REVIEW

CURRENT
OPINION Opioid-induced hyperalgesia in clinical anesthesia
practice: what has remained from theoretical
concepts and experimental studies?
Lena Weber, David C. Yeomans, and Alexander Tzabazis

Purpose of review
This article reviews the phenomenon of opioid-induced hyperalgesia (OIH) and its implications for clinical
anesthesia. The goal of this review is to give an update on perioperative prevention and treatment
strategies, based on findings in preclinical and clinical research.
Recent findings
Several systems have been suggested to be involved in the pathophysiology of OIH with a focus on the
glutaminergic system. Very recently preclinical data revealed that peripheral m-opioid receptors (MORs) are
key players in the development of OIH and acute opioid tolerance (AOT). Peripheral MOR antagonists
could, thus, become a new prevention/treatment option of OIH in the perioperative setting. Although the
impact of OIH on postoperative pain seems to be moderate, recent evidence suggests that increased
hyperalgesia following opioid treatment correlates with the risk of developing persistent pain after surgery.
In clinical practice, distinction among OIH, AOT and acute opioid withdrawal remains difficult, especially
because a specific quantitative sensory test to diagnose OIH has not been validated yet.
Summary
Since the immediate postoperative period is not ideal to initiate long-term treatment for OIH, the best
strategy is to prevent its occurrence. A multimodal approach, including choice of opioid, dose limitations
and addition of nonopioid analgesics, is recommended.
Keywords
acute opioid tolerance, acute opioid withdrawal, management, mechanisms, opioid-induced hyperalgesia,
perioperative

INTRODUCTION symptoms of OIH but are also seen with acute

Opioids are a crucial part of modern anesthesia. In opioid tolerance (AOT) and acute opioid with-
particular, remifentanil is frequently the opioid of drawal (AOW), making it very difficult to dis-
&

choice due to its unique pharmacokinetic properties tinguish these three phenomena [4 ].
allowing for a fast onset of action and a predictable The overall impact of OIH on postoperative
&

and rapid recovery, independent of the infusion pain is reported to be moderate [1 ]. No strong
&
duration [1 ]. correlation was found for OIH-induced wound
Although opioids in general are given to alle- hyperalgesia and spontaneous pain after surgery
&

viate pain, there is more and more evidence that
these molecules can also enhance pain. In 1870, this
property was first described by the English phys-
ician T. Clifford Albutt who asked: ‘Does morphia
tend to encourage the very pain it pretends to
relieve?’ [2]. Today this paradoxal enhancement
of pain is termed opioid-induced hyperalgesia
(OIH). Presumably via sensitization of opioid sig-
naling pathways [3], OIH results in generalized,
diffuse pain and hypersensitivity, which is not
necessarily located at the source of injury or disease
&
[4 ]. Allodynia and hyperalgesia are measurable
[1 ,5–7]. Of bigger concern, however, is the finding
that the size of the hyperalgesic area surrounding
the wound correlates with the risk of developing
persistent pain after surgery [6,8–10].
Department of Anesthesia, Pain and Perioperative Medicine, Stanford
University, Stanford, California, USA
Correspondence: David C. Yeomans, Department of Anesthesia, Pain
and Perioperative Medicine, Stanford University, 300 Pasteur Dr, S268A,
Stanford, CA 94305, USA. E-mail: dcyeomans@stanford.edu
Curr Opin Anesthesiol 2017, 30:458–465
DOI:10.1097/ACO.0000000000000485

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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

