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American Journal of Therapeutics 22, e62–e74 (2015)
Remifentanil—Acute Opioid Tolerance and Opioid-Induced
Hyperalgesia: A Systematic Review
Sang Hun Kim, MD, PhD,1,2* Nicoleta Stoicea, MD, PhD,2
Suren Soghomonyan, MD, PhD,2 and Sergio D. Bergese, MD2,3
The use of opioids may seem to be a double-edged sword; they provide straight analgesic and
antihyperalgesic effects initially, but subsequently are associated with the expression of acute opioid
tolerance (AOT) and opioid-induced hyperalgesia (OIH) that have been reported in experimental
studies and clinical observations. It has been suggested that opioids can induce an acute tolerance
and hyperalgesia in dose- and/or time-dependent manners even when used within the clinically
accepted doses. Recently, remifentanil has been used for pain management in clinical anesthesia and
in the intensive care units because of its rapid onset and offset. We reviewed articles analyzing AOT
and/or OIH by remifentanil and focused on the following issues: (1) evidence of remifentanil inducing AOT and/or OIH and (2) importance of AOT and/or OIH in considering the reduction of
remifentanil dosage or adopting preventive modulations. Twenty-four experimental and clinical
studies were identified using electronic searches of MEDLINE (PubMed, Ovid, Springer, and Elsevier). However, the development of AOT and OIH by remifentanil administration remains controversial. There is no sufficient evidence to support or refute the existence of OIH in humans.
Keywords: remifentanil, opioid-induced hyperalgesia, opioid tolerance, intraoperative, postoperative
INTRODUCTION
Studies on pharmacokinetic and pharmacodynamic of
remifentanil showed that remifentanil increases analgesia and respiratory depression in a dose-dependent
manner.1–5 However, after discontinuing administration of the drug, these effects disappear rapidly
because of the extremely short elimination half-life
1
Department of Anesthesiology and Pain Medicine, School of
Medicine, Chosun University, Gwangju, Korea; and Departments
of 2Anesthesiology and 3Neurological Surgery, Ohio State University Medical Center, Columbus, OH.
Supported by a research fund from Chosun University, 2012, and
in collaboration with Division of Neuroanesthesia, Department of
Anesthesiology, Ohio State University Wexner Medical Center.
The authors have no conflicts of interest to declare.
*Address for correspondence: Department of Anesthesiology and
Pain Medicine, School of Medicine, Chosun University, 309
Pilmun-daero, Dong-gu, Gwangju 501-759, Korea. E-mail:
ksh3223@Chosun.ac.kr
(9.5 6 4 minutes). The context-sensitive half-time and
terminal elimination half-life of remifentanil are shortest among other opioids after 3-hour infusion.4 Therefore, remifentanil can be given in high doses
throughout surgery without the risk of delayed postoperative recovery or respiratory depression. Because
of its rapid onset and offset, remifentanil has been
used in clinical anesthesia as an induction and maintenance agent, and postoperative pain management in
the intensive care units.
Most of the studies conducted with remifentanil
showed cardiovascular responses during perioperative
manipulations. Perioperative use of remifentanil during
laryngoscopy and tracheal intubation suggested that
a bolus of remifentanil of 1 mg/kg was more effective
than 0.5 mg/kg in reducing the pressor response to
intubation. Also, a less decrease in systolic arterial pressure was noticed compared with the dose 1.25 mg/kg,
resulting in a more rapid return to baseline values of
heart rate and arterial pressure.6,7 However, while the
cardiovascular responses reaches a peak 1–2 minutes
after laryngoscopy and intubation, and usually subsides
1075–2765 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Remifentanil-Induced Tolerance and Hyperalgesia
within 5–6 minutes,8 the context-sensitive half-time of
bolus remifentanil is only 3.2 minutes.1,4 Therefore, remifentanil bolus alone is not enough to attenuate the
responses and the use of a bolus-infusion regimen is
required.6 The commonly accepted and recommended
dose of remifentanil is 1 mg/kg followed by an infusion
of 0.5–1 mg$kg21$min21 for induction of anesthesia or
0.05–2.0 mmg$kg21$min21 for maintenance of anesthesia.9–11 In postoperative period, remifentanil continuous
infusion (CI) can be used for controlling the pain, and
the final remifentanil infusion rates have been reported
as 0.05–0.26 mg$kg21$min21 for satisfactory analgesia
after surgery.11–15
Common concerns regarding the use of opioids are
potential detrimental side effects, physical dependence, and addiction. However, recently, an additional
concern has risen that these opioids can induce an
acute tolerance and hyperalgesia in dose- and/or
time-dependent manner even when used within clinically accepted doses. They provide straight analgesic
and antihyperalgesic effects originally, but subsequently are associated with expression of hyperalgesia.16 Therefore, the use of opioids may seem to be
a double-edged sword. In other words, patients receiving opioids to control their pain somewhat paradoxically may become more sensitive to pain as a direct
result of opioid therapy.
