Anesthesiology Clin N Am

23 (2005) 185 – 202

Multimodal Analgesia Techniques and

Postoperative Rehabilitation
Girish P. Joshi, MB, BS, MD, FFARCSI
Perioperative Medicine and Ambulatory Anesthesia, University of Texas,
Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9068, USA

Advances in our understanding of the pathophysiology of postoperative pain

have led to the development of effective perioperative analgesic regimens [1]. It
is now well recognized that pain is a complex and multifactorial phenomenon
and therefore requires a multimodal therapy [1]. The concept of multimodal or
‘‘balanced’’ analgesia suggests that combinations of several analgesics of
different classes and different sites of analgesic administration rather than single
analgesic or single technique provide superior pain relief with reduced analgesic-
related side effects [1–3].
It has been assumed that multimodal analgesia regimens will improve pain
relief, reduce opioid requirements, and opioid-related side effects and thus will
improve surgical outcome. However, although numerous studies [3–8] have
shown opioid sparing effects of multimodal analgesia techniques, this method
has not resulted in reduced opioid-side effects. Furthermore, the improved pain
relief from multimodal analgesia techniques has not translated into improved
postoperative outcome [4–8]. The reasons for the lack of improved postoperative
outcome are not yet clear. Reasons may in part be inappropriate combinations of
analgesics or techniques. The combinations used may not be rational, because
they may not block the different types of pain responses resulting from surgical
insult (ie, inability to block nociceptive as well as inflammatory pain responses).
Another reason may be the use of analgesic techniques that may improve pain
relief at rest but may not control movement-evoked pain (dynamic pain relief).
Most importantly, even though dynamic pain relief is achieved, it is not always
integrated with a multimodal postoperative rehabilitation program [5–8].

E-mail address: [email protected]

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doi:10.1016/j.atc.2004.11.010 anesthesiology.theclinics.com
186 joshi

This article reviews the analgesic options for postoperative pain management
and their benefits and limitations, but it is not intended to provide detailed
discussion on individual analgesic techniques because they are covered else-
where in this issue. In addition, the optimal analgesic combinations are sug-
gested, and the role of multimodal rehabilitation techniques in improving
surgical outcome is discussed.

Analgesia options for multimodal techniques

In addition to opioids, the analgesic modalities available for postoperative

pain management include regional or local analgesia techniques such as epidural
analgesia and peripheral nerve blocks as well as wound infiltration and intra-
articular or intracavity administration of local anesthetics. In addition, cyclo-
oxygenase (COX) enzyme blockers such as acetaminophen, nonsteroidal
anti-inflammatory drugs (NSAIDs) or COX-2– specific inhibitors are becoming
popular. Recently, there has been an increased interest in using analgesic adjuncts
such as N-methyl-d-aspartate (NMDA) receptor antagonists (eg, ketamine and
dextromethorphan), a2 agonists (eg, clonidine and dexmedetomidine), anti-
convulsants (eg, gabapentin and pregabalin), and corticosteroids.

Opioids

Opioids are efficacious analgesics that are particularly suited for moderate to
severe postoperative pain. However, they are limited by their significant side
effects. Opioid use has been associated with dose-related adverse effects
including nausea, vomiting, sedation, dizziness, drowsiness, bladder dysfunction,
and constipation, all of which may contribute to a delayed recovery [9]. Opioids
also reduce gastrointestinal motility and contribute to postoperative ileus. In
addition, opioids affect sleep patterns, which may increase postoperative fa-
tigue [10]. Furthermore, recent data [11,12] suggest that clinically relevant
tolerance to opioids can occur within hours of their use, which may reduce their
analgesic efficacy.
Although opioids, particularly when administered through an intravenous
patient-controlled analgesia (IV-PCA) system, improve patient satisfaction,
they do not improve postoperative morbidity or reduce hospital stay [13,14].
The lack of improved outcome with opioids, irrespective of the route of admin-
istration, may be related to their inability to reduce surgical stress responses.
Furthermore, although opioids reduce spontaneous pain (rest pain), their ability
to control dynamic pain is limited [14]. Recent evidence suggests that dynamic
pain may contribute to postoperative physiologic impairment, and dynamic pain
has also been identified as a major risk factor in the development of chronic
persistent postoperative pain.
Therefore, it is now well recognized that opioids should be used sparingly.
The concept of opioid-free or opioid-reduced analgesia is receiving increasing
 multimodal analgesia and postoperative rehabilitation 187

attention [15]. Thus, it is recommended that nonopioid analgesics and tech-

niques be used as the first line of therapy and that opioids should be reserved
for more severe pain that is not adequately controlled with nonopioids.