 Opioid hyperalgesia in clinical anesthesia practice Weber et al.
KEY POINTS
 Recent preclinical research found peripheral MORs to
be critical for the development of OIH.
 OIH, acute opioid withdrawal and AOT have different
underlying mechanisms but are clinically difficult to
differentiate. The clinical significance of OIH in
particular is not undisputed.
 Prevention of all three is key.
 Coadministration of nonopioids, combined regional/
local anesthesia and gradual withdrawal of opioids at
the end of surgery to reduce intraoperative
administered opioid doses seem to be beneficial in
preventing OIH although only limited evidence exists.
Similar strategies can be used to treat existing OIH in
the immediate postoperative period.
 Identifying patients and close consultation with pain
specialists for downward titration or complete
discontinuation of opioids are preferred long-term
treatment approaches.
The goal of this review is to provide an update on
recent findings relevant to OIH, both in terms
of underlying mechanisms but also – and most
important for practitioners – prevention and treat-
ment strategies in the perioperative setting.
OPIOID-INDUCED HYPERALGESIA, ACUTE
OPIOID TOLERANCE AND ACUTE OPIOID
WITHDRAWAL
OIH, AOT and AOW, summarized in Table 1,
describe distinct phenomena with overlapping phe-
nomenology and symptoms. From the clinical
perspective, OIH is very easy to confuse with AOT,
which is the desensitization of pain signaling path-
ways to opioids [3]. Both phenomena can result
from acute and long-term exposure to opioids and
& example ketamine and methadone, reduce OIH
present as an increased opioid requirement [11 ].
Escalating doses of opioids improve or worsen AOT-
induced and OIH-induced pain states, respectively.
However, while quantitatively measured pain sen-
sitivity remains unaltered with AOT, OIH is charac-
terized by a gradual increase in pain sensitivity and
lowering of thresholds. The comparison of the
dose–effect relationship of both AOT and OIH by
&
Angst [1 ] illustrates, however, that the pharmaco-
logical mechanisms underlying these phenomena
are distinct (Table 1). Another condition that can –
especially in the perioperative setting – easily be
confused with OIH is AOW. The most important
characteristics of AOW are summarized in Table 1.
From a pain management perspective, a quick and
precise diagnostic of these phenomena is desirable,
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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
but the distinction among AOT, OIH and AOW
remains difficult, if not impossible in clinical prac-
tice. Theoretically, serial quantitative sensory test-
ing (QST) is required, which is very time consuming
and to date, there is disagreement around the
optimal testing paradigm [1 ,12].
&
RECENT FINDINGS IN ANIMAL RESEARCH
Although it is still an area of debate amongst
&
researchers [13 ], there is accumulating evidence
both in animal and clinical research that OIH is
distinct from AOT and AOW. In preclinical studies,
progressive reduction in baseline pain thresholds
indicative for OIH has been shown for morphine
[14], fentanyl [15], heroin [16] and remifentanil
[3,17]. The mechanisms underlying OIH remain
controversial. In the following sections, the main
concepts are summarized. For a more comprehen-
& &
sive review, please refer to [11 ,18 ,19].
Central sensitization and neurotransmitter
systems
Central sensitization of nociceptive pathways
results in reduced nociceptive thresholds, which is
&
characteristic for OIH [11 ,20]. One mechanism by
which central sensitization can occur is through
suppressed reuptake or increased release of excit-
atory neurotransmitters such as glutamate, aspar-
tate and substance P. The N-methyl-D-aspartate
(NMDA) receptor and its ligands glutamate and
aspartate have been shown to be critical to neuro-
plasticity, long-term potentiation, learning and
&
memory [11 ] and are also thought to play an
important role in the development of OIH. In
particular, NMDA receptors in the spinal dorsal horn
and rostroventral medulla have been linked to OIH
[21,22]. Studies both in animals and humans have
demonstrated that NMDA receptor antagonists, for
[5,23–27], supporting the role of NMDA as well as
the potential of these drugs in prevention and treat-
ment strategies for OIH.
Descending facilitation
In addition to central sensitization, pain can also be
potentiated by the descending pain modulatory
system. This system includes the periaqueductal
gray matter, the nucleus raphe magnus and adjacent
structures of the rostral ventromedial medulla
which project to the spinal dorsal horn along
the dorsolateral funiculus. These projections can
have either inhibitory or facilitating effects on noci-
ception [28]. For instance, injections of lidocaine in
the rostral ventromedial medulla or bilateral lesions
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Drugs in anesthesia

Table 1. Differentiation among opioid-induced hyperalgesia, acute opioid tolerance and acute opioid withdrawal:
mechanisms, prevention, diagnosis, therapy and dose/effect relationship
Opioid-induced hyperalgesia Acute opioid tolerance Acute opioid withdrawal

Mechanisms Opioid-mediated sensitization of Desensitization of pain signaling Abrupt offset of opioid effect
pain signaling pathways [3] pathways to opioids ¼ loss of
potency [3]
Induced by high rather than low Induced by high rather than low Relative under-dosing of opioids
doses of opioids [1 ] doses of opioids [1 ]
& &

Patients with chronic opioid

treatment are at higher risk
Prevention (pre/ Avoid exposure to high Might be preventable by use of Avoid abrupt offset of opioids
intraoperative) intraoperative opioid doses [1 ] lower intraoperative opioid doses
&

