system, although the
company producing the product reports that in 3
multicenter, randomized, double-blind, placebo-con-
trolled, Phase II, clinical trials, patients undergoing
unilateral knee arthroplasty or major abdominal surgery
experienced significantly less postoperative pain with
the sufentanil PCSA system.78
CONCLUSION
Many new analgesic medications and techniques have
been developed that target the preoperative, intraoper-
ative, or postoperative periods to reduce acute postop-
erative pain. These include preoperative use of NSAIDs,
anxiolytics, and anticonvulsants; intraoperative use of
neuraxial analgesia, continuous local anesthetic wound
infusion, TAP block, EREM, intravenous acetamino-
phen, and intravenous ketamine; and postoperative use
of intravenous ibuprofen, new opioids (eg, tapentadol)
or opioid formulations (morphine–oxycodone), and
PCA approaches (eg, PCRA, PCINA, PCTA, PCSA).
Many of these analgesic medications and techniques
have demonstrated analgesic superiority to placebo and
comparable analgesic efficacy to traditional approaches,
coupled with a reduction in adverse events. Several of
the newer medications and techniques show potential to
improve analgesia and minimize the risk of adverse
events, although additional research is needed to estab-
lish their efficacy and safety profile. New targeted
approaches to acute postoperative pain management
may provide safer and more effective analgesia than
traditional approaches such as postoperative oral
analgesics.
Advances in Acute Postoperative Pain  485
ACKNOWLEDGEMENTS
Technical editorial and medical writing support for the
development of this article was provided by Karamarie
Fecho, PhD, for Synchrony Medical Communications,
LLC, West Chester, PA. Funding for this support was
provided by Mallinckrodt Inc, the Pharmaceuticals
business of Covidien, Hazelwood, MO.
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