Curr Pain Headache Rep (2017) 21: 3
DOI 10.1007/s11916-017-0607-y
OTHER PAIN (N VADIVELU AND A KAYE, SECTION EDITORS)
Multimodal Analgesia, Current Concepts, and Acute Pain
Considerations
Erik M. Helander 1 & Bethany L. Menard 1 & Chris M. Harmon 1 & Ben K. Homra 2 &
Alexander V. Allain 1 & Gregory J. Bordelon 1 & Melville Q. Wyche 1 & Ira W. Padnos 1 &
Anna Lavrova 1 & Alan D. Kaye 1,3
Published online: 28 January 2017
# Springer Science+Business Media New York 2017
Abstract
Purpose of Review Management of acute pain following sur-
gery using a multimodal approach is recommended by the
American Society of Anesthesiologists whenever possible.
In addition to opioids, drugs with differing mechanisms of
actions target pain pathways resulting in additive and/or syn-
ergistic effects. Some of these agents include alpha 2 agonists,
NMDA receptor antagonists, gabapentinoids, dexamethasone,
NSAIDs, acetaminophen, and duloxetine.
Recent Findings Alpha 2 agonists have been shown to have
opioid-sparing effects, but can cause hypotension and brady-
cardia and must be taken into consideration when adminis-
tered. Acetaminophen is commonly used in a multimodal ap-
proach, with recent evidence lacking for the use of IVover oral
formulations in patients able to take medications by mouth.
Studies involving gabapentinoids have been mixed with some
showing benefit; however, future large randomized controlled
trials are needed. Ketamine is known to have powerful anal-
gesic effects and, when combined with magnesium and other
agents, may have a synergistic effect. Dexamethasone reduces
postoperative nausea and vomiting and has been demonstrated
to be an effective adjunct in multimodal analgesia. The
Ben K. Homra and Alexander D. Allain are Senior Medical Student
(expected graduation December 2017).
This article is part of the Topical Collection on Other Pain
* Alan D. Kaye
akaye@lsuhsc.edu
1
Department of Anesthesiology, LSUHSC, New Orleans, LA, USA
2
University of Queensland, Brisbane, Australia
3
Department of Pharmacology, LSUHSC, New Orleans, LA, USA
serotonin–norepinephrine reuptake inhibitor, duloxetine, is a
novel agent, but studies are limited and further evidence is
needed.
Summary Overall, a multimodal analgesic approach should
be used when treating postoperative pain, as it can potentially
reduce side effects and provide the benefit of treating pain
through different cellular pathways.
Keywords Multimodal analgesia . Opioids . NSAIDs . Alpha
2 agonists . Clonidine . Dexmedetomidine . Acetaminophen .
Ketamine . Magnesium . Duloxetine . Dexamethasone
Introduction
Postoperative pain and its management continue to be popular
topics for discussion in the field of anesthesiology. It is impor-
tant to ensure that the safest and most efficacious methods are
being utilized to treat pain in the acute post-operative period.
Adequacy of pain relief, minimization of side effects, and
preventing delays in discharge from the recovery unit are all
key factors in deciding the best approach. A prospective study
of 1490 surgical inpatients receiving standard postoperative
pain treatment according to an acute pain protocol showed
that 41% of patients reported moderate or severe pain in the
recovery room, 30% on postoperative day 1, and 19% on day
2 [1]. Inadequately controlled postoperative pain can have a
significant impact on patients’ recovery and quality of life.
Many anesthesiologists have adopted multimodal techniques
to help address these factors and optimize patient satisfaction.
In addition to traditional opiate-based regimens, there are a
number of other agents that can aid in reducing opiate require-
ments. Important ones include NSAIDs, acetaminophen, ke-
tamine, alpha 2 agonists, glucocorticoids, gabapentinoids, and
duloxetine. Multimodal analgesia involves using a variety of
3 Page 2 of 10
combinations of these drugs, each with a different mechanism
of action. This can potentially reduce undesirable effects of
opiates such as nausea and vomiting or respiratory depression,
and in doing so reduce the risk of more serious complications.
