REVI EW ARTI CLE

Recent Management Advances in Acute

Postoperative Pain
Charles E. Argoff, MD
Albany Medical College Neurology Group, Albany, New York, U.S.A.
& Abstract
Introduction: Acute postoperative pain remains a major
problem, with both undertreatment and overtreatment
leading to serious consequences, including increased risk of
persistent postoperative pain, impaired rehabilitation,
increased length of stay and/or hospital readmission, and
adverse events related to excessive analgesic use, such as
oversedation. New analgesic medications and techniques
have been introduced that target the preoperative, intraop-
erative, and postoperative periods to better manage acute
postoperative pain, with improvements in analgesic efcacy
and safety over more traditional pain management
approaches. This review provides an overview of these new
analgesic medications and techniques. Specic topics that are
discussed include the use of preoperative nonsteroidal anti-
inammatory drugs, anxiolytics, and anticonvulsants; intra-
operative approaches such as neuraxial analgesia, continuous
local anesthetic wound infusion, transversus abdominis plane
block, extended-release epidural morphine, intravenous
acetaminophen, and intravenous ketamine; and postopera-
tive use of intravenous ibuprofen, new opioids (eg, tapent-
adol) or opioid formulations (morphineoxycodone), and
patient-controlled analgesia.
Conclusion: New, targeted, analgesic medications and tech-
niques may provide a safer and more effective approach to
the management of acute postoperative pain than tradi-
tional approaches such as postoperative oral analgesics. &
Key Words: acute pain, analgesia, preoperative, intraop-
erative, postoperative, perioperative, review
INTRODUCTION
An estimated 25 million inpatient surgeries and an
additional 35 million ambulatory surgeries are per-
formed annually in the USA.
1,2
Greater than 80% of
surgical patients experience postoperative pain, and
39% experience severe to extreme postoperative
pain.
3
The mismanagement of postoperative pain,
whether undertreatment or overtreatment, is associated
with a variety of negative consequences, including
cardiac alterations and increased risk of myocardial
ischemia or infarction, thromboembolic and pulmonary
complications, immune alterations, increased risk of
persistent postoperative pain, impaired rehabilitation,
increased length of stay and/or hospital readmission,
decreased quality of life, and adverse events related to
excessive analgesic use.
48
The consequences of overtreatment are often
overlooked but can be life-threatening. Indeed, an
observational study of surgical patients found high rates
of analgesic-induced oversedation in the rst 12 post-
operative hours, with dangerous levels of sedation
occurring in 72.7% of patients on patient-controlled
analgesia (PCA).
4
A chart review of trauma center site
surveys reported to the American College of Surgeons
Address correspondence and reprint requests to: Charles E. Argoff,
MD, Albany Medical College, 47 New Scotland Avenue, MC 70, Physicians
Pavilion, 1st Floor, Albany, NY 12208, U.S.A. E-mail: argoffc@mail.amc.edu.
Disclosures: Dr. Argoff has worked in an advisory/speakers bureau/
investigator capacity and received honoraria or grants from Endo Phar-
maceuticals Inc, Pzer Inc, Eli Lilly and Company, Forest Laboratories Inc,
and NeurogesX. He has also worked as an advisor for King Pharmaceu-
ticals, sano-aventis, Boehringer Ingelheim GmbH, Nuvo Research Inc, and
Jazz Pharmaceuticals plc, and has received honoraria from these compa-
nies for his expertise. Dr. Argoff has additionally served in the PriCara
speakers bureau and has received honorarium monies for his participa-
tion.
Submitted: February 06, 2013; Revision accepted: July 09, 2013
DOI. 10.1111/papr.12108
2013 World Institute of Pain, 1530-7085/13/$15.00
Pain Practice, Volume 14, Issue 5, 2014 477487
Committee onTrauma as part of their vericationprocess
identied 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.
PAINMANAGEMENT APPROACHES TARGETEDAT
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 fromthe
surgery itself; it is slowly replacing preemptive analgesia
as the more encompassing approach to postoperative
pain management.
9,10
Nonsteroidal anti-inammatory 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-inammatory drugs (NSAIDs) are
widely used analgesics, antipyretics, and anti-inam-
matory agents that act by inhibiting the enzyme
cyclooxygenase, which is responsible for the biosynthesis
of prostaglandins.
11
Inammation 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 signicantly less intense pain for
the rst 8 hours. However, the 2treatment groups didnot
differ from the placebo group in time to rst dose or
amount of postoperative analgesic used (recorded at
48 hours), or in pain intensity from 12 to 48 hours.
13
These ndings suggest limited efcacy 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 ndings 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 efcacy of NSAIDs should be weighed
against the risk of serious adverse events affecting the
gastrointestinal,
16
rensal,
17
and cardiovascular
18
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 efcacy and
safety of selective COX-2 inhibitors in the perioperative
setting identied 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 conicting, 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
478 ARGOFF
Anxiolytics
Anxiety is common prior to surgery and is associated
with poor outcomes, including severe postoperative
pain.
