Trends in Anaesthesia and Critical Care 4 (2014) 10e18

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Trends in Anaesthesia and Critical Care

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REVIEW

Systemic non-opioid adjuvant analgesics: Their role in acute

postoperative pain in adults
Robert Loveridge a, Santosh Patel b, c, *
a
North West Deanery, Manchester, UK
b
Pennine Acute NHS Trust, UK
c
School of Biomedicine, Faculty of Medical and Human Sciences, University of Manchester, UK

s u m m a r y
Keywords: Non-opioid adjuvants can enhance analgesia when co-administered with a known analgesic, such as an
Acute pain opiate. This can be beneficial in patients in whom pain control with opioids is difficult or when it is
Postoperative analgesia
preferable for opioid consumption to be minimised for enhanced recovery. Alpha-2 adrenoreceptor
Adjuvant
Non-opiate
agonists (clonidine and dexmedetomidine), gabapentinoids (gabapentin and pregabalin), N-methyl-D-
aspartate (NMDA) receptor antagonists (ketamine and magnesium), lidocaine and dexamethasone can all
be systemically administered perioperatively to reduce pain intensity to differing degrees. Adjuvants can
also reduce opioid related side effects, however, they may cause other side effects limiting their use. They
have variable effects on pain scores and opioid consumption. The optimal regimens for systemic
administration of these agents have yet to be determined as has the clinical significance of this reduction
in pain intensity and reduced opioid consumption. Their routine use as a part of miultimodal analgesia is
not yet widely established and their role in the perioperative outcome remains unclear.
Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction
With a trend towards enhanced recovery programs for many
types of surgery there is increasing pressure on anaesthetists and
acute pain teams to provide effective postoperative pain relief,
enabling early mobilisation and return to normal function without
the postoperative nausea and vomiting (PONV), decreased gastro-
intestinal function, respiratory depression, urinary retention and
sedation associated with opioid analgesics. The use of regional
anaesthesia is one method, but another technique is through the
use of adjuvant analgesics. An adjuvant analgesic is a medication
that is not primarily an analgesic, although it may have an analgesic
action. It can enhance analgesia when co-administered with a
known analgesic, such as an opioid while decreasing the amount of
opioids administered in the perioperative period. This can be of
particular benefit where pain control with opioids may be difficult
due to tolerance or side effects. Some of the adjuvants can be
effective to manage opiate induced hyperalgesia, a phenomenon in
which patients experience acute tolerance and a paradoxical in-
crease in pain intensity with the use of an opioid.
* Corresponding author.
E-mail address: santosh.patel@pat.nhs.uk (S. Patel).
This review outlines the physiology of acute pain and the cur-
rent evidence regarding the perioperative use of systemic non-
opioid adjuvants (NoA). We have mainly reviewed the findings of
recent meta-analyses. We have focused on their effects on pain
scores, morphine consumption and other risks and benefits. We
have not included established drugs used for multimodal analgesia
such as non-steroid anti-inflammatory drugs and paracetamol.
2. Physiology of acute pain
Multiple peripheral and central mechanisms interact to enable
the detection of potentially damaging or noxious stimuli. This
process of detection and processing is known as nociception and
can be thought of in terms of four processes1 transduction, trans-
mission, perception and modulation. NoA may act on multiple
processes (Fig. 1).
2.1. Transduction
Nociception begins with the transduction of a noxious stimulus
into a nociceptive impulse via an action potential. This is achieved
by free nerve endings called nociceptors. Nociceptors are distrib-
uted throughout the body and are comprised of small unmyelin-
ated C fibres and larger myelinated A-d fibres.

2210-8440/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tacc.2013.10.002
 R. Loveridge, S. Patel / Trends in Anaesthesia and Critical Care 4 (2014) 10e18 11

Fig. 1. Major factors involved in pain processing and proposed sites of action of non-opioid adjuvants.