Epidural analgesia

Epidural analgesia provides superior dynamic pain relief and reduces the
endocrine-metabolic stress response to surgery, which may prevent postoperative
organ dysfunction and reduce morbidity. As a consequence, epidural analge-
sia may reduce postoperative complications and enhance rehabilitation [16–20].
However, numerous meta-analyses and systematic reviews [21] have reported
conflicting results. These controversial findings may be the result of an in-
adequate number of appropriately designed randomized, controlled trials and the
inclusion of studies with numerous variables that influence the efficacy of epi-
dural analgesia (eg, the choice of analgesic, catheter surgical incision con-
gruence, and duration of analgesia) in the same analysis. Importantly, the value
of epidural analgesia in improving postoperative outcome and reducing hospital
stay remains controversial [5–8].
The lack of consistently improved outcome with epidural analgesia may in
part be caused by incongruence between the epidural catheter site and surgical
injury and the use of a predominantly opioid-based rather than local anesthetic-
based epidural solution. An optimum epidural analgesia technique includes
catheter placement in a location congruent to the surgical incision dermatome
(eg, thoracic epidural for thoracic and upper abdominal surgery or lumbar
epidural for lower limb surgery) and an infusion consisting of a local anesthetic
with or without low-dose opioid that is administered for at least 24 to 48 hours.
The use of adjuncts (eg, epinephrine, clonidine, and ketamine) along with the
local anesthetic solution remains controversial, and its routine use is not
recommended at this time.
It is now recognized that the inflammatory responses to injury (eg, increase in
cytokines) are not modified by neural blockade. Current evidence [22] suggests
that the combination of COX-2 inhibitors (ie, NSAIDs and COX-2– specific
inhibitors) with epidural analgesia (both initiated preoperatively and continued
during the postoperative and rehabilitative phase) reduces postoperative pain and
opioid consumption and reduces the recovery time.

Continuous peripheral nerve blocks and paravertebral blocks

Peripheral nerve blocks provide superior dynamic pain relief and should also
reduce surgical stress and enhance rehabilitation. Because these techniques
provide site-specific analgesia, they are associated with fewer side effects com-
pared with other analgesic techniques [23]. However, the duration of analgesia
after a single-shot technique is limited. In fact, the abrupt termination of the
188 joshi

analgesic effect may lead to an increased perception of pain after the recovery
from the neural blockade [24]. In addition, single-shot techniques may not have
any long-term benefits compared with general anesthesia [25]. Continuous
peripheral nerve blocks should prolong the benefits of single-shot peripheral
nerve blocks and thus should form the basis of postoperative pain management
whenever possible. Similarly, continuous paravertebral blocks provide segmen-
tal analgesia, which may be similar to thoracic epidural analgesia but with lower
incidence of side effects such as hypotension and urinary retention. Continu-
ous peripheral nerve blocks and paravertebral blocks have a major role in pain
management because they enhance ambulation, reduce opioid-related side
effects, facilitate early hospital discharge, and expedite the return to daily living.
However, these techniques have been underused. The use of continuous periph-
eral nerve blocks and paravertebral blocks is reviewed elsewhere in this issue.
Concerns regarding continuous peripheral nerve blockade include patient
injury related to the insensate extremity, particularly after discharge. Catheter
migration, potential local anesthetic toxicity, masking of surgical-related nerve
injury, and compartment syndrome are other concerns. There is clearly a need for
a refinement of peripheral nerve block techniques and the development of more
effective methods for continuous administration. The availability of longer-
acting, slow-release preparations that incorporate local anesthetics into liposomes
(or microspheres), which extend the duration of action, should enhance the
efficacy of local anesthetic techniques. However, these agents are not yet avail-
able for clinical use. Most importantly, there is a need for larger, well-designed
studies showing improved postoperative outcomes with continuous peripheral
nerve blocks and continuous paravertebral blocks.