Alpha 2 Agonists
Another class gaining favor as a component of multimodal
analgesia is alpha 2 agonists. In addition to their
anti-hypertensive effects, they are also effective sedatives, an-
xiolytics, and analgesics. They accomplish this by reacting
with the prejunctional alpha 2 receptors and inhibiting norepi-
nephrine release, resulting in a sympatholytic effect [2]. The
two drugs most focused on in recent literature are clonidine
and dexmedetomidine. Care must be taken when administer-
ing these medications as side effects may include bradycardia,
hypotension, and sedation, all of which are undesirable in the
post-operative setting. A recent meta-analysis of randomized
controlled trials showed that both clonidine and
dexmedetomidine reduce postoperative opiate requirements,
with dexmedetomidine having a more pronounced
opioid-sparing effect averaging 15 mg of morphine compared
to 4 mg. Clonidine was shown to have a greater incidence of
postoperative hypotension, and postoperative bradycardia was
noted with the administration of dexmedetomidine. It was
noted that despite these adverse effects, there were no increase
in recovery times associated with the use of alpha 2 agonists in
the PACU [3••]. Another prospective randomized controlled
trial showed that the use of the combination of sufentanil
(0.02 μg/kg/h) and dexmedetomidine (0.05 μg/kg/h) was
found to be associated with less PCA requirement, better an-
algesic effect within the initial 72 h, and better patient satis-
faction compared with the use of sufentanil (0.02 μg/kg/h)
plus a lower dose of dexmedetomidine (0.02 μg/kg/h) or
sufentanil (0.02 μg/kg/h) alone [4]. Though both demonstrate
efficacy at reducing postoperative opiate requirements, it is
important to weigh the benefit with the side effect profiles of
these medications.
Acetaminophen
Acetaminophen is used for the treatment of mild to moderate
pain. It comes in single formulations or mixed with other
drugs such as opioids. The exact mechanism of action is still
unclear; however, it is thought to exert its effects by inhibiting
the cyclooxygenase enzyme. Absorption mainly takes place in
the small intestine, with very little taking place in the stomach
[5]. Intravenous infusion of acetaminophen results in a maxi-
mum drug concentration (Cmax) up to 70% higher than oral,
but overall drug exposure is very similar between the two. A
systematic review concluded that strong evidence is lacking
Curr Pain Headache Rep (2017) 21: 3
for the use of intravenous administration over oral in treating
postoperative pain in patients who have a properly functioning
gastrointestinal tract and are able take medications by mouth
[6].
In a study conducted by Jelacic et al., patients undergoing
cardiac surgery received 1000 mg of acetaminophen IV after
induction anesthesia at the end of surgery and then every 6 h
for the first 24 h in the intensive care unit. Patients who re-
ceived acetaminophen compared to placebo had reduced opi-
oid consumption and increased satisfaction scores. However,
administration of acetaminophen did not reduce opioid-related
side effects [7]. In bariatric surgery patients, Chaar et al. con-
cluded that the use of IVacetaminophen reduced indirect costs
and ED visits within the first 30 days postoperatively [8].
A Cochrane Review concluded that acetaminophen com-
pared to placebo has a number needed to treat (NNT) of 4.6
for one patient to achieve at least 50% pain relief after a single
1 g dose [9••]. IV acetaminophen has shown to decrease pain
by 50% in 37% of patients, while lowering opioid use by 30
and 16% at 4 and 6 h, respectively [10].
Acetaminophen is frequently used for the treatment of
acute pain in the perioperative period as it can reduce opioid
requirements and pain scores in patients. However, it is still
unclear if IVadministration provides a significant benefit over
PO administration.
Non-selective NSAIDs
Combining NSAIDs together with low doses of opioids is one
of the most commonly used and successful techniques of bal-
anced analgesia [11]. This class of drug is a heterogeneous
group of chemicals (e.g., salicylates, benzothiazines,
indolacetic acids, pyrrolacetic acids, etc.) that all exert a sim-
ilar effect [11]. When tissue is damaged, arachidonic acid is
released from membrane phospholipids. Arachidonic acid is
then metabolized to prostaglandins, which lower the pain
threshold in peripheral nociceptors [12]. NSAIDs exert their
effect at a specific enzyme called cyclooxygenase (COX).