Use of nonopioid-based analgesic Use of nonopioid-based analgesic Avoid under-dosing of opioids

strategies incl. regional anesthetic strategies incl. regional anesthetic (especially for patients with
techniques [1 ] techniques [1 ] chronic opioid therapy)
& &

Diagnosis/ Increased opioid requirement [1 ] Increased opioid requirement [1 ] Increased opioid requirement
& &

differentiation
(postoperative)
Worsens with increasing opioid Improves with increasing opioid Improves with increasing opioid
doses [1 ] doses [1 ], unusual high doses doses
& &

might be needed
Increase in pain sensitivity over time No increase in pain sensitivity over No increase in pain sensitivity
(assessed with serial QSTa) time (assessed with serial QSTa) over time (assessed with serial
[1 ,12] [1 ] QSTa)
& &

Therapy (postoperative) Opioid rotation [11 ] Increase of opioid dose [1 ] Increase of opioid dose
& &

Long-term: opioid downward dose Long-term: opioid rotation [11 ] Opioid rotation
&

titration/cessation [11 ]
&

Use of nonopioid-based analgesic Use of nonopioid-based analgesic

strategies incl. regional anesthetic strategies incl. regional anesthetic
techniques [1 ] techniques [1 ]
& &

Dose/effect relationship Downward shift of the dose vs. Right shift of the dose vs. effect Unchanged
effect relationship [1 ] relationship [1 ]
& &

QST, quantitative sensory testing.

a &
A specific QST for this purpose is not validated yet [1 ,12].

of the dorsolateral funiculus were demonstrated to
abolish opioid-induced pain, implicating a key role
of descending facilitation in the development of
&
OIH [29]. More recently, Lu et al. [30 ] found a
downregulation of m-opioid receptors (MORs) in
the periaqueductal gray after remifentanil infusion,
which could be restored by blocking the neuron-
restrictive silencer factor (NRSF), a regulator of MOR
expression. NRSF in the periaqueductal gray could,
therefore, be a potential target in the treatment of
OIH. Descending facilitation might also be the
mechanism by which the 5HT3-receptor antagonist
ondansetron exerts its demonstrated OIH preven-
tive and reversing effects, but data to support this
theory are not available yet [31,32].
Neuroimmune mechanisms (microglial
activation)
It has been suggested that changes in glial cells
&
contribute to OIH and AOT [33 ]. Microglia and
astrocytes are activated by chronic opioid use;
depressors of glial activation have been shown to
reduce OIH and AOT [34,35]. Ferrini et al. [36] found
that OIH, but not AOT, is dependent on microglial
activation in particular. Microglial activation leads
to the disruption of neuronal calcium homeostasis
in lamina I of the spinal dorsal horn. Ferrini also
concluded that MORs, which they and others found
to be present in microglia cell culture, initiate this
process [36,37]. Other studies, however, suggest
that morphine activates microglia by binding to
Toll-like receptor 4 (TLR4) [35,38]. Consistent with
this latter concept, antagonizing TLR4 activity was
demonstrated to potentiate morphine analgesia
and to decrease morphine tolerance [39]. In con-
trast, others showed that microglial activation
involved in morphine tolerance is independent
of TLR4 [40,41]. Also under debate is the fact that
most of the experiments supporting the microglial
activation theory were performed in male animals.
In two studies, Sorge et al. [42,43] reported the

