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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.
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.
acute opioid tolerance, acute opioid withdrawal, management, mechanisms, opioid-induced hyperalgesia,

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

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

Opioid hyperalgesia in clinical anesthesia practice Weber et al.

but the distinction among AOT, OIH and AOW

KEY POINTS remains difficult, if not impossible in clinical prac-
 Recent preclinical research found peripheral MORs to tice. Theoretically, serial quantitative sensory test-
be critical for the development of OIH. ing (QST) is required, which is very time consuming
and to date, there is disagreement around the
 OIH, acute opioid withdrawal and AOT have different optimal testing paradigm [1 ,12].

underlying mechanisms but are clinically difficult to

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

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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
& &

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

460 Volume 30  Number 4  August 2017

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Opioid hyperalgesia in clinical anesthesia practice Weber et al.

involvement of spinal TLR4 in mechanical allody- could be the receptor that initiates analgesia, whereas
nia, and the prevention of mechanical allodynia by the 6 TM could be responsible for OIH [18 ]. This
glial inhibitors to be male specific. Thus, the role of would open up new therapeutic strategies in the
microglia in OIH remains controversial and is in management of OIH [18 ,46]. In this context, b-2-
need of further investigation. 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-
m-Opioid receptors on nociceptors ism is supported by a study in healthy volunteers,
Very recently, Corder et al. [44 ] published compre- which found the b-2-AR antagonist propranolol to
hensive data, suggesting a crucial role for peripheral reduce remifentanil-induced mechanical hyper-
MORs on primary afferent nociceptors as critical to algesia [49].
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 Other recent findings
presence of MOR in mouse microglia. Due to their In a rodent model of incisional pain, Liu et al. [50 ]
finding that morphine-treated MOR knockout mice found N-acetyl-cysteine to reduce remifentanil-
did develop microglial activation, but not OIH, they induced hyperalgesia by suppressing the activation
concluded that opioid-induced microglial acti- of matrix metalloproteinase-9 in dorsal root ganglia,
vation must occur through a receptor different from thereby suggesting another treatment option for
MOR. After administering a combination of mor- OIH. Members of the transient receptor potential
phine and methyl naltrexone bromide, a blood– (TRP) cation channel family, for example the cap-
brain-barrier-impermeable MOR antagonist avail- saicin receptor transient receptor potential vanilloid
able for the treatment of opioid-induced consti- 1 and the menthol transient receptor potential
pation, they observed a dose-dependent reduction member 8 (TRPM8) also seem to be involved
in the onset of OIH and AOT. Importantly, this in the development of OIH [18 ]. For instance,
cotreatment did not impact the analgesic effects knockout of TRPM8 in mice was shown to decrease
of morphine. Clinical studies are now needed to morphine-induced cold analgesia [51], but also
confirm these preclinical data. prevented the development of cold hyperalgesia
after chronic administration of morphine [52 ]. In
addition, inhibition of another subfamily member,
Factors influencing opioid-induced the transient receptor potential canonical channel
hyperalgesia (sex, species and genetic TRPC6, was recently demonstrated to block mor-
variability) phine-induced tolerance and hyperalgesia [53 ].

Sex, species or genetic background can influence Whether antagonizing of individual TRP channels
the development of OIH. Strain differences have can be useful in the prevention and/or treatment of
been observed for the development of OIH both in OIH, will have to be determined by further preclin-
rats and mice [18 ]. Sex-related differences have also ical and clinical research.
been demonstrated in OIH development [42,43].
For example, Arout et al. [45 ] found a reduction of
morphine-induced hyperalgesia by MC1R melano- RECENT FINDINGS IN CLINICAL RESEARCH
cortin receptor antagonist MSG606 in female mice A recent study by Ohnesorge et al. [54 ] compared
and by the NMDA antagonist MK-801 in male mice preoperative and postoperative somatosensory
but not vice versa. Genetic variability is also sus- thresholds as measured by QST in patients under-
pected to influence the development of OIH. For going breast surgery. Patients were randomized to
instance, MOR has been shown to be critical to OIH remifentanil or sufentanil and maintained on bis-
and at least 19 splice variants of the MOR have been pectral index-guided propofol infusion. In their
discovered in humans [46]. The most common iso- relatively small patient population, they could
form is the seven transmembrane domain (7 TM) G not find significant differences between the remi-
protein-coupled MOR, though relative expression fentanil and the sufentanil group. Limitations
levels of the different variants are not yet clear. Of of this study are that the procedure length was
particular interest for OIH is the 6 TM receptor var- relatively short (<90 min) and the coadministra-
iant, because contrary to the inhibiting effect of 7 TM tion of propofol, which might have prevented/
MOR receptors, the 6 TM variant exerts excitatory reduced OIH.
effects on neurons [18 ,46]. Silencing of one 6 TM Another recently published study by Sanfilippo
splice variant, MOR-1K, was shown to reduce OIH in et al. [55 ] presents patient-reported outcomes after
mice [47 ]. It is now hypothesized that the 7 TM MOR thyroidectomy with a focus on the patients’ pain