C fibres are much more abundantly distributed when compared
to A-d fibres, and due to their being small in diameter and unmy-
elinated, they have a much slower conduction time. They are pol-
ymodal receptors and respond to mechanical, thermal and
chemical stimuli via various receptors. They result in a pain that is
described as dull, aching and often diffuse.
By comparison, A-d fibres have a much faster conduction time.
They are high threshold receptors that respond to mechanical or
thermal stimuli. They result in sharp, well-localised pain.
Immune and inflammatory responses result in the release of
several chemical substances that either act themselves as ligands or
function as mediators to sensitise nociceptors. These modulators
include cytokines (TNFa, IL-1, IL-6, IL-10), chemokines, neuropep-
tides, substance P and enzymes such as cyclo-oxygenase 2 (COX-2)
and proteinases.
2.2. Transmission
This involves the transmission of the nociceptive impulse from
the peripheral afferent neuron to the brain via the spinal cord. In
order for an action potential to be propagated there must be
movement of sodium at cell membranes.
The primary afferents from the head and neck are contained
within the trigeminal nerve and pass to the trigeminal nucleus
within the brainstem. The primary afferents that innervate the
trunk, limbs and viscera synapse with nociceptive specific neurons
within laminas I, II and V of the dorsal horn. These primary afferent
terminals contain excitatory neurotransmitters, which are released
to transmit the nociceptive impulse across the synaptic cleft to
the nociceptive dorsal horn neuron. These neurotransmitters
include glutamate, aspartate, bradykinin, adenosine triphosphate,
12 R. Loveridge, S. Patel / Trends in Anaesthesia and Critical Care 4 (2014) 10e18
brain derived neurotrophic factor, substance P and calcitonin gene-
related peptide.
Repeated C-fibre stimulation causes depolarisation of the
postsynaptic membrane. This results in the release of glutamate,
which causes the activation of the N-methyl-D-aspartate (NMDA)
receptor via the displacement of magnesium from it.
Cells within the dorsal horn can demonstrate altered sensi-
tivity following the stimulation by primary afferents. Following
repeated C-fibre stimulation of the dorsal horn a greater dorsal
horn output is seen with each additional impulse, this phenom-
enon is termed “wind up”. A similar phenomenon is “long-term
potentiation”, this results following high frequency C-fibre acti-
vation and leads to an exaggerated response that outlasts the
stimulus. These changes together with increased descending
facilitation and functional connection of A-b fibres can cause
“secondary hyperalgesia”.
Although distinct entities, all three of these phenomena evolve
because of a complex interaction between ion channel and re-
ceptor activity as well as an increase in intracellular calcium. They
are encompassed under the umbrella term of “central
sensitisation”.
As well as excitatory activity there is also inhibitory processes
happening within the dorsal horn. These are endogenous mecha-
nisms activated via GABAergic and glycinergic interneurons and
inhibitory neurotransmitters such as endorphins, enkephalins, se-
rotonin and noradrenaline.
From the dorsal horn the nociceptive impulse is transmitted to
the thalamus and somatosensory cortex via ascending tracts; these
are the spinoparabrachial, spinoreticular and spinothalamic tracts.
2.3. Perception
The perception of pain is anatomically and physiologically
complex. Multiple areas of the brain are involved including the
somatosensory cortex, the reticular system and the limbic system.
This is the end result of pain detection and is the point at which
pain becomes a complex and multi-factorial experience. A bio-
psychosocial model of pain2 has been suggested that encompasses
all of these interacting factors.
2.4. Modulation
The modulation of pain involves multiple complex descending
pathways interacting with nociceptive transmission via actions on
pre-synaptic or post-synaptic neurons or by affecting neurons
within the dorsal horn. Modulating pathways can be either inhib-
itory or excitatory. Descending inhibitory pathways originate in the
cortex and hypothalamus and involve inhibitory neurotransmitters
that partially or totally inhibit the transmission of nociceptive im-
pulses. These inhibitory neurotransmitters include endorphins,
enkephalins, serotonin, noradrenaline, gamma-aminobutyric acid
(GABA), oxytocin and acetylcholine.
2.5. Clinical application