Non-selective NSAIDs act on both isoenzymes of cyclooxy-
genase (COX-1 and COX-2), reversibly inhibiting COX and
subsequently decreasing prostaglandin synthesis [13]. When
given with opioids, there is an additive effect, which can re-
duce the overall dose of opiates. Studies have shown that this
sparing effect varies between a 20 and 35% reduction in opi-
oid requirements when NSAIDs are administered postopera-
tively [11, 14, 15].
In theory, decreasing opioid dosages with NSAIDs serves
the purpose of limiting common opioid side effects and man-
aging postoperative pain with a drug that has minimal side
effects, is intrinsically safe, and can be managed by a patient
and their family away from the hospital [16•]. Currently, ex-
tensive data demonstrates the effectiveness of NSAIDs at
Curr Pain Headache Rep (2017) 21: 3
reducing opioid requirements [14, 15, 17–19]; however, there
is less evidence that they minimize opioid side effects. A sys-
tematic review looking into the reduction of morphine-related
side effects after major surgery did not find a statistically sig-
nificant reduction in side effects with the addition of NSAIDs
[15].
Importantly, non-selective NSAIDs have their own side
effect profile. Prostaglandins not only act on peripheral
nociceptors but also have deleterious effects on gastrointesti-
nal, renal, cardiovascular, hematological, and musculoskeletal
physiology. These side effects are primarily determined by the
particular COX isoenzyme targeted by the NSAID as well as
the dosage and duration of the drug. It is well established that
chronic use of non-selective NSAIDs for pain may cause side
effects including peptic ulcers, acute renal failure, myocardial
infarctions, bleeding, and impaired bone healing. Again, this is
dependent on the dose and duration of the particular
NSAID. The impact of these side effects when NSAIDs are
used for a short period of time in the post-operative setting is
less well studied. Of the available research investigating the
short-term use of NSAIDs, it appears that renal and cardiovas-
cular side effects are uncommon in patients without renal or
cardiac risk factors [17].
COX-2-Specific NSAIDs
In 1999, celecoxib was introduced in the USA and attempted
to improve upon already available non-selective NSAIDs. The
benefit of coxib drugs lies in its selectivity for the COX-2
isoenzyme. This mechanism theoretically improves the side
effect profile of this class of drugs. COX-1 is a constitutively
active enzyme that protects gastric mucosa, promotes platelet
aggregation, and increases renal blood flow [13].
Non-selective NSAIDs block both COX-1 and COX-2,
resulting in many of the aforementioned side effects such as
gastric ulcers, bleeding, and acute renal failure. Coxib drugs
block COX-2, which is induced by tissue injury and releases
pro-inflammatory prostaglandins [13].
Although COX-2-selective drugs have been involved in
controversy surrounding their cardiotoxicity [20], a more re-
cent meta-analysis of parecoxib and valdecoxib after surgery
did not increase the cardiovascular risk in noncardiac surgical
patients [21]. It is therefore considered “safe” to use coxibs in
patients with low cardiovascular risk factors that have not
undergone cardiac surgery. Additionally, a Cochrane
Database Systematic Review on single dose oral celecoxib
for acute postoperative pain in adults found that 400 mg
celecoxib was just as effective as 400 mg ibuprofen [22].
Together with COX-2 selective drug’s better side effect profile
and comparable effectiveness compared to ibuprofen,
celecoxib can be considered in post-operative pain
management.
Page 3 of 10 3
In summary, both nonselective NSAIDs and COX-2 selec-
tive are effective analgesics to use postoperatively. To com-
pare their efficacy against one another, the Oxford league table
expresses each drug’s efficacy as the NNT, that is, the number
of patients that need to receive the drug in order to achieve at
least 50% pain relief compared with placebo over a 4–6 h
treatment period. The most effective drugs have the lowest
NNT [13]. These NNT values range from 1.5 (etoricoxib
120/240 mg) to 4.5 (celecoxib 200 mg) with all doses of both
selective and non-selective NSAIDs lying between. Despite
their effectiveness, caution must still be used when selecting
an NSAID as patients with certain risk factors should refrain
from using these drugs.