Therefore, a review of literature was carried out to
analyze acute tolerance and/or postoperative hyperalgesia induced by remifentanil using electronic
searches of MEDLINE (PubMed, Ovid, Springer, and
Elsevier). The objective was to address the following
issues: (1) what is the definition of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH)?
(2) what mechanisms contribute to AOT and OIH?
(3) Is it true that remifentanil may induce the acute
tolerance and hyperalgesia? and (4) Are AOT and
OIH significant enough to consider reducing the dose
of remifentanil or adopting preventive modulations?
DEFINITION OF AOT AND OIH
The use of opioids can be associated not only with
tolerance but also with hyperalgesia. Before we discuss
AOT and OIH, we have to understand the definitions
of AOT and OIH.
OIH is defined as a state of nociceptive sensitization,
which is characterized by a paradoxical response,
whereby a patient receiving opioids for pain treatment
might have an increased sensitivity to painful stimuli.16,17 Although controlled preclinical experiments
have defined OIH in animals as a decrease in pain
threshold from baseline after chronic administration of
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e63
opioids,18 there is still no accepted operational definition
of OIH among researchers in human clinical trials; hyperalgesia is defined as decrease in either pain threshold
or pain tolerance after chronic opioid exposure.19 Pain
threshold is the lowest intensity of stimulation at which
pain is experienced, and pain tolerance is the amount of
pain from a given stimulus a person can handle before
seeking relief. OIH often is confused with opioid tolerance and allodynia because of the manifestations of similar symptoms. Allodynia is the pain due to a stimulus
that normally does not provoke pain (eg, neuropathy,
fibromyalgia) and can be treated with opioids, nonopioid analgesics, or surgical intervention.
AOT is defined as an increase in the dose required
maintaining adequate analgesia in patients receiving
opioid medication for the treatment of pain in clinical
settings.16,17 AOT, unlike OIH, can be overcome by
increasing the dosage. Increasing the dosage only worsens the pain, and consequently, pain is reduced by
reducing or eliminating the opioid. Clinical data indicate that early postoperative pain scores and subsequent greater demand of opioids could be attributed
to tolerance, whereas the greater requirement for
opioids at a later recovery stage could be associated
with OIH after high-dose remifentanil anesthesia.
Furthermore, some authors used the term tolerance
in their articles on OIH when referring to increase opioid consumption and shorten time to the first postoperative analgesic requirement.20
CELLULAR MECHANISMS OF AOT
AND OIH
The underlying mechanism of AOT and OIH is still
unclear. The AOT is likely to involve multiple mechanisms, such as decoupling from transduction systems,
antianalgesia systems, and alterations of the N-methylD-aspartate (NMDA) receptor and its intracellular second messenger systems.21 OIH also may be explained
by multiple mechanisms, including activation of central
NMDA nociceptive systems,22,23 extensive internalization and thereby inactivation of m-opioid receptors,24
upregulation of the cyclic adenosine monophosphate
pathway,25 and spinal dynorphin release.26,27 Thus,
OIH may reflect similar mechanisms.