Clinically, acute postoperative pain may be somatic or visceral.
Somatic pain is often deep, originating in muscles, joints, tendons
and ligaments (e.g. orthopaedic surgery) or superficial (e.g. skin,
subcutaneous tissue and mucous membranes). Visceral pain is
difficult to localise and may be referred to other areas and is often
associated with autonomic symptoms. Acute postoperative pain is
multifactorial and results from injury, inflammation and ischaemia of
tissues. Nerve injury, resection or entrapment leading to acute
neuropathic pain are not uncommon following thoracic, breast and
hernia surgery and limb amputations. In addition to the time course
and severity of these pathophysiological changes, several other fac-
tors like the presence of preoperative pain and the patient’s psy-
chology are also important determinants of an acute postoperative
pain score. It stands to reason that drugs interacting with one or
several of these fundamental processes or amplification factors can
have a useful role in a postoperative analgesic regimen. NoA can be
useful to control somatic, visceral or neuropathic pain. They may act
on single or multiple sites (Fig. 1). They have been used to control
pain following various surgery. However, they have variable effects
on pain scores and morphine consumption (Tables 1 and 2).
3. Alpha-2 adrenoreceptor agonists
The stimulation of pre-synaptic alpha-2 receptors inhibits
noradrenaline release. Alpha-2 receptor agonists are thought to
have both peripheral and central modes of action.3 They possess
a peripheral antinociceptive effect by causing membrane
hyperpolarisation via K channels and reducing calcium conduc-
tance, this ceases transmission through C fibres.4 Another theory
is that they exert an effect because of similarities between alpha-
2-adrenoceptors and A1 adenosine receptors and mu opioid re-
ceptors.5 This may explain the synergistic effect seen when
systemic alpha-2 agonists are administered with opioids.6 Cen-
trally, stimulation of alpha-2 adrenoceptors within the dorsal
horn reduces excitability7 and inhibits the release of substance P
at this level.8 Supraspinal actions are debatable, although stim-
ulation of alpha-2 adrenoceptors within the locus coeruleus
seem to inhibit the release of their neurotransmitters and
decrease the firing of nociceptive neurons stimulated by pe-
ripheral A and C fibres.9
3.1. Clonidine
Clonidine is an imidazoline compound, and the prototypal
alpha-2 adrenoreceptor agonist. As well as analgesic action it also
causes anxiolysis and sedation. Clonidine has a similar half-life
following oral or intravenous administration which is approxi-
mately 10e12 h. Epidural clonidine is twice as effective as an
analgesic than intravenous clonidine.10
Bernard et al.11 administered a 5 mcg/kg bolus dose over an
hour followed by an infusion of 0.3 mcg/kg/h following spinal
fusion surgery. In comparison to placebo, clonidine significantly
reduced pain scores, time to first opioid analgesia and morphine
consumption in the 12 h following surgery. De Kock et al.12
compared intraoperative administration of IV clonidine to con-
trol in patients undergoing major abdominal surgery. 4 mcg/kg of
clonidine was given over 30 min followed by an infusion of 2 mcg/
kg/h until the peritoneum was closed. Clonidine reduced pain
scores and morphine consumption in the 12 h following surgery.
In contrast to Bernard et al.11 no significant increase in post-
operative bradycardia and hypotension was seen in the clonidine
group. Both studies suggested that clonidine has useful analgesic
properties.
In a recent meta-analysis by Blaudszun et al.13 clonidine was
found to reduce morphine consumption 12e24 h postoperatively
(Table 1). This prolonged analgesic effect may explain the decrease
in PONV also seen. Pain scores were also improved during the first
24 h. At 48 h postoperatively no analgesic benefit was seen. This
meta-analysis also reported haemodynamic effects following
clonidine administration (Table 2). There was an increase in
intraoperative and postoperative hypotension, although post-
operative hypertension was also reduced. The clinical significance
of this was not investigated but these adverse effects need to be
viewed with caution in light of the outcomes seen in the POISE
trial.14 None of the trials reported an effect on chronic post-surgical
Table 1
Effect of perioperative non-opioid adjuvant use on early and late pain scores. Pain score recorded using 11 point (0e10) numeric rating scale.