Opioids
Opioid analgesics have been the mainstay of postoperative
analgesia for decades and are the most commonly used class
of drug for the management of postoperative pain. They re-
main as a key tool in the armamentarium of the anesthesiolo-
gist. Opioids bind μ, δ, and κ opioid G protein-couple recep-
tors (GPCRs) in the nervous system, with specificity for the
receptor subtypes varying throughout the class. Opioid anal-
gesics can be administered via IV, PO, SC, transdermal or
transmucosal routes and are used extensively in regional an-
esthetic techniques. Current practice guidelines favor the use
of epidural, intrathecal, and systemic administration over the
use of IM opioids in the perioperative and postoperative set-
ting [23]. A meta-analysis including eight trials of preemptive
opioid administration analyzing pain intensity scores, supple-
mental analgesic consumption, and time to first analgesic con-
sumption did not find any measurable effect of preemptive
opioid use on the measured outcomes [24].
Parenteral Opioids
Parenteral opioids offer the advantages of more rapid onset of
pain relief, consistent bioavailability, and independence of a
patient’s ability to tolerate oral intake. Morphine is a
mu-opioid receptor agonist. When compared to other, more
lipophilic opioid compounds such as fentanyl, it has a longer
time to onset (around 6 min, vs 2 and 1 min for fentanyl and
alfentanil, respectively) and duration of action (78–96 vs 7
an d 2 m i n) [25 ]. Morphine’s a ctive m etabolites
(morphine-6-glucuronide and morphine-3-glucuronide) can
modulate the effects of their parent drug and cause delayed
respiratory depression [26]. Morphine PACU titration proto-
cols which used small doses (less than 5 mg) and short inter-
vals (less than 5 min between doses) with no upper limit to the
dose were effective in providing pain relief while at the same
time avoiding severe adverse events. In these protocols, titra-
tion was stopped if the patient dropped below a threshold
3 Page 4 of 10
respiratory rate of 12, oxygen saturation of 95%, or exhibited
signs of sedation [27, 28].
Hydromorphone is a semisynthetic derivative of morphine
with 5–10 times the potency. Hydromorphone reaches peak
efficacy at around 20 min, and its analgesic effect lasts around
4 h [2]. Parenteral hydromorphone has demonstrated compa-
rable efficacy and side effects to morphine and can be consid-
ered as an alternative. Choice between the two opioids should
therefore be guided by individual patient responses and histo-
ry [29, 30].
Parenteral oxycodone, when compared to morphine, has
been demonstrated in a randomized double-blind study to
achieve effective pain relief faster and with less sedation when
titrated at doses of 0.05 mg/kg. Oxycodone was also found to
exhibit lower depressions of mean arterial pressure [31, 32]. In
another comparison of parenteral oxycodone vs morphine af-
ter laparoscopic hysterectomy, oxycodone was found to have
greater potency in regards to visceral pain and was associated
with less sedation than morphine [33]. Further studies com-
paring morphine patient-controlled analgesia (PCA) boluses
of 45 μg/kg and oxycodone boluses of 30 μg/kg after surgery
found no difference in drug consumption, analgesic effect, or
adverse effects between the two drugs [34]. A randomized
double-blind study comparing oxycodone vs fentanyl PCA
in postoperative laparoscopic cholecystectomy patients dem-
onstrated significant reduced cumulative dosing in the oxyco-
done group. While the oxycodone group did exhibit increased
nausea, there was no difference in patient satisfaction, seda-
tion, or other side effects [35].
Fentanyl is a synthetic opioid 100 times more potent than
morphine and is a common analgesic in the perioperative set-
ting. Fentanyl and its derivatives (namely sufentanil and
alfentanil) exhibit a rapid onset of action and short duration,
due largely to the drug’s hydrophobicity [25]. Fentanyl is a
common choice in PCA infusion with proven efficacy with
demand bolus dosing at 40 μg [2, 36]. Patient-controlled
transdermal fentanyl via iontophoresis has shown equivalence
to intravenous morphine patient-controlled delivery and offers
the advantage of not requiring IV access [37].
There has been a demonstrated wide variability between
patients as regards to the efficacy of analgesia in the treatment
of acute postoperative pain with regard to standard dosing [2].