Acetaminophen

Acetaminophen is a widely used over-the-counter analgesic and antipyretic

drug; however, it is underused in the perioperative period. Although the
mechanism of action of acetaminophen is poorly understood, it is believed to act
by the inhibition of the COX-3 isoenzyme and subsequent reduced prostanoid
release in the central nervous system [26–28]. In addition, there is some
suggestion that it acts on the opioidergic system and NMDA receptors.
Acetaminophen is devoid of some of the side effects of nonselective NSAIDs,
such as impaired platelet aggregation, gastrointestinal ulceration and hemor-
rhage, and cardiorenal adverse effects [29,30]. Furthermore, unlike nonselective
NSAIDs and COX-2–specific inhibitors, acetaminophen does not have clinically
significant effects on bone and ligament healing [29,30]. Although it is gen-
erally considered safe, acetaminophen is associated with liver and gastrointes-
tinal toxicity at high doses [31–33]. It is a weak analgesic, and therefore it is only
suitable for the treatment of mild pain [29,30]. Furthermore, it has a weak anti-
inflammatory activity and may not be suitable for blocking inflammatory pain
response [26].
 multimodal analgesia and postoperative rehabilitation 189

The availability of injectable forms of acetaminophen (prodrug, propacetamol,

and paracetamol) has expanded our knowledge of the pharmacodynamics of
acetaminophen, such as the relationship between peak concentrations and clinical
efficacy [34]. Recently, a ready-to-use intravenous formulation of paracetamol
has been made available in Europe. Intravenous paracetamol, 1 g, has similar
analgesic efficacy as propacetamol, 2 g, the prodrug of acetaminophen. The
initial dose of injectable acetaminophen may be administered intraoperatively
and may be followed by an oral administration after the patient is discharged.
Compared with oral formulations, parenteral acetaminophen has a predictable
onset and duration of action [34]. In addition, oral acetaminophen may be less
efficacious because intraoperative opioids as well as inhaled anesthetics delay
gastric emptying and reduce gastrointestinal absorption of orally administered
drugs [35,36].
Acetaminophen has a favorable efficacy-side effect profile and is therefore rec-
ommended as the first-line analgesic. Although acetaminophen is a weak anal-
gesic and may not be adequate as the sole analgesic, it may be combined with
other analgesics to provide superior analgesia and reduce opioid requirements
[37,38]. However, acetaminophen displays an analgesic ceiling effect similar to
NSAIDs and COX-2–specific inhibitors [39]. Importantly, patients should be
warned that commonly used opioid combinations consist of acetaminophen.

Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2–specific inhibitors

The nonselective (traditional) NSAIDs are one of the most widely used
analgesics [40,41]. With the introduction of parenteral preparations of NSAIDs
(eg, ketorolac, diclofenac, and ketoprofen), these drugs have become more
popular in the management of postoperative pain. The mechanism of the NSAID
analgesic effect is the inhibition of the COX-2 enzyme. It has been increasingly
apparent that, in an inflammatory model, the COX-2 enzyme plays an important
role in peripheral and central sensitization [1]. Emerging evidence [1] from
animal studies indicates that the early and sustained inhibition of the COX-2
enzyme may prevent the damaging modifications to neuronal function that would
otherwise result in postoperative morbidity.
Therefore, the nonspecific NSAIDs should reduce sensitization of nocicep-
tors, attenuate inflammatory pain response, prevent central sensitization, and thus
improve postoperative pain relief. The other potential advantages of NSAIDs
include reduced opioid requirements and possibly opioid-related side effects.
Macario and Lipman [42] compiled randomized, controlled trials of ketorolac
versus placebo with opioids given for breakthrough pain that were published in
English-language journals from 1986 to 2001. They found that 70% of patients
in control groups experienced moderate-to-severe pain at 1 hour postoperatively,
whereas 36% of the control patients had moderate-to-severe pain 24 hours
postoperatively. Although ketorolac was efficacious, analgesia was improved in
patients receiving a combination of ketorolac and opioids. Depending on the
type of surgery, ketorolac reduced opioid dose requirements by a mean of 36%
190 joshi