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experience. Patients reported significantly higher PREVENTION STRATEGIES

‘worst pain’ and lower satisfaction when they It needs to be emphasized that none of the preven-
received remifentanil infusion compared with tion strategies for OIH have strong evidence
patients receiving fentanyl as intraoperative opioid. (i.e. category A, level 1: multiple randomized con-
Although patients in the remifentanil group more trolled trials; aggregated findings are supported by
frequently received nonopioid analgesics, it is not meta-analysis) and should, therefore, not be gener-
clear whether these results can be explained by OIH alized: each patient should be considered as an
alone or whether there could also be other effects, individual. Exemplary interventions could be as
such as AOW, that contributed to those obser- follows:
Comelon et al. [56 ] randomized volunteers in a (1) Choosing the ‘best’ opioid (combination):
double-blinded, placebo-controlled, crossover study Although available literature suggests a higher
to remifentanil infusion (TCI 2.5 ng/ml) with either incidence of OIH with the use of remifentanil,
abrupt or gradual withdrawal and placebo. Patients this could be secondary to a selection bias. For
were tested for heat and cold pain. Although they example, studies that require high levels of
could not find a significant difference in pain scores intraoperative opioid concentrations will more
between placebo and gradual withdrawal, scores likely use remifentanil because of its favorable
after abrupt withdrawal were higher in the heat pain pharmacokinetic profile. Nevertheless, many
test. For the cold pain test, pain scores were signifi- anesthesiologists will consider using an opioid
cantly increased after both abrupt and gradual with- that has a longer half-life than remifentanil,
drawal compared with placebo. Although those are such as fentanyl or sufentanil, for patients that
interesting findings, it is not clear whether Comelon they feel are prone to development of OIH/AOT.
et al. actually measured OIH, that is whether Another approach is to bridge patients over to a
changes in pain score can be interpreted as develop- longer acting opioid at the end of the surgery
ment of OIH or if they could also be secondary prior to emergence.
to AOW. (2) Limiting opioid dose: The data for limiting
Mauermann et al. [57 ] published a double- dose/infusion rates are relatively strong and
& &
blind randomized, crossover volunteer study in have been reviewed elsewhere [1 ,4 ,12]. For
which patients received low or high-dose fentanyl. remifentanil, the infusion rate that increases
4.5–6.5 h after administration they observed an risk of OIH seems to be somewhere among 0.1
& &
increase in the hyperalgesic area as measured by [59], 0.2 [60 ] and 0.3 mg/kg/min [1 ,61].
pin-prick testing around the stimulation site but Although some studies report only cumulative
reduced pain scores in their standardized pain doses that are associated with OIH, such as less
model (intracutaneous electrical stimulation) with than 40 mg/kg of remifentanil [1 ], we find that
the higher dose. this is a less intuitive approach since length of
Much attention was paid to the studies of Lav- surgery is usually not highly predictable. A rule
and’homme et al. [9,10], Salengros et al. [6] and of thumb could be: as little as possible, as much
others [5,58] that found increased postoperative as needed.
wound hyperalgesia correlated with higher cumu- (3) Administering coanalgesics/nonopioid analge-
lative opioid, in particular remifentanil, doses. sics: Administration of coanalgesics and nonop-
Salengros et al.’s study [6] even found a correlation ioid analgesics are thought to be useful for several
between chronic postthoracotomy pain and reasons. On one hand, they can directly block
increases in immediate postoperative wound hyper- initiation of a cascade of mechanisms, for
algesia and, therefore, also for increased intra- example by blocking the NMDA receptor,
operatively administered remifentanil doses. decreasing not only postoperative pain ratings
When using low-target-controlled or high-target- but also opioid requirements [62]. On the other
controlled sufentanil infusion for cardiac surgery hand, they help in limiting perioperative admin-
similar increases of wound hyperalgesia could istered opioid doses/infusion rates, for example
not be observed [58]. There was, however, a signifi- premedication with gabapentoids [63], acetami-
cant increase in postoperative morphine con- nophen [64], celecoxib [65] or a combination
sumption and pain ratings in the group that of all three. It should be noted that there is
received the higher intraoperative sufentanil evidence that propofol [60 ,66,67], but also
target. More studies are needed to determine the nitrous oxide [68] has antihyperalgesic effects.
correlation, not to mention causality, between Intraoperative lidocaine infusion has been
intraoperatively administered opioids (and doses shown to have low–to-moderate effects on post-
thereof) and chronic persistent pain after surgery. operative pain ratings [69].