Among the potential mechanisms leading to AOT
and OIH, NMDA pain-facilitator processes seem to
play a key role.22,23,28,29 Experimental studies performed in animals and humans have shown that
NMDA receptor antagonists, such as ketamine, inhibit
central sensitization and prevent OIH.29–32 Multiple
studies demonstrated that OIH was blocked by pretreatment with NMDA receptor antagonists,28,29,33,34
American Journal of Therapeutics (2015) 22(3)
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e64
which may be useful adjuncts to morphine to control
postoperative pain after opioid-based anesthesia. Zhao
and Joo35 also presented that clinically relevant concentrations of remifentanil induce rapid persistent increases in NMDA responses, which reflect the
development of remifentanil-induced hyperalgesia
and tolerance. However, there were controversial
results in human study. Some authors suggested that
the remifentanil-induced hyperalgesia was prevented
by small-dose ketamine.31,32,36,37 Other authors suggested that NMDA antagonists did not prevent the
remifentanil-induced hyperalgesia.38 Koppert et al37
documented that ketamine did not reduce the elevated
pain ratings after infusion, although it abolished the
remifentanil-induced hyperalgesia. And then, they suggested that there might be different mechanisms of antianalgesia and secondary hyperalgesia. Luginbuhl et al38
suggested that AOT and remifentanil-induced hyperalgesia were not affected by ketamine and depended on
the type of nociceptive stimulus; it might be explained
by an alternative mechanism, such as internalization of
m-opioid receptors in spinal interneurons that are
induced by remifentanil, but not by morphine or
endogenously released opioids.24 Extensive internalization and thereby inactivation of m-opioid receptors by
remifentanil would leave fewer functional receptors in
the postinfusion period. This might explain transient
inhibition of analgesic effects of endogenous opioids,
correlated with remifentanil’s very short half-life. It
would also exhibit the absence of postinfusion antianalgesia when opioids with longer half-life are tested in the
same experimental mode.39
CONTROVERSIAL RESULTS ON
DEVELOPMENT OF AOT AND OIH
BY REMIFENTANIL
Recently, many studies have focused on the development of acute tolerance and hyperalgesia after using
opioids based on idea that OIH might be a potential
risk factor for the development of chronic pain after
surgery (Table 1).48–50 However, there is no information regarding dose-dependent induction of tolerance
and hyperalgesia after infusing remifentanil and other
opioids. Most authors have suggested that the higher
dose of opioids induce the higher tolerance and/or
hyperalgesia. OIH was observed either to follow
analgesia and lasted long after opioid exposure
ended29,30,51 or during continuous opioid exposure.27,33 It has been reported that high intraoperative
doses of opioids not only increase postoperative pain
scores and acute morphine consumption but also
American Journal of Therapeutics (2015) 22(3)
Kim et al
induce significant nociceptive threshold changes,
defined as AOT and hyperalgesia.21,31,36,52–55 The circumstances under which OIH may occur are also not
yet entirely understood but may include high doses,
long-term treatment, or abrupt changes in concentrations.56 Celerier et al29 showed that fentanyl injection
was associated with sustained lowering of the nociceptive threshold below baseline value, and the higher the
fentanyl dose used, the more pronounced was the
fentanyl-induced hyperalgesia. Laulin et al33 reported
that repeated once-daily heroin injections induced
a gradual lowering of the nociceptive threshold, which
progressively masked a sustained heroin analgesic
functional effect, which is suggested as opiate tolerance. If all types of opioids have been shown to induce
such a dose-dependent hypersensitivity, exposure to
short-acting opioids, such as remifentanil, seems more
likely to be responsible for postoperative high pain
scores, high morphine consumption, and hypersensitivity to pain.21,31,57,58 A relatively large-dose of intraoperative remifentanil has been shown to induce
postoperative hyperalgesia more rapidly and more frequently as compared with longer-acting opioids.36,59,60
These results are in agreement with the clinical observation of increased postoperative pain and morphine
requirement.21,32,61
As a sole agent, remifentanil, as many articles suggest, could induce AOT and/or OIH. In the view of
AOT, studies performed in animals and human volunteers showed that an acute analgesic opioid tolerance
developed a couple of hours after the initiation of remifentanil administration through CI.34,62–64 Aguado
et al34 mentioned that the acute tolerance was induced
by remifentanil infusion alone in the dose-dependent
manner, and its effect was observed approximately 1.5
hours later in the rat model. Remifentanil of 0.3
mg$kg21$min21 induced AOT within the first few
hours in a rabbit model.62 A study performed by Vinik
and Kissin,63 which was neither placebo controlled nor
blinded, replicated these findings in healthy human
volunteers. They suggested that acute tolerance was
profound and developed very rapidly, and remifentanil of 0.1 mg$kg21$min21 resulted in the maximum
analgesic effect in 60–90 minutes, and then began to
decline despite the constant-rate infusion, eventually
reaching 1/4 of the peak value after 3 hours of infusion, measuring by cold thermal and mechanical noxious stimulation. Gomez de Segura et al64 suggested
that intraoperative remifentanil infusion induced
a rapid acute tolerance revealed by diminished remifentanil efficacy in reducing the sevoflurane minimum
alveolar concentration within 90 minutes or less, and
increased opioid doses required to maintain intraoperative analgesia during sevoflurane anesthesia.