(range 0%–73%), but this did not result in a concomitant reduction in opioid side
effects (eg, nausea and vomiting). This may have resulted from the studies
having sample sizes that were inadequate for detecting differences in the inci-
dence of opioid-related side effects. The risk for adverse events increased with
high doses, with prolonged therapy (N5 days), and in the elderly. The authors
concluded that although ketorolac appears to be safe, it should be used at the
lowest dose necessary.
Despite numerous benefits [40–42], nonselective NSAIDs are not routinely
used because of concerns regarding their potential side effects such as impaired
coagulation (and increased perioperative bleeding), gastric irritation (particularly
when these drugs are administered in fasting patients), and renal dysfunction
[43]. NSAIDs should not be used in patients with pre-existing coagulation
defects or those undergoing certain surgical procedures (eg, tonsillectomy and
plastic surgery). Similarly, this group of drugs should be avoided in patients with
pre-existing renal dysfunction, hypovolemia, cardiac failure, sepsis, or end-stage
liver disease [44]. Finally, NSAIDs should be used with caution in the elderly
and in clinical situations in which prostaglandins have proven therapeutic
benefits, such as circulatory insufficiency, myocardial ischemia, and coronary
vasospasm [45].
A large prospective, randomized multicenter European trial [46] evaluated the
risks of death, increased surgical site bleeding, gastrointestinal bleeding, acute
renal failure, and allergic reactions with the short-term use (5 days) of
appropriate doses of ketorolac compared with diclofenac or ketoprofen. Of the
11,245 patients included in the study, 5634 patients received ketorolac, and
5611 patients received one of the comparators. In the 30-day postoperative
follow-up, 155 (1.38%) patients experienced a serious adverse outcome, with
19 (0.17%) deaths, 117 (1.04%) with surgical site bleeding, 12 (0.12%) with
allergic reactions, 10 (0.09%) with acute renal failure, and four (0.04%) patients
with gastrointestinal bleeding [46]. There were no differences between ketorolac
and ketoprofen or diclofenac. Postoperative anticoagulants increased equally the
risk of surgical site bleeding with both ketorolac and the comparators. Other risk
factors for serious adverse outcomes were age, American Society of Anesthesi-
ologists physical status, and the type of surgical procedure (eg, plastic, ear, nose
and throat, gynecological, and urological surgery). The authors concluded that
the side effect profile of ketorolac is similar to other injectable nonselective
NSAIDs, provided the contraindications to its use are observed [46].
Thus, although the overall adverse events with nonselective NSAIDs are not
increased in the perioperative period, the contraindications to their use are
numerous [43–47]. Therefore, the limitations of nonselective NSAIDs prevent
their use even when they would otherwise be desirable. The development of
COX-2–specific inhibitors, a new group of anti-inflammatory and analgesic
drugs, which selectively target COX-2 while sparing COX-1, were developed to
obtain the therapeutic benefits of NSAIDs while overcoming their limitations
(see elsewhere in this issue). Although COX-2–specific inhibitors seem to have
analgesic efficacy that is similar to nonselective NSAIDs, they may have an
 multimodal analgesia and postoperative rehabilitation 191

advantage over nonselective NSAIDs because they do not affect platelet function
and reduce the risk of gastrointestinal ulceration [48–51]. Because of the lack of
antiplatelet effects and improved gastrointestinal tolerability, COX-2–specific
inhibitors may be safely administered preoperatively.
Until recently, three COX-2–specific inhibitors, celecoxib, rofecoxib, and
valdecoxib, were available in the United States. However, rofecoxib was recently
removed from the market because of concerns over its association with an
increased risk of cardiovascular events. Parecoxib is the first injectable
COX-2–specific inhibitor approved in Europe for the short-term treatment of
moderate to severe postoperative pain. It is currently undergoing Phase III
clinical trials for approval by the US Food and Drug Administration [52,53].
The perioperative dosage of celecoxib is initially 400 mg, followed by 200 mg
twice per day, whereas the dosage for valdecoxib is initially 40 mg, followed
by 20 mg twice per day. Of note, the COX-2–specific inhibitors also exhibit a
‘‘ceiling effect’’ with respect to their maximum analgesic effect, similar to
nonspecific NSAIDs. Furthermore, the currently available COX-2–specific
inhibitors (ie, celecoxib and valdecoxib) are contraindicated in patients with a
history of sulphonamide allergy, and the cardiorenal precautions with these drugs
are similar to those of nonselective NSAIDs.