This variability may cause ineffective analgesia and can be
mitigated by the use of PCA. Careful attention should be
placed as regards to optimizing the initial bolus dose, demand
dosing, and lockout interval in order to maximize analgesic
effects while minimizing the adverse effects of the adminis-
tered opioids. Lockout intervals between 7 and 11 min did not
exhibit any differences in analgesic efficacy or side effects and
were consistent with both morphine and fentanyl at
equianalgesic doses [37]. Continuous background opioid in-
fusion, when added to PCA regimens, has been associated
with increased incidence of respiratory depression [38].
Curr Pain Headache Rep (2017) 21: 3
Thus, background infusion is not recommended in adult pa-
tients, but can be considered in patients with a high demand
and/or signs of opioid tolerance [39]. Meta-analysis of 49
studies involving PCA and control groups found that patients
receiving PCA had lower pain intensity scores, increased sat-
isfaction, higher opioid consumption, and a higher incidence
of pruritus. The incidence of other opioid related adverse
events was similar across groups [40].
Neuraxial Opioids
Intrathecal or epidural dosing of opioid analgesics is an effec-
tive mode of analgesia in the perioperative period. Opioids
used in this setting can be divided into two broad categories
based on the agent’s lipo- or hydrophilicity. Lipophilic opioids
such as fentanyl and sufentanil are generally cleared from the
cerebrospinal fluid very quickly which limits their spread in
the CSF and the associated opioid-related side effects.
Lipophilic opioids also demonstrate an onset of action in mi-
nutes and a shorter duration of action of 1–4 h [41].
Hydrophilic opioids, such as hydromorphone and morphine,
exhibit a slower onset of more than 30 min and duration of
action longer than 6 h. There is also an increased risk of re-
spiratory depression secondary to spread of the analgesic
throughout the CSF [41]. A recently published prospective
study demonstrated that fentanyl caused less sedation when
compared to the more hydrophilic hydromorphone in elective
surgery patients [42]. Meta-analyses of the efficacy of postop-
erative epidural analgesia vs parenteral opioid analgesia dem-
onstrated superior pain control regardless of the type of opioid
or the site of catheter placement [43, 44].
Gabapentinoids
Gabapentinoids, namely gabapentin and pregabalin, act on the
α-2-δ-1 and α-2-δ-2 subunits of voltage-gated calcium chan-
nels on neuronal cells to reduce the amount of voltage-gated
calcium channels trafficked to the cellular membrane. This
then decreases the eventual release of neurotransmitters into
the synapse [45]. Drugs in this class have been shown to limit
the release of glutamate, norepinephrine, serotonin, dopamine,
and substance P. This neurotransmitter-reducing activity is the
source of the drugs’ anticonvulsant and nociceptive blocking
activity [46]. Clinically available gabapentinoids are orally
administered and cleared largely unchanged via the kidneys
[46]. Gabapentin achieves maximum plasma concentrations
within 4 h of administration and intestinal absorption is zero
order, with bioavailability dropping as dosages increase past
900 mg. Pregabalin attains maximum plasma concentrations
at 1 h, exhibits a linear first-order absorption, and maintains
bioavailability of around 90% at any dose. Both drugs exhibit
half-lives of around 6 h [47]. The most commonly reported
Curr Pain Headache Rep (2017) 21: 3
adverse effects of gabapentinoids have been sedation and diz-
ziness [46, 48].
Gabapentin has traditionally been employed as an anticon-
vulsant and as a first-line agent in the treatment of chronic
neuropathic pain. The drug has proven efficacy in the periop-
erative setting due to its demonstrated ability to attenuate pain
and reduce opioid consumption. Randomized,
placebo-controlled, double-blind studies have shown that
perioperative administration of 1200 mg of gabapentin result-
ed in a reduction of postoperative morphine use and decreased
pain after mastectomy, abdominal hysterectomy, vaginal hys-
terectomy, and spinal surgery [49–54]. Similar effects were
seen with a 300-mg dose before laparoscopic cholecystecto-
my [55]. A meta-analysis of preoperative administration of
gabapentin (300–1200 mg) demonstrated reduced opioid con-
sumption equivalent to 30 mg of morphine in the first 24 h
after a procedure. The adverse effects of opioid usage were
also shown to be limited. Gabapentin administration
prevented nausea with a number needed to treat (NNT) of
25, vomiting (NNT = 6), and urinary retention (NNT = 7)
[48]. Further meta-analyses have continued to show that peri-
operative administration of gabapentin improves pain scores
and decreases opioid consumption [56–58].