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 Opioid hyperalgesia in clinical anesthesia practice Weber et al.
involvement of spinal TLR4 in mechanical allody-
nia, and the prevention of mechanical allodynia by
glial inhibitors to be male specific. Thus, the role of
microglia in OIH remains controversial and is in
need of further investigation.
m-Opioid receptors on nociceptors
&
Very recently, Corder et al. [44 ] published compre-
hensive data, suggesting a crucial role for peripheral
MORs on primary afferent nociceptors as critical to
the development and maintenance of OIH and AOT.
In contrast to other studies (as reported above)
[35,36,38], this group found no evidence for the
presence of MOR in mouse microglia. Due to their
finding that morphine-treated MOR knockout mice
did develop microglial activation, but not OIH, they
concluded that opioid-induced microglial acti-
vation must occur through a receptor different from
MOR. After administering a combination of mor-
phine and methyl naltrexone bromide, a blood–
brain-barrier-impermeable MOR antagonist avail-
able for the treatment of opioid-induced consti-
pation, they observed a dose-dependent reduction
in the onset of OIH and AOT. Importantly, this
cotreatment did not impact the analgesic effects
of morphine. Clinical studies are now needed to
confirm these preclinical data.
Factors influencing opioid-induced
hyperalgesia (sex, species and genetic
variability)
Sex, species or genetic background can influence
the development of OIH. Strain differences have
been observed for the development of OIH both in
&
rats and mice [18 ]. Sex-related differences have also
been demonstrated in OIH development [42,43].
&
For example, Arout et al. [45 ] found a reduction of
morphine-induced hyperalgesia by MC1R melano-
cortin receptor antagonist MSG606 in female mice
and by the NMDA antagonist MK-801 in male mice
but not vice versa. Genetic variability is also sus-
pected to influence the development of OIH. For
instance, MOR has been shown to be critical to OIH
and at least 19 splice variants of the MOR have been
discovered in humans [46]. The most common iso-
form is the seven transmembrane domain (7 TM) G
protein-coupled MOR, though relative expression
levels of the different variants are not yet clear. Of
particular interest for OIH is the 6 TM receptor var-
iant, because contrary to the inhibiting effect of 7 TM
MOR receptors, the 6 TM variant exerts excitatory
&
effects on neurons [18 ,46]. Silencing of one 6 TM
splice variant, MOR-1K, was shown to reduce OIH in
&
mice [47 ]. It is now hypothesized that the 7 TM MOR
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could be the receptor that initiates analgesia, whereas
&
the 6 TM could be responsible for OIH [18 ]. This
would open up new therapeutic strategies in the
&
management of OIH [18 ,46]. In this context, b-2-
adrenoreceptor (b-2-AR) antagonists were shown to
have potential in reducing OIH by interfering with
&
6 TM MOR-b-2-AR heterodimers [48 ]. This mechan-
ism is supported by a study in healthy volunteers,
which found the b-2-AR antagonist propranolol to
reduce remifentanil-induced mechanical hyper-
algesia [49].
Other recent findings
&
In a rodent model of incisional pain, Liu et al. [50 ]
found N-acetyl-cysteine to reduce remifentanil-
induced hyperalgesia by suppressing the activation
of matrix metalloproteinase-9 in dorsal root ganglia,
thereby suggesting another treatment option for
OIH. Members of the transient receptor potential
(TRP) cation channel family, for example the cap-
saicin receptor transient receptor potential vanilloid
1 and the menthol transient receptor potential
member 8 (TRPM8) also seem to be involved
&
in the development of OIH [18 ]. For instance,
knockout of TRPM8 in mice was shown to decrease
morphine-induced cold analgesia [51], but also
prevented the development of cold hyperalgesia
&
after chronic administration of morphine [52 ]. In
addition, inhibition of another subfamily member,
the transient receptor potential canonical channel
TRPC6, was recently demonstrated to block mor-
phine-induced tolerance and hyperalgesia [53 ].
&
Whether antagonizing of individual TRP channels
can be useful in the prevention and/or treatment of
OIH, will have to be determined by further preclin-
ical and clinical research.
RECENT FINDINGS IN CLINICAL RESEARCH
&
A recent study by Ohnesorge et al. [54 ] compared
preoperative and postoperative somatosensory
thresholds as measured by QST in patients under-
going breast surgery. Patients were randomized to
remifentanil or sufentanil and maintained on bis-
pectral index-guided propofol infusion. In their
relatively small patient population, they could
not find significant differences between the remi-
fentanil and the sufentanil group. Limitations
of this study are that the procedure length was
relatively short (<90 min) and the coadministra-
tion of propofol, which might have prevented/
reduced OIH.
Another recently published study by Sanfilippo
&
et al. [55 ] presents patient-reported outcomes after
thyroidectomy with a focus on the patients’ pain
www.co-anesthesiology.com 461
Drugs in anesthesia
experience. Patients reported significantly higher
‘worst pain’ and lower satisfaction when they
received remifentanil infusion compared with
patients receiving fentanyl as intraoperative opioid.