Author & year Drug/no of Dose range/route Dose timing Surgery No. trials reporting Early pain scores (<6 h) Late pain scores
trials (patients) (number of trials) pain data (patients, expressed as 100 mm VAS (<24 h) expressed
timing etc.) as 100 mm VAS

Blaudszun 201213 Clonidine Various as per route Preop Abdominal (9) 19 (594 vs 562 controls) Nil significant
15 mm (95% CI
21 to
10) at 12 h
19 (594 vs IV/PO/TD Intraop Gynae (5)
562 controls) Postop Spinal (2)
ENT (1)
7 mm (95% CI
12 to
1) at 24 h
Vascular (1)
Ortho (1)
Dexmedetomidine 0.1e80 mcg/kg Preop Abdominal (5) 11 (339 vs 297 controls)
14 mm (95% CI
27
6 mm (95% CI
9 to
2) at 24 h
11 (339 vs IV Intraop Various (3) to
2) at 1 h

R. Loveridge, S. Patel / Trends in Anaesthesia and Critical Care 4 (2014) 10e18

297 controls) Postop Spinal (2)
Gynae (1)
Mathiesen 200721 Gabapentin 300e1200 mg Preop Hysterectomy 5 (137 vs 134 controls)
11 mm (95% CI
21 Nil significant
23 (810 vs PO Postop to
2 mm) at rest
719 controls)
8 mm (95% CI
13
to
3 mm) on movement
Spinal surgery 4 (143 vs 104 controls)
17 mm (95% CI
31
12 mm (95% CI
23 to
1 mm) at rest
to
3 mm) at rest
24
Ho 2006 Gabapentin 16 300e1200 mg Preop Gynae (5) 5 e Multiple dose Nil significant Nil significant
(584 vs PO Postop Spinal (4) (139 vs 135 controls)
537 controls) Breast (2) 8 1200 mg
16.55 mm (95% CI)
10.87 mm (95% CI) with 1200 mg
Ortho (2) (219 vs 201 controls) with 1200 mg
Abdominal (2) 5 e <1200 mg
22.43 mm (95% CI)
13.18 mm (95% CI) with <1200 mg
ENT (1) (276 vs 236 controls) with <1200 mg
Zhang 201128 Pregabalin 11 50e600 mg Preop Gynae (5) 5 e <300 mg/day Nil significant Nil significant
(521 vs 378 PO Postop Abdominal (3) (262 vs 194 controls)
controls Dental (1) 7 e 300 mg/day
Thyroid (1) (437 vs 281 controls)
Ortho (1)
Elia 200533 Ketamine 0.1e1.6 mg/kg Intraop Abdominal (7) 16 (509 vs 341 controls)
8.9 mm (95% CI
11.3
3.5 mm (95% CI
6.0 to
0.9)
16 (509 vs 341 IV Gynae (4) to
6.5)
controls Ortho (3)
MaxFax (1)
Outpatient (1)
Albrecht 201339 Magnesium 1.03 ge23.5 g Preop Abdominal (12) 14 (at rest at 24 h)
6.5 mm (95% CI
10.0
4.2 mm (95% CI
6.3 to
2.1) at rest at 24 h
25 (731 vs 730 IV Intraop Gynae (6) (464 vs 466 controls) to
2.9) on movement
controls) Postop Ortho (6)
6.9 mm (95% CI
9.6
9.2 mm (95% CI
16.1 to
2.3) on
Cardiac (1) 5 (on movement at 24 h) to
4.2) at rest movement at 24 h
(112 vs 113 controls)
Sun 201253 Lidocaine 100 mg or 1.5e2 mg/kg Preop Abdominal 11 (at rest at 6 h)
8.07 mm (95% CI e14.69
4.41 mm (95% CI:
7.70 to
1.13) at rest
21 Trials (548 vs bolus followed by Postop (335 vs 345 patients) to
1.49) at rest
560 controls) infusion of 1.5 mg/kg/h 7 (on activity at 6 h)
10.56 mm (95% CI e16.89
4.04 mm (95% CI:
8.00 to
0.09)
or 2e3 mg/min. (208 vs 208 patients) to
4.23) during activity during activity
IV
Waldron 201356 Dexamethasone 1.25e20 mg Preop Not stated 19 (at 2 h) *
0.49 at rest (95% CI
0.83 *
0.48 (95% CI
0.62 to
0.35) at 24 h
45 (2997 vs IV Intraop (1135 vs 905 controls) to
0.15) at 2 h
2799 controls) 28 (at 24 h)
(1988 vs 1793 controls)
(continued on next page)

13
 14 R. Loveridge, S. Patel / Trends in Anaesthesia and Critical Care 4 (2014) 10e18

pain. No increase in sedation or delay in recovery from anaesthesia

*
0.39 (95% CI
0.66 to
0.12) on movement

*
0.52 (95% CI
1.02 to
0.03) on movement

*
3.16 (95% CI
4.95 to
1.38) on movement

*
0.47 (95% CI
0.68 to
0.25) at rest was seen.

*
0.41 (95% CI
0.80 to
0.03) at rest

*
1.00 (95% CI
1.77 to
0.26) at rest

3.2. Dexmedetomidine

Dexmedetomidine is the S-enantiomer of medetomidine, and is

a highly selective and potent alpha-2 agonist. It is approximately 8
times more specific to alpha-2 adrenergic receptors than clonidine.
It has proved useful in anaesthesia and critical care and is utilised
(<24 h) expressed

for sedation and anxiolysis and as an anaesthetic adjunct. Its short

Late pain scores

as 100 mm VAS

half-life when compared to clonidine (2 h vs 10 h) and minimal

respiratory depression make it an attractive agent.
Dexmedetomidine has been studied less extensively compared
to clonidine but it has been shown to have similar advantages.
Blaudszun et al.13 also evaluated the use of dexmedetomidine for
acute postoperative pain relief (Tables 1 and 2). Most studies
No significant difference at rest

administered a bolus dose of between 0.1 and 1 mcg/kg, although

expressed as 100 mm VAS

higher doses were used in some studies. In addition to a bolus dose,

Early pain scores (<6 h)

to
0.03) on movement

to
0.35) on movement

to
0.42) on movement
*
0.43 (95% CI
0.84

*
0.33 (95% CI
0.52

*
0.65 (95% CI
0.96

*
0.29 (95% CI
0.57

*
1.09 (95% CI
1.77

in some trials, infusions were administered mostly in a range of

0.4e0.5 mcg/kg/h. Like clonidine, dexmedetomidine was seen to
to
0.13) at rest

to
0.02) at rest

reduce morphine consumption in the postoperative period. It did

so from between 2 and 24-h, which was an earlier onset of benefit
than seen with clonidine. As with clonidine there was decreased
VAS scores seen up to 24-h postoperatively and lower rates of
nausea and vomiting. Lower rates (NNT 2.3 vs 13 in clonidine) of
intraoperative hypertension were seen (Table 2). Although only 3
4 (on movement at 24 h)
3 (on movement 0e4 h)

trials included in the meta-analysis reported on haemodynamic

consequences, an increased risk of post-operative bradycardia was
pain data (patients,
No. trials reporting

12 (at rest at 24 h)
Intermediate dose
11 (at rest 0e4 h)
5 (at rest at 24 h)

6 (at rest at 24 h)
6 (at rest 0e4 h)

5 (at rest 0e4 h)

seen, the clinical consequences of these bradycardias were not

investigated and remain unclear.
timing etc.)