Pregabalin has been found to reduce postoperative mor-
phine use after mammoplasty, hip arthroplasty, and laparo-
scopic cholecystectomy [59–61]. Improved analgesia after
pregabalin administration was only demonstrated in two of
the four trials reviewed [59, 61]. A meta-analysis of
pregabalin trials showed that administration of the drug in
the perioperative period significantly reduced cumulative opi-
oid consumption in the first 24 h. It also showed a reduction in
opioid-related adverse effects after surgery. However, this
analysis failed to elucidate any improvement in post-
operative pain [62].
There is a body of evidence in the literature that suggests
administration of gabapentinoids as an adjunct to adequate
multimodal analgesia regimens does not provide any syner-
gistic effects [63–68]. These studies all failed to demonstrate
any reduction in acute pain or decreases in opioid consump-
tion in gabapentinoid groups compared to controls. Further
studies investigating the timing, dose, duration of administra-
tion, and comparisons to current multimodal regimens would
all help to further elucidate the clinical utility of
gabapentinoids in the perioperative setting. Further large, ran-
domized control studies would also be beneficial in compar-
ing the efficacy of pregabalin vs. controls with respect to post-
operative pain intensity.
Ketamine and Magnesium
Ketamine is a commonly used modality of perioperative pain
control. Ketamine is phencyclidine derivative that acts as an
Page 5 of 10 3
N-methyl-D-aspartate (NMDA) receptor antagonist. It func-
tions as a powerful analgesic through blockage of the noci-
ceptive and inflammatory pain transmission functions of this
receptor. Tissue injury leads to glutamate release from the
dorsal horn of the spinal cord. Glutamate binds to the
NMDA receptor and leads to an upregulation in gene expres-
sion of pro-inflammatory cytokines [69]. These cytokines ul-
timately lead to central sensitization, opioid-induced
hyperalgesia, and opioid tolerance [69, 70].
Because ketamine is highly lipid soluble, it allows for very
rapid onset of its effect. Ketamine is useful in general induc-
tion of anesthesia along with perioperative pain management.
It is said to produce a dissociative amnesia, is a powerful
analgesic, and it also allows for preservation of normal pha-
ryngeal reflexes [71]. After administration, ketamine is
redistributed to inactive tissues, and its metabolism occurs
primarily in the liver through the cytochrome P-450 system.
Ketamine has an active metabolite norketamine, which is re-
ported to be up to one third the potency of ketamine [72].
Ultimately, ketamine is inactivated though hydroxylation
and conjugation then excreted through the urine [73].
Many studies have been conducted to investigate ketamine
as a modality in the multimodal approach to perioperative pain
control. In a review from 2011, Laskwoski et al. systematical-
ly reviewed 70 studies, which were randomized,
doubled-blinded, placebo-controlled studies using intrave-
nous ketamine for post-operative pain relief. The studies in-
volved 4701 patients and showed that when ketamine was
used, there was a decrease in total opioid consumption
amongst all studies. The greatest effect was found in thoracic,
abdominal, and major orthopedic surgeries. The review also
demonstrated that the treatment group also reported
experiencing less pain when ketamine was administered [74•].
In 2015, a review was done by Jouguelet-Lacoste et al. to
investigate the use of intravenous infusion or single, low-dose
ketamine use for postoperative pain control. A total of 39
clinical trials were reviewed. The findings of the review
showed low-dose intravenous ketamine infusion (infusion rate
<1.2 mg/kg/h) use decreased opioid consumption by as much
as 40% and also lowered pain scores. Although there were no
reported complications with use of a ketamine infusion at 48 h
after surgery, they were not able to demonstrate an optimal
dose or regimen [75].
Kaur et al. studied 80 patients undergoing open cholecys-
tectomy. The treatment group received an initial ketamine
bolus of 0.2 mg/kg followed by an infusion of 0.1 mg/kg/h,
while the control group received the same regimen and dos-
ages of saline. Results of their study showed patients receiving
the ketamine infusions had reduced pain scores and decreased
opioid requirements in first 6 h after surgery [76].