Although patients in the remifentanil group more
frequently received nonopioid analgesics, it is not
clear whether these results can be explained by OIH
alone or whether there could also be other effects,
such as AOW, that contributed to those obser-
vations.
&
Comelon et al. [56 ] randomized volunteers in a
double-blinded, placebo-controlled, crossover study
to remifentanil infusion (TCI 2.5 ng/ml) with either
abrupt or gradual withdrawal and placebo. Patients
were tested for heat and cold pain. Although they
could not find a significant difference in pain scores
between placebo and gradual withdrawal, scores
after abrupt withdrawal were higher in the heat pain
test. For the cold pain test, pain scores were signifi-
cantly increased after both abrupt and gradual with-
drawal compared with placebo. Although those are
interesting findings, it is not clear whether Comelon
et al. actually measured OIH, that is whether
changes in pain score can be interpreted as develop-
ment of OIH or if they could also be secondary
to AOW.
&
Mauermann et al. [57 ] published a double-
blind randomized, crossover volunteer study in
which patients received low or high-dose fentanyl.
4.5–6.5 h after administration they observed an
increase in the hyperalgesic area as measured by
pin-prick testing around the stimulation site but
reduced pain scores in their standardized pain
model (intracutaneous electrical stimulation) with
the higher dose.
Much attention was paid to the studies of Lav-
and’homme et al. [9,10], Salengros et al. [6] and
others [5,58] that found increased postoperative
wound hyperalgesia correlated with higher cumu-
lative opioid, in particular remifentanil, doses.
Salengros et al.’s study [6] even found a correlation
between chronic postthoracotomy pain and
increases in immediate postoperative wound hyper-
algesia and, therefore, also for increased intra-
operatively administered remifentanil doses.
When using low-target-controlled or high-target-
controlled sufentanil infusion for cardiac surgery
similar increases of wound hyperalgesia could
not be observed [58]. There was, however, a signifi-
cant increase in postoperative morphine con-
sumption and pain ratings in the group that
received the higher intraoperative sufentanil
target. More studies are needed to determine the
correlation, not to mention causality, between
intraoperatively administered opioids (and doses
thereof) and chronic persistent pain after surgery.
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PREVENTION STRATEGIES
It needs to be emphasized that none of the preven-
tion strategies for OIH have strong evidence
(i.e. category A, level 1: multiple randomized con-
trolled trials; aggregated findings are supported by
meta-analysis) and should, therefore, not be gener-
alized: each patient should be considered as an
individual. Exemplary interventions could be as
follows:
(1) Choosing the ‘best’ opioid (combination):
Although available literature suggests a higher
incidence of OIH with the use of remifentanil,
this could be secondary to a selection bias. For
example, studies that require high levels of
intraoperative opioid concentrations will more
likely use remifentanil because of its favorable
pharmacokinetic profile. Nevertheless, many
anesthesiologists will consider using an opioid
that has a longer half-life than remifentanil,
such as fentanyl or sufentanil, for patients that
they feel are prone to development of OIH/AOT.
Another approach is to bridge patients over to a
longer acting opioid at the end of the surgery
prior to emergence.
(2) Limiting opioid dose: The data for limiting
dose/infusion rates are relatively strong and
& &
have been reviewed elsewhere [1 ,4 ,12]. For
remifentanil, the infusion rate that increases
risk of OIH seems to be somewhere among 0.1
& &
[59], 0.2 [60 ] and 0.3 mg/kg/min [1 ,61].
Although some studies report only cumulative
doses that are associated with OIH, such as less
&
than 40 mg/kg of remifentanil [1 ], we find that
this is a less intuitive approach since length of
surgery is usually not highly predictable. A rule
of thumb could be: as little as possible, as much
as needed.
(3) Administering coanalgesics/nonopioid analge-
sics: Administration of coanalgesics and nonop-
ioid analgesics are thought to be useful for several
reasons. On one hand, they can directly block
initiation of a cascade of mechanisms, for
example by blocking the NMDA receptor,
decreasing not only postoperative pain ratings
but also opioid requirements [62]. On the other
hand, they help in limiting perioperative admin-
istered opioid doses/infusion rates, for example
premedication with gabapentoids [63], acetami-
nophen [64], celecoxib [65] or a combination
of all three. It should be noted that there is
&
evidence that propofol [60 ,66,67], but also
nitrous oxide [68] has antihyperalgesic effects.
Intraoperative lidocaine infusion has been
shown to have low–to-moderate effects on post-
operative pain ratings [69].
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 Opioid hyperalgesia in clinical anesthesia practice Weber et al.
(4) Gradual withdrawal: Recent evidence [56 ]
&
suggests that gradual withdrawal of remifenta-
nil might be beneficial for preventing develop-
ment of OIH. This might simply be secondary to
a reduction in abrupt analgesic offset and is
usually common clinical practice anyway, as