Nitric oxide-releasing derivatives of acetaminophen and nonsteroidal

anti-inflammatory drugs

The nitric oxide (NO) moiety significantly improves the analgesic effects of
acetaminophen and NSAIDs, possibly because of the involvement of NO in
the nociceptive process [54,55]. NO modulates spinal and sensory neuron
excitability through multiple mechanisms. In particular, the moiety stimulates the
formation of cGMP by guanylyl cyclase in neurons and, depending on the
expression of cGMP-gated ion channels, may result in an increased or reduced
neuronal excitability [54,55]. Moreover, NO is involved in inflammatory
processes associated with neuropathic pain subsequent to peripheral nerve
injury. In addition, animal studies [56–58] indicate that the gastrointestinal
mucosal damage, prostaglandin release, and changes in mucosal blood flow
associated with some analgesics are significantly reduced because of NO-
dependent mechanisms. This has lead to the development of combinations of a
nitrate with a conventional analgesic, the NO-releasing analgesics [56–58]. The
NO-donating analgesics should have enhanced efficacy and an improved side
effect profile compared with their parent drug. There is increasing evidence
suggesting that NO-donating NSAIDs (eg, NO-aspirin, NO-naproxen, NO-
flurbiprofen, NO-diclofenac, NO-ibuprofen, and NO-acetaminophen) have anti-
inflammatory and antinociceptive effects similar to that of their parent compound
but without the adverse effects such as gastrointestinal toxicity and hepato-
tocixity, because of the protective effects of NO on the gastric mucosa and
hepatocytes. For example, NCX-701 is an NO-releasing derivative of acetamino-
phen, synthesized for the potential treatment of inflammation and pain [59].
192 joshi

N-methyl-D -aspartate receptor antagonists

Recently, excitatory neurotransmitters acting through NMDA receptors have

been incriminated in the development and maintenance of hyperalgesia and
allodynia and persistent postoperative pain. [1]. Although the analgesic proper-
ties of ketamine have been well known for a long time, the precise mechanisms
are still unclear. In addition to its effects on the NMDA receptor [60], ketamine
may also act on several receptor systems such as opioidergic and cholinergic as
well as monoaminergic systems and may have local anesthetic effects through
the sodium channel blockade. Therefore, ketamine may play a role in peri-
operative pain management [61–63]. However, the optimal dose and route of
administration of ketamine remain controversial.
Low-dose ketamine (0.25–0.5 mg/kg, IV, or 25–50 mg/kg/min infusion)
reduces opioid consumption, prolongs analgesia, and improves pain relief
prevents tolerance to opioids. De Kock et al [64] found that intravenous but not
epidurally administered ketamine reduced mechanical hyperalgesia surrounding
the surgical wound, reduced early morphine consumption, and diminished the
incidence of residual pain as expressed by analgesic requirements until the sixth
postoperative month. These findings correlate with those of Zahn and Brennan
[65] who reported the lack of neuraxial effects of ketamine in a rat postoperative
model. Similarly, the administration of ketamine with IV-PCA morphine does
not appear to provide any benefit over IV-PCA morphine alone. However, be-
cause of the lack of consistent benefits and possibility of side effects (eg, hemo-
dynamic and psychotomimetic effects), ketamine may be reserved for situations
in which routine analgesics are ineffective or limited by their side effects.

a2 Receptor agonists

a2 Receptor agonists (eg, clonidine and dexmedetomidine) provide sedative

and analgesia sparing effects through central actions in the locus ceruleus and in
the dorsal horn of the spinal cord, respectively [66]. When administered orally,
intravenously, or transdermally, clonidine may reduce opioid requirements and
improve analgesia. Similarly, the addition of clonidine to the local anesthetic
solution for neuraxial or peripheral nerve blocks may enhance and prolong
analgesia. However, the analgesic benefits of clonidine remain controversial. In
addition, clonidine is limited by its side effects, including bradycardia, hypo-
tension, and excessive sedation.
Compared with clonidine, dexmedetomidine is more selective and has a
shorter duration of action. When used in the perioperative period, it has anes-
thetic and opioid sparing effects. Dexmedetomidine does not cause respiratory
depression, despite its potent sedative effects. Because of its opioid sparing
effects [67], it is increasingly used in patients at high risk of airway obstruction
and respiratory depression associated with opioids (eg, patients with sleep apnea
and morbid obesity). Initial studies recommended a loading dose of dexmede-
 multimodal analgesia and postoperative rehabilitation 193

tomidine, 1 mg/kg, followed by an infusion of 0.4 mg/kg/h. However, this

regimen may increase cardiovascular side effects (bradycardia and hypotension).
Therefore, the avoidance of a loading dose may be preferred. Of note, most
studies have evaluated the use of dexmedetomidine in the intraoperative or
immediate postoperative period, therefore its long-term benefits are not yet clear.