In 2016, Gorlin et al. composed a review article regarding
ketamine’s ability to blunt central pain sensitization at low
dosages (0.3 mg/kg or less). The studies reviewed showed
3 Page 6 of 10
low-dose ketamine administration was an effective analgesic
in the perioperative period and was also associated with fewer
incidences of psychomimetic adverse effects. In multiple stud-
ies, including those mentioned above, Gorlin reported that
sub-anesthetic doses of ketamine improved pain scores and
decreased overall opioid consumption [77].
Other recent areas of interest have been in the administra-
tion of ketamine in opioid-dependent patients. Loftus et al.
studied 101 opioid-dependent patients undergoing spinal sur-
gery. Intravenous ketamine was administered to the treatment
group which resulted in a nearly 40% reduction in morphine
consumption over a 48-h period after surgery even though
there was no significant difference in pain scores. However,
at a 6-week follow-up period, patients receiving ketamine re-
ported 26% lower pain scores [78].
Ano th er studie d area of ketamin e’s use is its
co-administration with magnesium. Magnesium also acts as
an NMDA receptor antagonist. The magnesium ion cannot
cross the blood–brain barrier to reach the CSF; therefore, its
action as an intravenously administered drug is limited [79].
Many studies have demonstrated that intravenous magnesium
does not improve pain relief and does not decrease analgesic
requirements [80, 81]. Conflicting results were demonstrated
in a meta-analysis done in 2013 by Albrecht et al., which
showed intravenous magnesium use in patients resulted in
decreases in overall morphine consumption within the first
24 h after surgery [82]. Intrathecally administered magnesium
has also been studied extensively. Several studies have proven
its effectiveness when co-administered intrathecally with mor-
phine. Magnesium is thought to potentiate morphine’s analge-
sic effect through its action on spinal NMDA receptors [83,
84]. Although there are conflicting studies of intravenously
administered magnesium as a potential pain modulator, it
has been demonstrated to be effective when it is
co-administered with ketamine. The two drugs have a syner-
gistic effect by both blocking the NMDA receptor and have
been shown to have an increased analgesic effect compared to
either drug administered separately [85, 86].
Dexamethasone
Dexamethasone is another highly studied drug used in the
multimodal approach to pain control in the perioperative pe-
riod. Dexamethasone is a glucocorticoid that can be used to
treat inflammatory and autoimmunune conditions. It is avail-
able in an oral formulation as well as an intravenous route.
Glucocorticoids like dexamethasone exert their
anti-inflammatory effects through inhibition of activated glu-
cocorticoid receptors and transcription factors nuclear
factor-kappa B and activator protein-1, which are involved
in pro-inflammatory gene expression [87]. An added desirable
property of dexamethasone is its anti-emetic property, which
Curr Pain Headache Rep (2017) 21: 3
can be used to prevent post-operative nausea and vomiting
[88]. Dexamethasone usually takes effect within 1–2 h [89].
In a meta-analysis by Waldron et al., 45 studies were in-
cluded to investigate the effect of perioperative dexametha-
sone administration on post-operative pain. Patients that re-
ceived 1.25–20 mg of dexamethasone had decreased pain
scores at 2 and 24 h after surgery. This meta-analysis also
showed that patient’s treated with dexamethasone had less
overall opioid consumption, increased time until first analge-
sic, and shorter stays in the post-anesthesia care unit [90].
In a recent randomized, double-blind, and placebo-
controlled study done by Kim et al., 59 patients under-
going uterine artery embolization were randomized to re-
ceive either 10 mg of dexamethasone or 10 mg normal saline.
Those in the treatment group receiving dexamethasone report-
ed significantly lower pain scores even though opioid con-
sumption was similar between both groups. Inflammatory
markers such as C-reactive protein, interleukin-6, and cortisol
were measured 24 h after surgery and were significantly lower
in the treatment group. In this study, patients also reported less
post-operative nausea and vomiting [91]. Asad and Khan
studied the effect of a single bolus of dexamethasone on in-
traoperative and postoperative pain in unilateral inguinal her-
nia surgery. They demonstrated that 8 mg of dexamethasone
in combination with low-dose fentanyl (0.75 mcg/kg) was
effective in reducing intraoperative and acute pain in the first
hour after surgery [92].