intraoperative opioid requirements are usually
higher than postoperative.
(5) Regional/local anesthesia: Although it seems
obvious that regional/local anesthesia would
be effective in preventing or decreasing OIH
the clinical evidence is somewhat limited [70].
Neuraxial anesthesia seems to have stronger evi-
dence for beneficial effects than peripheral nerve
blocks but secondary to inconsistent protocols,
for example different types of surgery, outcome
measures etc., large clinical studies are needed.
(6) Chronic pain patients: For chronic pain patients
dose equivalence should be formally calculated.
For example, 150 mg of oral oxycodone equals
about 8.5 mg of intravenous hydromorphone
(with a 20% dose reduction). This does not
include any additional opioid requirements sec-
ondary to the surgical procedure. Formal dose
equivalence calculations are helpful in prevent-
ing relative underdosing of patients, which can
be misinterpreted as OIH. Another important
aspect is that it is preferable that chronic pain
patients should be treated at a facility that can
keep them overnight if pain control proves to
be difficult.
MANAGEMENT OF OPIOID-INDUCED
HYPERALGESIA
The most promising long-term treatment strategy
for OIH is to slowly reduce doses of or even com-
pletely discontinue opioids. Obviously, a patient
just recovering from surgery is not an ideal candi-
date for this kind of management, and therefore,
other options need to be considered. Those options
are very similar to the above mentioned prevention
strategies. Rotating to a different opioid, preferable
one with a longer half-life, adding nonopioid anal-
gesics, but also ‘rescue’ blocks, that is regional blocks
for localized pain exacerbations, should be con-
sidered. Another important aspect is to identify
OIH patients and bring them to the attention of
the pain service since they will benefit from indi-
vidualized, long-term treatment that in most cases
the primary service has less experience with.
It is important to remember that inadequate
pain relief with administration of (non) opioid anal-
gesics in the immediate postoperative period can
also be secondary to (surgical) complications, such
as compartment syndrome or nerve damage after
positioning injuries.
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CONCLUSION
In summary, OIH is a complex syndrome with a
variety of proposed underlying mechanisms, which
also appears to be influenced by individual factors
including sex, race and genetic variance. Recently,
preclinical research revealed promising findings
with regard to pathogenesis and treatment strategies
of OIH, for example the new discovered role of
&
peripheral MORs [44 ]. However, clinical studies
are now needed to confirm these data.
Although AOW, AOT and OIH seem to have
distinct underlying pathophysiologies, it is ex-
tremely difficult, if not impossible for clinicians to
clearly differentiate them in the immediate post-
operative period. Many individual studies and meta-
analyses use ‘OIH related outcome measures’ such as
increased pain ratings or increased postoperative
opioid consumption to provide insight as to effects
of treatments on OIH. Those measures are, however,
not exclusively consequences of OIH and can be
easily explained by AOW and/or AOT – which
decreases the potential impact of these studies in
general. Even if there was a generally accepted test to
correctly diagnose OIH in the perioperative setting,
for example serial QST, such measures would be
untenable in the postoperative period given the
time constraints and production pressures.
The clinician’s focus needs to be on preventing
the potential occurrence of all three entities by
working closely with pain specialists and the pre-
operative clinic staff to identify patients at risk,
choosing the intraoperative opioid wisely, limiting
opioid doses as much as possible, making plans for
transitioning to postoperative pain management,
adding coanalgesics and/or nonopioids and/or
local/regional anesthesia techniques if applicable.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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READING
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This is a very important study, which demonstrated that m-opioid receptors (MORs)
expressed by primary afferent nociceptors are critical for the development of AOT
and OIH. Their preclinical data revealed peripheral MOR antagonists as a new
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Volume 30  Number 4  August 2017
 Opioid hyperalgesia in clinical anesthesia practice Weber et al.
50. Liu Y, Ni Y, Zhang W, et al. N-Acetyl-cysteine attenuates remifentanil-induced
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A small but important study that used quantitative sensory testing in a patient
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& hyperalgesia in healthy volunteers? Anesthesiology 2016; 124:453–463.
This prospective volunteers study reported an increase hyperalgesia area with high
doses of fentanyl despite lower reported pain scores.
0952-7907 Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
58. Fechner J, Ihmsen H, Sch€ uttler J, Jeleazcov C. The impact of intraoperative
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A thorough review of remifentanil-induced OIH and AOT in the perioperative
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