High dose
Low dose

The reduction in morphine consumption and the advantage of

little or no respiratory depression make dexmedetomidine an
attractive agent for use in bariatric practice. Several studies have
shown that dexmedetomidine can significantly reduce opioid
(number of trials)

consumption in an obese population.15e17

Abdominal (9)

Anorectal (2)

Thyroid (1)

Various (1)
Gynae (4)

Breast (1)

Spinal (1)

4. Gabapentinoid anticonvulsants
Ortho (1)
Surgery

ENT (4)

Gabapentinoids are primarily anticonvulsant drugs that exert

Pain score recorded using 11 point (0–10) numeric rating scale. CI – confidence interval.

their effects by interacting with voltage gated calcium channels.

Dose timing

The binding of gabapentin and pregabalin to the a2d sub-unit of the

voltage gated calcium channel within cortical neurons reduces the
Intraop
Preop

release of biochemical substances, such as glutamate, noradrena-

line and substance P.18 Inhibition of neuropeptide release at the
dorsal horn decreases hyperexcitability and therefore modulates
central sensitisation and acute pain. In addition, gabapentin and
pregabalin may also prevent chronic post-surgical pain by several
Dose range/route

0.11e0.2 mg/kg

other mechanisms.19
>0.21 mg/kg
<0.1 mg/kg

4.1. Gabapentin
IV

IV

IV

Gabapentin is a structural analogue of GABA and was originally

used as an anticonvulsant. For many years it has been used in the
Dexamethasone

treatment of chronic and later acute pain.

trials (patients)

1252 controls)

Typically studies investigating gabapentin administer either a

Drug/no of

24 in total

single dose of 300e1200 mg preoperatively or less commonly as

(1499 vs

repeated pre or postoperative dosing regimens. Gabapentin

administration by these various means has been found to reduce
postoperative pain and reduce opioid consumption 24 h post-
De Oliveira 201157

operatively.20,21 The pain relief is seen on rest and at movement.

Table 1 (continued )

Author & year

Reported adverse effects included sedation, nausea, vomiting, light

headedness and dizziness.
Seib22 and Hurley23 conducted meta-analyses to quantify these
effects and have found that a preoperative dose of gabapentin 300e
1200 mg resulted in reduced pain scores and decreased analgesic
*
 R. Loveridge, S. Patel / Trends in Anaesthesia and Critical Care 4 (2014) 10e18 15

Table 2
Morphine sparing and other effects of perioperative non-opioid adjuvant analgesics.

Author & year Drug Surgery type(s) Cumulative opiate reduction PONV Other effects
(weighted mean difference IV
morphine equivalent)

Blaudszun 201213 Clonidine Abdominal (9)
9.8 mg (95% CI
16.2 to
3.4) at 12 h Y N&V (NNT 8.9) Y postoperative hypertension
(NNT 13.0)
Gynae (4) [ intraoperative hypotension
Spinal (2) (NNH 9.0)
Lower
abdo/Gynae (1)
ENT (1)
4.1 mg (95% CI
6.0 to
2.2 mg) at 24 h [ postoperative hypotension
Vascular (1) (NNH 20.0)
Orthopaedic (1)
Dexmedetomidine Abdominal (5)
6.3 mg (95% CI
8.3 to
4.2) at 2 h Y N&V (NNT 9.3) Y intraoperative hypertension
Various (3)
6.0 mg (95% CI
8.9 to
3.0) at 12 h (NNT 2.3)
Spinal (2) [ postoperative bradycardia
Gynae (1)
14.5 mg (95% CI
22.1 to
6.8 mg) (NNH 3.1)
at 24 h
Mathiesen 200721 Gabapentin Hysterectomy
13 mg (95% CI
19 to
8) at 24 h Y nausea. RR 0.7 Nil significant
(95% CI 0.5e0.9)
Spinal surgery
31 mg (95% CI
53 to
10 mg) at 24 h Nil significant Nil significant
Ho 200624 Gabapentin Gynae (5)
27.9 mg (95% CI
31.52 to
24.29) Y vomiting OR 0.58 [ sedation OR 3.86
Spinal (4) with 1200 mg at 24 h (95% CI 0.39e0.86) NNT 11 (95% CI 2.50e5.94). NNH 8.
Breast (2)
Ortho (2)
15.98 mg (95% CI
23.45 to
8.50) Y pruritis OR 0.27
Abdominal (2) with <1200 mg at 24 h (95% CI 0.10e0.74) NNT 15
ENT (1)
Zhang 201128 Pregabalin Gynae (5)
8.8 mg (95% CI
16.65 to
0.94 mg) Y vomiting RR 0.73 [ visual disturbance RR 3.29
with <300 mg at 24 h (95% CI 0.56e0.95) (95% CI 1.95e5.57)
Abdominal (3)
Dental (1)
13.4 mg (95% CI
22.78 to
4.02 mg)
Thyroid (1) with>300 mg at 24 h
Ortho (1)
Elia 200533 Ketamine Abdominal (7)
15.7 mg (95% CI
20.9 to
10.5) at 24 h Nil significant [ hallucinations. OR 2.28
Gynae (4) (95% CI 1.19e4.40)
Ortho (3) [ nightmares. OR 2.64
(95% CI 0.76e9.12)
MaxFax (1) [ pleasant dreams OR 1.96
(95% CI 1.01e3.81)
Outpatient (1) [visual disturbances. OR 2.34
(95% CI 1.09e5.04)
39
Albrecht 2013 Magnesium Abdominal (12)
7.6 mg (95% CI
9.5 to
5.8) at 24 h Nil significant Increased incidence of
Gynae (6) bradycardia RR 1.76
Ortho (6)
3.6 mg (95% CI
5.2 to
2.1) (95% CI 1.01e3.07)
Cardiac (1) immediately postop
Sun 201253 Lidocaine Abdominal
7.04 mg (95% CI e10.40 to
3.68 mg) Y nausea (RR: 0.76 Y time to pass first
surgery at 48 h (95% CI: 0.58, 0.99) flatus.
6.92 h
NNT 20) (95% CI e9.21,
4.63)
Y time to first bowel
movement.
11.74 h
(95% CI e16.97 to
6.51)
Reduced hospital stay following
open procedures
0.71 days
(95% CI
1.35 to
0.07)
Waldron 201356 Dexamethasone Not stated
0.87 mg (95% CI
1.40 to
0.33) at 2 h Previously observed Y rescue analgesia
benefit Y time to first analgesic use