Gabapentin and pregabalin

Gabapentin and pregabalin are structural analogs of g-aminobutyric acid and

can be used for the treatment of persistent neuropathic pain [68]. Although the
mechanisms of action of gabapentin and pregabalin are not clear, it is believed
they act through the modulation of the a2d-1 subunit of the voltage-dependent
calcium channels in the dorsal horn of the spinal cord [69]. Recent studies have
evaluated the efficacy of gabapentin in the management of postoperative pain.
Fassoulaki et al [70] compared the analgesic effects of gabapentin, 1200 mg,
and mexiletine, 600 mg, after breast surgery for cancer. They found that both
gabapentin and mexiletine equally reduced analgesic requirements at rest; how-
ever, gabapentin was more effective in reducing pain after movement. Similarly,
Dirks et al [71] reported that gabapentin, 1200 mg, before surgery reduced
postoperative morphine requirements and movement-related pain after radical
mastectomy. Pregabalin, 300 mg orally, has been shown to reduce pain after third
molar extraction [72]. However, gabapentin and pregabalin cause dizziness and
somnolence. Studies with larger sample sizes and optimal dosing regimens are
required before gabapentin or pregabalin can be recommended in the periopera-
tive period.

Glucocorticoids

Glucocorticoids have anti-inflammatory properties, block the COX and

lipooxygenase enzymes, and have the potential to reduce pain and to improve
postoperative outcome by reducing the inflammatory response to surgical stress.
Recently, preoperative dexamethasone (4–8 mg, IV) has been shown to have
analgesic effects and to reduce postoperative nausea and vomiting. Although no
side effects have been observed with a single dose of dexamethasone in large
studies [73], there is a potential for increased gastrointestinal side effects as well
as delayed wound healing.

Optimal multimodal analgesia techniques

An ideal analgesic combination would reduce the intensity of movement-

evoked pain and the surgical stress response, improve postoperative outcome,
and reduce the need for hospitalization. Another potential benefit of multimodal
analgesia techniques is the reduction of analgesic-related adverse effects. It is
crucial to reduce not only major adverse effects (eg, respiratory depression with
194 joshi

opioids) but also minor, so-called annoying, side effects because patients usually
choose pain relief for less upsetting or less severe side effects [74]. Most
importantly, an optimal analgesic technique would be individualized to each
patient’s needs and specific to a surgical procedure.
Kehlet and Dahl [2] reported improvement in postoperative analgesia using
multimodal analgesia techniques. Almost a decade after their initial report,
Kehlet et al [3] reassessed the benefits of multimodal analgesia and found that
combining different analgesics improved postoperative analgesia. However, they
did not find any reduction in analgesic adverse effects. Jin and Chung [4]
analyzed randomized, controlled trials published up until 2000, evaluating the
effects of multimodal analgesia on postoperative pain relief and recovery pro-
file after outpatient and inpatient surgery. They too found that multimodal
analgesia techniques improved postoperative pain relief in both outpatients
and inpatients. However, an improvement in recovery profile (eg, reduced dis-
charge time, early mobilization, and early convalescence) was not consistently
observed. They noted that, unfortunately, not all studies evaluated postoperative
recovery profile.
Although initially it was assumed that multimodal analgesia would reduce the
incidence of adverse effects, most studies have not been able to validate these
assumptions [2–4]. For example, the use of NSAIDs has been shown to reduce
opioid requirements by 20% to 40%. However, these studies have not shown a
consistent reduction in opioid-related side effects [2–4]. Similarly, commonly
used combinations of acetaminophen and NSAIDs have not been shown to
reduce opioid side effects [38]. Unfortunately, most studies evaluating multi-
modal analgesia techniques are inadequately powered to detect a reduction in
side effects, or they have not adequately evaluated analgesic side effects. For
example, most commonly, only the incidence of side effects is evaluated but
not their severity or resultant patient distress (ie, bothersomeness). However,
more recent studies have used a symptom distress scale, which examines opioid
side effects in much greater detail and provides information on clinically
meaningful events [52,53]. It appears that an optimal analgesic technique should
be potent enough to reduce opioid requirements by at least 30% to reduce opioid
side effects [75].
How does one determine optimal analgesic combinations? With numerous
analgesic options, it can be difficult for clinicians to decide on the optimal
number and type of analgesic combination for a specific surgical procedure.
The choice of analgesic combination is generally based on the type, efficacy,
and side effect profile of the analgesic modality for a specific surgical procedure.
Neural blockade should be used whenever possible. The choice of the local
anesthetic technique would depend on the type of surgical procedure. For
example, for minor outpatient surgical procedures, local anesthetic infiltration
of the surgical wound, intracavity, or field blocks may be adequate. For more
extensive ambulatory surgical procedures, peripheral nerve block or para-
vertebral blocks may be preferred. Continuous peripheral nerve or paravertebral
blocks provide prolonged analgesia after discharge and may be used, parti-
 multimodal analgesia and postoperative rehabilitation 195