22
Researchers have explored the use of anxiolytics
for managing anxiety and pain, with positive results.
Midazolam is a benzodiazepine that is commonly
administered to decrease preoperative anxiety and
produce anesthesia.
23
A recent, randomized, double-
blind, clinical trial compared the efcacy and safety of
preoperative diclofenac (an NSAID) with or without
midazolam in patients undergoing hernia repair surgery
under general anesthesia.
24
The results showed that
compared with patients receiving diclofenac alone,
patients receiving preoperative midazolam in combina-
tion with diclofenac experienced signicantly less post-
operative pain in the rst 3 postoperative hours (6-point
Verbal Rating Scale [VRS] score, median [range]: 1.4 [0
to 4] vs. 2.4 [1 to 5]; P < 0.001). Thus, preoperative
midazolam can enhance the analgesic effects of diclofe-
nac. The combination of midazolam and diclofenac also
resulted in signicantly less nausea/vomiting, but with a
greater degree of sedation and hypotension than that
observed with diclofenac alone.
24
Whether midazolams analgesic effect is secondary to
its anxiolytic effect is unclear, although intrathecal
administration of midazolam to rats has been shown to
produce analgesic effects by actions on the GABA
A
receptor complex.
25
A randomized casecontrol study
of human patients undergoing lower abdominal, gyne-
cological, or orthopedic surgery under spinal anesthesia
found that intrathecal midazolam signicantly increased
the time to rst use of postoperative analgesics and
prolonged the duration of sensory blockade, without
increasing the incidence of sedation.
26
Anticonvulsants
Gabapentin and pregabalin are anticonvulsant drugs
that act at the a
2
d subunit of presynaptic, voltage-gated,
Ca
2+
channels.
27,28
The efcacy of preoperative gaba-
pentin and pregabalin in decreasing postoperative pain
has been investigated in randomized clinical trials and in
meta-analyses.
Arandomized, placebo-controlled, clinical trial of the
effects of a single preoperative dose (600 mg) of gaba-
pentin in patients undergoing cesarean delivery under
spinal anesthesia found a reduction in pain scores on
movement and at rest in the gabapentin group compared
with the placebo group, although postoperative opioid
consumption was similar in the two groups.
29
Severe
sedation was greater in the gabapentin group, but no
signicant group difference was found in the incidence of
postoperative nausea and vomiting, or in neonatal
outcomes.
29
A meta-analysis of the effects of gabapentin in
randomized, controlled, clinical trials found that pre-
operative gabapentin produced a signicant decrease in
postoperative analgesic consumption.
30
In this review,
preoperative gabapentin was found to produce a signif-
icant decrease in vomiting (but not nausea); however, its
use was associated with a signicant increase in sedation
and dizziness.
30
A randomized, double-blind, placebo-controlled,
clinical trial of the effects of 2 perioperative doses of
pregabalin (75 mg each, administered 1 hour before
surgery and 12 hours after the rst dose) in patients
undergoing mastectomy under general anesthesia
showed that compared with patients receiving placebo,
patients receiving pregabalin experienced less pain at
rest over the rst 48 postoperative hours (48-hour 11-
point Verbal Numerical Rating Scale [VNRS] score at
rest, median [range]: 0 [0 to 4] for pregabalin vs. 2 [1 to
5] for placebo; P < 0.001) and with arm abduction for
1 week after surgery (1-week VNRS score, median
[range]: 1 [0 to 4] for pregabalin vs. 3 [0 to 5] for
placebo; P < 0.001), with an exception of the 6-hour
postoperative time point).
31
There was no group differ-
ence in sedation, postoperative nausea and vomiting, or
postoperative analgesic use.
31
A meta-analysis of the effects of pregabalin in
randomized, placebo-controlled, clinical trials found
that perioperative (preoperative or pre/postoperative)
administration of pregabalin produced a signicant
decrease in postoperative pain at rest (Hedges g effect
size: 0.31; 95% condence interval [CI]: 0.50, 0.12)
and with movement (Hedges g effect size: 0.27; 95%
CI: 0.50, 0.05), and in postoperative analgesic use
(Hedges g effect size: 0.32; 95% CI: 0.49, 0.14 for
studies with no group difference in pain scores at rest;
Hedges g effect size: 0.98; 95% CI: 1.58, 0.38 for
studies with a group difference in pain scores at rest).
32
However, these effects were accompanied by an increase
in dizziness or lightheadedness andvisual disturbances.
32
PAINMANAGEMENT APPROACHES TARGETEDAT
THE INTRAOPERATIVE PERIOD
Intraoperative analgesic techniques and formulations
include neuraxial analgesia, continuous local anesthetic
Advances in Acute Postoperative Pain 479
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 eld, periph-
eral nerve blocks targeting the nerve innervating the
surgical eld, and local nerve blocks targeting local
tissue in the surgical eld.