2.33 mg (95% CI
4.39 to
0.26) at 24 h Y time to PACU discharge
[ Blood glucose 24 h postop
Perineal pruritis when given
pre-induction
De Oliveira 201157 Dexamethasone Abdominal (9) No difference with doses <0.1 mg/kg Previously observed No ill effects
ENT (4) benefit
Gynae (4)
Anorectal (2)
0.82 mg (95% CI 1.22e0.42)
Ortho with doses 0.11e0.2 mg/kg
Thyroid
Breast
0.84 mg (95% CI
1.24 to 0.45)
Spinal with doses >0.21 mg/kg
Mixed

N&V – nausea and vomiting, NNT – number needed to treat, NNH – number needed to harm, CI – confidence interval, RR – relative risk.
16 R. Loveridge, S. Patel / Trends in Anaesthesia and Critical Care 4 (2014) 10e18
requirement postoperatively. These differences were within the
first 24 h only, with no increase in side effects.
Ho et al.24 analysed benefit according to the gabapentin dosing
regimen and found that multiple perioperative doses of gabapentin
did not result in any improvement in pain scores, it is possible that
this was because only 2 trials were included in that meta-analysis.
There was however a decrease in opioid consumption. This may
explain the decreased risk of nausea, pruritus and constipation. Pre-
operative gabapentin at a single dose of 1200 mg or <1200 mg
reduced post-operative pain scores (Table 1), these effects were
more pronounced at 6 h but were still significant at 24 h. Both
dosing regimens reduced 24-h opioid requirements postoperatively.
Patients receiving 1200 mg gabapentin had a lower risk of nausea
and urinary retention (Table 2). No increased risk of sedation was
seen in this group but interestingly this was seen in patients
receiving bolus doses of <1200 mg. This may represent selection
bias, as adverse effects are usually secondary outcomes in trials.
Mathiesen et al.21 conducted a subgroup analysis, looking spe-
cifically at patients following hysterectomy and spinal surgery
(Tables 1 and 2). Hysterectomy patients given gabapentin had
improved pain scores 6 h postoperatively, both at rest and on
movement. There was decreased 24-h cumulative opioid con-
sumption and a significant reduction in the risk of postoperative
nausea. There was no difference seen in other adverse effects.
Following spinal surgery, patients in the gabapentin groups had
decreased cumulative 24-h opioid consumption and decreased
pain scores at rest for up to 24 h. There was no significant difference
in the adverse effects.
4.2. Pregabalin
While pregabalin is similar to gabapentin in terms of its struc-
ture and its uses, it has the advantage of binding to the a2d sub-unit
with more affinity and causes fewer adverse effects.25 It also has
preferable pharmacokinetics with a bioavailability of over 90% and
linear absorption, compared to gabapentin’s bioavailability of 30e
60% resulting from saturable and non-linear absorption. Pregabalin
also requires less frequent dosing.26
A Cochrane review in 201027 concluded that there was no clear
evidence of beneficial effects of pregabalin in established acute
postoperative pain. In a more recent meta-analysis, Zhang et al.28
grouped trials into those that gave doses over 300 mg and those
that gave doses under 300 mg. They found that although pregabalin
offered no improvement in pain scores (Table 1) it did reduce cu-
mulative 24-h postoperative opioid consumption (Table 2). The
trials that used doses over 300 mg had a greater reducing effect
than those that used doses less than 300 mg. A reduction in post-
operative vomiting was seen, although the risk of visual distur-
bances was greater. This is in contrast with the meta-analysis by
Engelman et al.29 who found an equally effective opiate sparing
effect in the groups receiving 300 mg and 600 mg of pregabalin.
They also found that pain scores were decreased, at the expense of
an increased risk of adverse effects such as dizziness, light-
headedness and visual disturbances. The observed difference in
pain scores between both meta-analyses published in 2011 may be
because of differences in the number of trials included. It is possible
that more trials powered the meta-analysis to detect a difference
between the groups, or that the extra trials included investigated
more painful operations and so this led to the difference being
observed in Engelman’s meta-analysis.
5. NMDA receptor antagonists
THE NMDA receptor is an ionotropic glutamate receptor that
when activated allows the non-selective passage of cations through
an ion channel. It requires two ligands to activate the channel;
glutamate and glycine, the binding sites for these are found on
different subunits. The NMDA receptor is also voltage gated and at
rest the ion channel is blocked by magnesium ions.
Increased nociceptive stimuli activate NMDA receptors within
the dorsal horn; these produce hyperexcitability of dorsal root
neurons. This process facilitates “wind up” and “central sensitisa-