cularly after extensive painful outpatient surgical procedures requiring rigor-

ous rehabilitation.
For major surgical procedures in hospitalized patients (eg, thoracic surgery,
upper abdominal surgery, major vascular surgery, and hip and knee surgery),
continuous epidural analgesia with local anesthetic-opioid combinations may be
beneficial. Continuous peripheral nerve or paravertebral blocks provide site-
specific analgesia and may be excellent alternatives to central neuraxial tech-
niques. In fact, these techniques may be superior to central neuraxial techniques
because of their superior adverse effect profile.
In addition to regional analgesic techniques, all patients may receive oral or
parenteral NSAIDs or COX-2–specific inhibitors, with or without acetaminophen
if there are no contraindications. Furthermore, there may be a benefit in
combining epidural or peripheral analgesia with COX-2–specific inhibitors in
improving analgesia and reducing local anesthetic requirements and associated
side effects (eg, reduced sympathetic blockade and motor blockade). For
inpatients in whom neuraxial or peripheral analgesia cannot be performed, IV-
PCA with opioid combined with NSAIDs or COX-2–specific inhibitors should
be considered. For outpatient surgical procedures, nonopioid analgesics may be
supplemented with oral opioids (eg, hydrocodone, oxycodone, and tramadol).
Furthermore, the number and type of analgesic combinations could also be
determined based on the possibility of the patient in developing significant or
persistent postoperative pain [76–79]. For example, patients at high risk of
development of persistent postoperative pain may benefit from administration of
corticosteroids, ketamine, a2 agonists, and gabapentin along with the regional
analgesia, NSAIDs, and opioids. This hypothesis needs to be confirmed in well-
designed studies in patients undergoing surgical procedures that pose a high risk
of persistent postoperative pain (eg, mastectomy and thoracotomy). Because of
significant variations in the degree of postoperative pain among patients under-
going similar surgical procedures, it would be helpful to identify the patients who
are most likely to have severe postoperative pain. This should allow for more
aggressive analgesic therapy in this high-risk patient population.

Multimodal analgesia as a part of preemptive analgesia techniques

The concept of preemptive analgesia (ie, analgesic intervention made before

noxious stimuli) to prevent the establishment of peripheral and central sen-
sitization and thus amplification and prolongation of pain has been over-
whelmingly demonstrated in animal studies using inflammatory models [1,80].
Thus, an optimal preemptive analgesic technique would start before the surgical
injury and continue until the response to pain is resolved. However, clinical
studies evaluating preemptive (or preventative) analgesia provide conflicting
results [81–84]. Recently published articles [82,84] that have critically reviewed
clinical studies related to the preemptive effect of analgesic therapies report
196 joshi

modest or equivocal benefits from preemptive analgesia. One of the reasons for
the failure of clinical studies to show benefits may be because of an inappropriate
definition of this concept [81,84]. Furthermore, most clinical trials were of short
duration and evaluated unimodal analgesia techniques (eg, local anesthesia alone
or NSAIDs alone) rather than multimodal analgesia techniques. Also, preemptive
analgesic techniques have not targeted the different analgesic pathways
simultaneously. Interestingly, animal studies using the incisional model have
not been able to show a benefit of preemptive analgesia. Nevertheless, the timing
of analgesic administration is crucial and should depend on the pharmacokinetics
of the analgesic. Therefore, it would be beneficial to administer analgesics
preoperatively or intraoperatively so that their peak analgesic effect occurs just
before emergence from anesthesia.