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 conicting evidence regarding the benet 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
eld was introduced as a simple alternative to neuraxial
or peripheral nerve blockade for the management of
postoperative pain. When infused into the surgical eld,
local anesthetics produce analgesic effects by direct
inhibition of afferent nociceptive signaling and direct
inhibition of the local inammatory 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 signicantly lower pain scores at rest over the rst
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 rst 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 signi-
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 signicantly 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 rst 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 conicting 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 rst described by Ra
40
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
identied 7 randomized, double-blind, clinical trials and
found that in 4 of the 7 trials, pain scores at rest and
with motion were signicantly decreased in the early
480 ARGOFF
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 conrmed 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 ndings 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
efcacy 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
EREMproduced 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 rst 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 signicant 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
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 signicantly 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 safetyandefcacy
of perioperative (primarily intraoperative) intravenous
acetaminophenfor 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 rst 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.
Advances in Acute Postoperative Pain 481
A randomized, double-blind, placebo-controlled,
clinical trial evaluated the effects of intravenous or
subcutaneous inltration 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 signicantly 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 signicantly
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 identied 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
PAINMANAGEMENT APPROACHES TARGETEDAT
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 constipation
56
with opioids,
and gastrointestinal injury,
16
myocardial infarction or
stroke,
18
and acute renal failure
17
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 signicant
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 rst 24 postoperative hours.
59
A 400-mg
intravenous dose of ibuprofen was less effective.
59
In
terms of adverse events, nausea and pyrexia were
signicantly less common among patients receiving
intravenous ibuprofen than among patients receiving
placebo, but dizziness was signicantly more common
among patients receiving the 800-mg dose of intrave-
nous ibuprofen.
59
A recent review of clinical trials on the efcacy and
tolerability of intravenous ibuprofen in hospitalized
adult patients concluded that 800 mg of intravenous
ibuprofen every 6 hours after surgery was efcacious 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, atulence, 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
482 ARGOFF
New Opioids and Opioid Formulations
New opioids and opioid formulations are being devel-
oped with unique pharmacodynamic proles 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 efcacy of tapentadol for the
treatment of pain after bunionectomy found that
tapentadol has similar efcacy 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 xed ratio (3:2) of
morphine to oxycodone.
65
A randomized, double-blind,
placebo-controlled, clinical trial of morphineoxyco-
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 morphineoxyco-
done had greater pain relief (responders: 65%for 18/12-
mg morphineoxycodone 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 morphineoxycodone vs.
3.3 0.31 for placebo; exact P value not reported)
over the rst 48 postoperative hours.
66
Nausea was the
most common adverse event among patients receiving
morphineoxycodone, occurring in 38% to 65% of
patients. Somnolence was the least common adverse
event, occurring in 2% to 8% of patients receiving
morphineoxycodone, 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 morphineoxycodone 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 rst
24 hours was superior with the morphineoxycodone
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
recognizedas a safe andeffective methodof 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-controlledintranasal 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 efcacy 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 basalbolus) 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 signicantly less supplemen-
tal ketoprofen (mean SD: 200 100 mg for continu-
ous ropivacaine infusion, 100 100 mg for basalbolus
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 inammation, over
72 postoperative hours.
69
Additionally, patients receiving
perineural PCRAwith ropivacaine (particularly by basal
bolus infusion) showed greater rehabilitation, including
Advances in Acute Postoperative Pain 483
walking for 10 minutes and participation in daily activ-
ities at home.
69
Another randomized, double-blind, placebo-con-
trolled, clinical trial compared the efcacy 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
efcacious 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 efcacy 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 rst 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 rst 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
comparedwith patients receiving PCINAwith 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
signicant.
73
Although nasal irritation is common after
PCINAwithketorolac, this approachappears tobe 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 PCArelated 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 efcacy of the fentanyl ITS with that of intravenous
PCAwith morphine in patients undergoing abdominal or
pelvic surgery.
76
A signicantly 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 rst 3 postoperative hours, and the incidence of
opioid-related adverse events was similar in the 2 groups.
While not superior tointravenous PCAwithmorphine, in
terms of safety or efcacy, 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
froma randomized, multicenter, clinical trial comparing
the safety and efcacy 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 efcacy (evaluated by pain intensity
scores, patient and investigator assessment, and supple-
mental analgesic use) for fentanyl ITS and intravenous
PCA with morphine over the rst 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
484 ARGOFF
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. Anew, 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 signicantly 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 (morphineoxycodone), and
PCA approaches (eg, PCRA, PCINA, PCTA, PCSA).
Many of these analgesic medications and techniques
have demonstrated analgesic superiority to placebo and
comparable analgesic efcacy 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 efcacy and safety prole. New targeted
approaches to acute postoperative pain management
may provide safer and more effective analgesia than
traditional approaches such as postoperative oral
analgesics.
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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