tion”. NMDA receptors are also involved in pain memory.
5.1. Ketamine
Ketamine is a phencyclidine derivative that has long been used
to provide anaesthesia and analgesia. It exerts its strong analgesic
effect by non-competitively antagonising NMDA receptor mediated
nociceptive signals at the level of the dorsal root ganglion. It also
affects opioid and monoaminergic receptors, as well as blocking
voltage gated sodium and calcium channels.30 Ketamine has been
found to act as an anti-inflammatory agent; a recent meta-analysis
concluded that perioperative ketamine administration significantly
inhibits early IL-6 concentration following surgery.31 Ketamine has
an elimination half-life of 100e180 min. However, prolonged
analgesic action may be due to its active metabolite norketamine.
S(þ) ketamine has a 4 times greater affinity for NMDA receptors
than the other isomer, R(
) ketamine.
A Cochrane review32 concluded that perioperative ketamine
reduced 24-h morphine consumption and PONV. Ketamine related
adverse effects were mild or absent. Several systematic reviews
have evaluated the perioperative use of IV ketamine for acute pain
control.33e35 Preoperative ketamine significantly reduces the 24-h
cumulative opioid consumption and improves pain scores for up
to 48 h32 postoperatively. The greatest benefit is seen in painful
surgeries such as upper abdominal or thoracic operations or when
large amounts of opioids are expected to be given.33,34 There was
variation in the amount and timing of ketamine dosage across these
trials. Elia et al.33 (Tables 1 and 2) found that the median IV dose of
ketamine given as either a bolus or perioperative infusion was
0.4 mg/kg (range 0.1e1.6). No significant difference was seen when
ketamine was administered in similar doses before or after sur-
gery.33 One meta-analysis35 found a difference in adverse effects
between the ketamine and control groups. The risk of hallucina-
tions and nightmares was increased while PONV was reduced in
those patients receiving ketamine efficacious for pain. Despite be-
ing widely studied, several issues with IV use of ketamine for acute
pain remain unclear including the optimal dose and regimen and
the prevention of chronic postsurgical pain. The impact of the
perioperative use of ketamine in prevention of chronic post-
surgical pain could not be elucidated.33
5.2. Magnesium
Magnesium has many uses within anaesthesia and critical care
including the treatment of cardiac arrhythmias, treatment and
prevention of eclampsia and control of blood pressure. Novel uses
such as neuroprotection and antinociceptive effects are currently
under evaluation.
Its antinociceptive effects are not fully understood but are
thought to be as a result of an antagonism of NMDA receptors36,37
and decreased intracellular calcium influx.38
Since the mid-1990s there has been much research on magne-
sium’s role in postoperative pain relief. Albrecht et al.39 recently
conducted a meta-analysis of 25 such trials. The trials were mostly
conducted on patients who underwent abdominal surgery, hys-
terectomy and orthopaedic surgery (Table 1). Typically magnesium
was administered either as a bolus dose of 30e50 mg/kg in isola-
tion or followed by an infusion. When it was used in infusion (15
 R. Loveridge, S. Patel / Trends in Anaesthesia and Critical Care 4 (2014) 10e18
trials) the dose was either 500 mg/h or 8e15 mg/kg/h. The post-
operative duration of infusion was variable amongst the studies.
Consequently, the total dose administered varied widely from
1.03 g to 23.5 g. Overall treatment with magnesium reduced the
cumulative 24-h opioid consumption (Table 2). Early and 24-h
postoperative pain scores at rest and on movement were signifi-
cantly reduced (Table 1). The risk of bradycardia was increased with
magnesium but there was no incidence of hypotension. Most
studies did not report pain relief beyond 24 h. Therefore, the role of
magnesium in the prevention of chronic pain is not known.
6. Lignocaine
Lignocaine is an amide local anaesthetic that has been shown to
have anti-inflammatory,40 analgesic41 and antihyperalgesic42
properties when administered systemically. It exerts its anti-
nociceptive effect by blocking voltage gated sodium channels both
peripherally and centrally. Peripheral Ad and C fibres appear
particularly sensitive to lidocaine.43
Other proposed central mechanisms of action include an inhi-
bition of NMDA44 and glycine receptors,45 an increase in the release
of endogenous opioids44,46 and increased descending inhibitory
activity.47,48 Peripherally it has been shown to reduce cytokine
induced tissue damage and the inflammatory response and
apoptosis seen following tissue ischaemia.49,50
The perioperative administration of IV lidocaine seems to have