Multimodal approach to shorten convalescence

In addition to providing dynamic pain relief and reduced surgical stress

responses, a prerequisite to improve surgical outcome and shorten postoperative
convalescence and debility is the implementation of a multimodal and multi-
disciplinary rehabilitation therapy [5–8]. This involves changes in current anes-
thesia practice emphasizing preoperative optimization, patient selection and
education, improved perioperative monitoring, early resuscitation, more respon-
sive fluid therapy (ie, avoidance of hypovolemia and hypervolemia), main-
tenance of normothermia, and prevention of postoperative nausea and vomiting
[8]. In addition, the surgical stress response (and associated organ dysfunction)
may be reduced by modern surgical techniques such as microscopic and
minimally invasive surgery, which reduce tissue handling, trauma, and blood
loss [8]. Furthermore, modifications of traditional postoperative care regimens
(ie, avoidance of tubes, catheters, drains, and restrictions), prevention of post-
operative hypoxemia, improved sleep, early oral feeding (avoidance of semi-
starvation and fatigue), and early mobilization are necessary parts of a fast-track
rehabilitation program [8].
Available data indicate that patients who are a part of a clinical pathway using
multimodal rehabilitation therapy may have a reduced length of stay, a lower
incidence of complications, and improved pain control [85–89]. Kehlet and
Wilmore [6] reviewed the effects of modifying perioperative care in noncardiac
surgical patients on morbidity and mortality. They found that the introduction of
these newer approaches to perioperative care (ie, fast-track surgery or accelerated
care programs) reduced postoperative morbidity and mortality and concluded
that the application of this new concept should reduce the need for postopera-
tive hospitalization and allow more surgical procedures to be performed on an
outpatient basis. Thus, the success of a fast-track surgery program requires a
multidisciplinary approach involving anesthesiologists, surgeons, nurses, and
physical therapists.
 multimodal analgesia and postoperative rehabilitation 197

Future considerations

Although the concept of multimodal analgesia has been well accepted and
included in our current pain management plan, it has not resulted in improved
postoperative outcome (eg, improved function and return to daily living and
reduced incidence of persistent postoperative pain). Many studies have insuffi-
cient study design because of an inappropriate combination of analgesic tech-
niques or inadequate duration of analgesia. Therefore, more studies are necessary
to identify optimal analgesic combinations and optimal administration tech-
niques with greater efficacy, improved safety, and the ability to improve post-
operative outcome.
Future therapies may be directed more specifically to the pathophysiologic
pain process [1]. In addition to currently used analgesics, future multimodal
analgesic techniques may also include the use of a2-adrenergic agonists, NMDA
receptor antagonists, anticonvulsants, and glucocorticoids. Furthermore, brady-
kinin, substance P antagonists, and leukotriene synthesis blockers may also be
used as part of a balanced analgesia regimen. The role of these analgesic
techniques needs to be clarified by further investigation and clinical experience,
which also focuses on patient outcome.
Future outcome studies are required to evaluate whether the introduction of
multimodal analgesia techniques, which optimize dynamic pain relief, integrated
with an accelerated multimodal rehabilitation (recovery) program would improve
postoperative outcome, reduce hospital stay, and shorten convalescence [8].
Future postoperative multimodal strategies will need to be patient-specific and
procedure-specific [89–91], both of which are integrated with clinical pathways
and acute pain services [92,93]. Such individualized analgesic regimens should
reduce postoperative pain intensity, morbidity, and the need for hospitalization as
well as allow an early return to daily living.

Summary

Although the management of postoperative pain poses some unique

challenges for the practitioner, an important reason for suboptimal pain
management is the inadequate or improper application of available information
and analgesic therapies. Multimodal analgesia techniques, including regional
analgesic techniques, acetaminophen, nonspecific NSAIDs or COX-2–specific
inhibitors, and opioids, have become standard practice. The choice of analgesic
combinations should depend not only on their analgesic efficacy but also on the
side effect profile of these combinations. Thus, even if a certain analgesic
regimen provides superior pain relief, it may not be clinically beneficial if it is
also associated with more adverse events.
Although it is clear that multimodal analgesia techniques improve post-
operative pain relief, there are insufficient data on the optimal multimodal
regimen for a particular patient undergoing a particular surgical procedure.
198 joshi

Nevertheless, regional analgesia techniques have evolved as a critical component

of a multimodal approach to achieving the goal of dynamic pain relief with
improved outcomes. Other nonopioid analgesics (eg, acetaminophen and non-
specific NSAIDs or COX-2–specific inhibitors) should be used, assuming there
are no contraindications, at their ceiling doses, administered on a round-the-clock
schedule of dosing. Opioids should be used as ‘‘rescue’’ analgesics on an as-
needed basis because opioid-related side effects can retard patients’ postoperative
recovery. In addition, nonpharmacologic interventions should become a standard
component of multimodal analgesia techniques. However, there is a need for the
development of an evidence-based approach to reliable, comprehensive,
individualized analgesic plans for specific surgical procedures.
Finally, because surgical morbidity is multifactorial, a multimodal approach
to perioperative care is required to achieve a significant improvement in post-
operative outcome and reduce convalescence. Therefore, it is important that
a multidisciplinary approach be used to manage postoperative care as a con-
tinuum from the preoperative period through the convalescence period.

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