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Remifentanil-Induced Tolerance and Hyperalgesia
e65
Table 1. Clinical research using remifentanil on acute opioid tolerance and opioid-induced hyperalgesia.
In high-dose remifentanil group
Study
No.
Protocol of remifentanil
patient
infusion
Crawford
et al40
30
Guignard
et al21
Joly et al36
50
Schmidt
et al41
Song et al42
42
Angst et al43
36
Cortinez
et al44
Hansen
et al45
Lahtinen
et al46
Yeom et al47
60
50
56
39
90
60
0.28 mg$kg21$min21 vs.
intermittent morphine
injection
0.3 vs. 0.1
mg$kg21$min21
0.4 vs. 0.05
mg$kg21$min21
0.4 vs. 0.1
mg$kg21$min21
0.2 vs. 0.05
mg$kg21$min21
0.0 and 2.4 ng/mL, vs.
0.8 and 3.2 ng/mL, or
vs. 1.6 and 4.0 ng/mL
0.23 vs. 0.1
mg$kg21$min21
0.40 mg$kg21$min21 vs.
saline
0.3 mg$kg21$min21 vs.
saline
0.16 vs. 0.03
mg$kg21$min21
Postoperative
pain score
AOT
OIH
Yes
No
examination
30% greater
NS
Yes
Yes
85% greater
50% higher
No
examination
No
examination
No
examination
No
Yes
Greater
NS
Yes
No examination
NS
Yes
NS
NS
No
examination
No examination
No examination
No
examination
No
NS
NS
NS
NS
No
examination
No
NS
NS
NS
NS
No
No
No
No
A small number of clinical studies have looked at
OIH in the setting of acute perioperative opioid exposure. A series of studies in patients undergoing surgery suggested that exposure to a high rather than to
a low intraoperative opioid dose was associated with
opioid consumption and/or increased pain in the postoperative period.21,36,52,65 A feasible explanation for
these findings is either the development of acute tolerance on the rescue opioids for controlling the postoperative pain or a possible OIH in patients exposed to
a high intraoperative opioid dose.16 Guignard et al21
suggested that AOT as well as OIH might be induced
by the acute exposure to large doses of opioids. They
assigned the patients to 2 anesthetic regimens: desflurane was kept constant at 0.5 minimum alveolar concentrations and a remifentanil infusion was titrated to
autonomic responses (remifentanil group); or remifentanil kept constant at 0.1 mg$kg21$min21 and desflurane titrated to autonomic responses (desflurane
group). The patients received 0.3 6 0.2 mg$kg21$min21
of the intraoperative remifentanil, in remifentanil
group, required morphine significantly earlier and
needed nearly twice more morphine in the first 24
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Postoperative
opioid
consumption
postoperative hours than those in the desflurane
group. Furthermore, higher pain scores were observed
in the remifentanil group despite higher morphine
requirement. Joly et al36 showed that remifentanil of
0.4 mg$kg21$min21 triggered the larger hyperalgesia
as well as the larger morphine consumption for 48
postoperative hours, compared with remifentanil of
0.05 mg$kg21$min21 in patients undergoing major
abdominal surgery, in their randomized double-blind
study. In prospective, randomized, double-blind
study, they suggested that remifentanil of mean 0.28
mg$kg21$min21 was associated with the development
of clinically relevant AOT, in patients who underwent
the general anesthesia using propofol infusion.40 However, they could not demonstrate the significant
increase of postoperative pain scores, although cumulative morphine consumption was more in remifentanil group than that in morphine group. Studies on OIH
in human volunteers have been performed to determine the effect of a short-term opioid infusion on an
experimental skin lesion rendered hyperalgesia before
starting the drug infusion,31,37,38,57,58,66 and the effects
of opioid antagonist precipitated withdrawal on cold
American Journal of Therapeutics (2015) 22(3)
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e66
pressor pain in volunteers after acute physical opioid
dependence.67,68 Several investigators observed significant enlargement of the area of mechanical hyperalgesia induced by transdermal electrical stimulation
after 30–90 minutes of exposure to remifentanil, and
it was related directly to the infusion duration and the