particular benefits in abdominal surgery. McCarthy,51 Marret,52
Sun53 (Table 2) and Vigneault54 have all conducted meta-analyses
that have suggested benefit. There was variation between dosing,
but a common regimen was a 1.5e2 mg/kg bolus administered
before surgery followed by an infusion of 1.5e3 mg/kg/h continued
postoperatively for up to 24-h. Intraoperative anaesthetic and
postoperative opioid analgesic requirements were reduced for up
to 48-h. Postoperative pain scores were also reduced for up to 24-h.
Importantly for abdominal surgery, the period of ileus was shorter
and gastrointestinal functional recovery was faster. This resulted in
reduced nausea, vomiting and length of hospital stay. Side effects
were minimal and included dry mouth and light headedness, these
required no intervention. Sun et al. reported reduced early and late
pain score both at rest and with activity (Table 1). They also found
lower postoperative IL-8 levels in lidocaine patients when
compared to controls.
Although Vigneault’s meta-analysis did include several other
forms of surgery, it seems that lidocaine is particularly effective in
abdominal surgery. This may be because IV lidocaine confers spe-
cific benefit to visceral pain.
7. Dexamethasone
Glucocorticoids inhibit the enzyme phospholipase A2. This
resulting decreased activity of the lipoxygenase and cyclo-
oxygenase pathways make glucocorticoids potentially useful in
pain management, in addition to their more traditional role of
treating inflammatory or immunologically mediated conditions.
Dexamethasone has also been seen to be of benefit in the
treatment of postoperative nausea and vomiting.55
Waldron56 conducted a meta-analysis evaluating the effect of a
single dose of dexamethasone on postoperative pain. Most of the
studies analysed were investigating dexamethasone’s role as an
antiemetic and so pain scores were often a secondary outcome.
Although this raises the possibility of selection bias, the study
concluded that those patients receiving single or multiple doses of
dexamethasone (1.25 mge20 mg) had lower pain scores 2-h after
surgery. Dexamethasone-treated patients used less opioids at 2-h and
24-h (Table 2), required less rescue analgesia, had longer time to first
17
dose of analgesic, and shorter stays in recovery. There was no dosee
response with regard to the opioid-sparing effect. Higher blood
glucose levels were seen at 24-h postoperatively in the dexametha-
sone group.
Similar outcomes were found by De Olivera,57 who investigated
the use of single dose dexamethasone on postoperative pain and
opioid use when compared to placebo. Dexamethasone was more
effective than placebo in reducing pain at rest and at movement for
up to 24-h (Table 1). A dose dependent effect was seen in cumu-
lative 24-h opioid consumption with an equally effective reduction
seen in moderate (0.11 mg/kge0.2 mg/kg) and high dose (>0.2 mg/
kg) groups. No effect was seen with low dose (<0.1 mg/kg) dexa-
methasone (Table 2). They also commented that preoperative
administration seemed to result in more effective analgesia when
compared to intraoperative administration.
Neither study found any evidence of dexamethasone decreasing
wound healing or causing an increase in wound infections.
8. Conclusions
NoA reduce postoperative opioid consumption and pain in-
tensity. They reduce opioid induced side effects to varying degrees
but may have side effects of their own, limiting their use. The
clinical significance of this reduction in pain intensity and reduced
opioid consumption has not been thoroughly evaluated. While a
reduction in pain scores and decreased opioid consumption intui-
tively suggests benefit, the clinical consequences of these benefits
of NoA need to be demonstrated in further high quality randomly
controlled trials and meta-analyses. It must also be remembered
that a reduction in the opioid requirement is not equivalent to
analgesic efficacy unless achieved with comparable pain scores.
Heterogeneity of the surgical population, small number of pa-
tients, inconsistent anaesthetic techniques, different protocols for
postoperative pain management and variable timings and regi-
mens for adjuvant administration are the main limitations of
studies evaluating the role of NoA. This heterogenicity is a reflec-
tion of the lack of sufficient evidence for the use of these agents.
Therefore, no universal regimens or protocols have been developed
to manage acute postoperative pain. There is a need for large
randomised controlled trials to identify surgery specific optimal
analgesic dosage and administration protocols and to evaluate the
effects on various outcomes. This may improve NoA usage during
the perioperative period in the future.
Funding
None.
Conflict of interest
None declared.
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