462 Volume 30  Number 4  August 2017

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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- In summary, OIH is a complex syndrome with a
nil might be beneficial for preventing develop- variety of proposed underlying mechanisms, which
ment of OIH. This might simply be secondary to also appears to be influenced by individual factors
a reduction in abrupt analgesic offset and is including sex, race and genetic variance. Recently,
usually common clinical practice anyway, as preclinical research revealed promising findings
intraoperative opioid requirements are usually with regard to pathogenesis and treatment strategies
higher than postoperative. of OIH, for example the new discovered role of
(5) Regional/local anesthesia: Although it seems &
peripheral MORs [44 ]. However, clinical studies
obvious that regional/local anesthesia would are now needed to confirm these data.
be effective in preventing or decreasing OIH Although AOW, AOT and OIH seem to have
the clinical evidence is somewhat limited [70]. distinct underlying pathophysiologies, it is ex-
Neuraxial anesthesia seems to have stronger evi- tremely difficult, if not impossible for clinicians to
dence for beneficial effects than peripheral nerve clearly differentiate them in the immediate post-
blocks but secondary to inconsistent protocols, operative period. Many individual studies and meta-
for example different types of surgery, outcome analyses use ‘OIH related outcome measures’ such as
measures etc., large clinical studies are needed. increased pain ratings or increased postoperative
(6) Chronic pain patients: For chronic pain patients opioid consumption to provide insight as to effects
dose equivalence should be formally calculated. of treatments on OIH. Those measures are, however,
For example, 150 mg of oral oxycodone equals not exclusively consequences of OIH and can be
about 8.5 mg of intravenous hydromorphone easily explained by AOW and/or AOT – which
(with a 20% dose reduction). This does not decreases the potential impact of these studies in
include any additional opioid requirements sec- general. Even if there was a generally accepted test to
ondary to the surgical procedure. Formal dose correctly diagnose OIH in the perioperative setting,
equivalence calculations are helpful in prevent- for example serial QST, such measures would be
ing relative underdosing of patients, which can untenable in the postoperative period given the
be misinterpreted as OIH. Another important time constraints and production pressures.
aspect is that it is preferable that chronic pain The clinician’s focus needs to be on preventing
patients should be treated at a facility that can the potential occurrence of all three entities by
keep them overnight if pain control proves to working closely with pain specialists and the pre-
be difficult. operative clinic staff to identify patients at risk,
choosing the intraoperative opioid wisely, limiting
MANAGEMENT OF OPIOID-INDUCED opioid doses as much as possible, making plans for
HYPERALGESIA transitioning to postoperative pain management,
The most promising long-term treatment strategy adding coanalgesics and/or nonopioids and/or
for OIH is to slowly reduce doses of or even com- local/regional anesthesia techniques if applicable.
pletely discontinue opioids. Obviously, a patient
just recovering from surgery is not an ideal candi- Acknowledgements
date for this kind of management, and therefore, None.
other options need to be considered. Those options
are very similar to the above mentioned prevention Financial support and sponsorship
strategies. Rotating to a different opioid, preferable None.
one with a longer half-life, adding nonopioid anal-
gesics, but also ‘rescue’ blocks, that is regional blocks Conflicts of interest
for localized pain exacerbations, should be con- There are no conflicts of interest.
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- REFERENCES AND RECOMMENDED
vidualized, long-term treatment that in most cases READING
Papers of particular interest, published within the annual period of review, have
the primary service has less experience with. been highlighted as follows:
& of special interest
It is important to remember that inadequate && of outstanding interest

pain relief with administration of (non) opioid anal-

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464 Volume 30  Number 4  August 2017

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

Opioid hyperalgesia in clinical anesthesia practice Weber et al.

50. Liu Y, Ni Y, Zhang W, et al. N-Acetyl-cysteine attenuates remifentanil-induced 58. Fechner J, Ihmsen H, Sch€ uttler J, Jeleazcov C. The impact of intraoperative
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