Multiple studies have researched various doses of dexa-
methasone in the use of perioperative pain control. In a study
done by Jan and Dua, 90 patients received dexamethasone
8 mg, dexamethasone 16 mg, or placebo. Results showed that
there were no difference in pain scores at rest amongst the
three groups; however, pain scores at motion were decreased
at 24 and 36 h in patients receiving dexamethasone 16 mg
[93].
Although there are multiple adverse effects with glucocor-
ticoid administration, most of the effects occur with long-term
corticosteroid use. Complications feared in operative patients
include infection and delayed healing, gastrointestinal prob-
lems, avascular necrosis, and hyperglycemia [94]. Several
studies have shown that a single dose of dexamethasone in
perioperative period does not impair wound healing [95, 96].
Single dose dexamethasone is also not associated with avas-
cular necrosis of the femoral head [97]. Dexamethasone and
other glucocorticoids have been well known to cause elevated
blood glucose levels; it is currently unclear if there is a clinical
significance to the hyperglycemia produced. However, cau-
tion should be used when administering glucocorticoids to
diabetic patients [98].
In conclusion, dexamethasone has been shown to be an effec-
tive modality in the perioperative period. At this point, further
studies are warranted to determine the most effective dosage for
patients undergoing surgery. Along with its analgesic properties,
Curr Pain Headache Rep (2017) 21: 3
dexamethasone has been proven to be an effective anti-emetic.
There are numerous adverse effects with the ad- ministration of
glucocorticoid use, although most of these oc-cur with prolonged
use.
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor
(SNRI) mainly used in the treatment of depression and anxi-
ety. It has also been shown to be effective in the treatment of
chronic as well as neuropathic pain. In addition to its SNRI
effects, duloxetine also blocks voltage-gated sodium channels
[99, 100]. These properties make duloxetine a promising
agent for the treatment of acute postoperative pain.
In one study of patients undergoing abdominal hysterecto-
my, administration of duloxetine 2 h prior to surgery and again
at 24 h after surgery resulted in reduced pain ratings and over-
all opioid consumption. Compared to placebo, patients also
had better postoperative quality of recovery, even when mul-
timodal analgesic strategies were used [101]. Duloxetine has
also showed to reduce morphine requirements after total knee
arthroplasty. In this study, patients were given 60 mg of
duloxetine 2 h prior to and 24 h after surgery. When compared
to placebo, patients receiving duloxetine had significantly
lower morphine requirements in the first 48 h after surgery,
but there was no significant difference in overall pain scores
[102].
Several studies have shown benefit in the use of duloxetine
for postoperative pain; however, more randomized controlled
trials are needed in this area.
Conclusion
Postoperative pain control continues to be a significant topic
for anesthesiologists today. Although traditional opioid-based
pain control remains an important method of reducing
post-operative pain, many studies have been done to evaluate
other routes of pain control in order to reduce opioid con-
sumption and improve patient’s recovery. The multimodal ap-
proach to pain control has proved to be an effective means to
reduce postoperative pain, improve patient satisfaction, and
decrease total opioid consumption in the postoperative period.
There are a number of drug classes currently being used in
multimodal treatment strategies, including NSAIDS, acet-
aminophen, ketamine, alpha 2 agonists, glucocorticoids,
gabapentinoids, and duloxetine. Many of these agents are cur-
rently administered in clinical practices and help to reduce
undesirable side effects from traditional opioid-based pain
control. Guidelines produced by the American Society of
Anesthesiologists state that anesthesiologists should exercise
a multimodal approach whenever it is possible based on the
Page 7 of 10 3
individual patient. They recommend considering the use of
regional blockade with local anesthetics along with regimens
of additional drug classes, such as those mentioned in this
review in order to optimize efficacy and minimize adverse
effects [103]. To continue to provide the best anesthetic expe-
rience for the patient, further research and adherence to the
ASA guidelines should be incorporated into every anesthesi-
ologist’s practice.
Compliance with Ethical Standards
Conflict of Interest Erik M. Helander, Bethany L. Menard, Chris M.
Harmon, Ben K. Homra, Alexander D. Allain, Gregory J. Bordelon,
Melville Q. Wyche, Ira W. Padnos, Anna Lavrova, and Alan D. Kaye
declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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