opioid dose.31,37,57,58,66 This aggravation was observed
up to 4 hours after stopping the remifentanil infusion,
but was no longer evident when assessed on the subsequent day.58 They also observed the increased pain
score as well as the decreased pain threshold by dosedependent manner after the discontinuation of
opioids.31,57,58 Contrasting with results obtained in
experimental hyperalgesic skin, heat pain sensitivity
in normal skin was not different before and after remifentanil exposure.31,58 Pain sensitivity to cold pressor pain also was accessed in a model of acute physical
opioid dependence, when withdrawal was precipitated with the opioid antagonist naloxone after a single
injection of morphine or hydromorphone.67,68 They
showed that sensitivity to cold pressor pain was significantly increased after injection of naloxone. It
means that OIH may be triggered if opioid effect is
suddenly disappeared or reversed. Finally, hyperalgesia can be induced by pressure-evoked pain after
a short-term infusion of remifentanil in volunteers.38
However, these investigators exposed volunteers to
significantly higher nociceptive input during remifentanil than during saline placebo administration. It
cannot be excluded that postinfusion hyperalgesia resulted from more intense noxious stimulation during
the remifentanil infusion rather than the opioid
administration itself. Taken together, these findings
provide that the OIH can develop differently for different types of pain.16
However, although many studies have indicated
that both acute tolerance and hyperalgesia could be
induced by using opioids, some studies have shown
controversial results on acute tolerance and/or hyperalgesia in humans.43–47,69,70 Gustorff et al,69 in randomized, placebo-controlled, double-blinded, crossover
study, suggested that there was no evidence of development of acute tolerance in volunteers assessed by
thermal (heat and cold) and electrical current quantitative sensory testing (QST) during the infusion of remifentanil of 0.08 mg$kg21$min21 for 3 hours. Angst
et al43 also documented that 3-hour infusion of
remifentanil of up to 4.0 ng/mL was not associated
with the development of significant tolerance to analgesic in placebo-controlled double-blind study.
Patient-controlled analgesia using remifentanil targetcontrolled infusion (TCI) did not show any evidence of
rapid development of acute tolerance.70 Cortinez
et al44 suggested that remifentanil-based anesthesia
American Journal of Therapeutics (2015) 22(3)
Kim et al
(0.23 6 0.10 mg$kg21$min21; average duration, 116 minutes) did not induce the AOT when compared with
sevoflurane-based anesthesia in patients undergoing
elective gynecologic surgery. Hansen et al45 investigated how remifentanil of 0.4 mg$kg21$min21 intraoperatively affected postoperative pain and opioid
consumption after major abdominal surgery. In a double-blind study, they indicated that no significant differences could be observed between the groups after 2
hours postoperatively. Although the authors of the
study did find a significant increase in visual analog
scale score in the remifentanil group compared with
placebo during the immediate postoperative period
that is, suggestive of OIH, this difference was no longer significant 2 hours after surgery or during the
remainder of the 24-hour observation period. A prospective, randomized, double-blind study showed that
3-hour infusion of remifentanil of 0.3 mg$kg21$min21
did not increase postoperative pain or opioid consumption in cardiac surgery patients who underwent
sufentanil/propofol-based general anesthesia.46 Yeom
et al47 suggested that remifentanil did not seem to
cause AOT and hyperalgesia in patients undergoing
spinal fusion, although the infusion rate of remifentanil was higher in propofol-based anesthesia (averaging
0.16 mg$kg21$min21) than that in sevoflurane-based
anesthesia (averaging 0.03 mg$kg21$min21) for a short
period of time (averaging 225 and 216 minutes,
respectively).
SUGGESTED DOSES OF
REMIFENTANIL INDUCING AOT
AND OIH
In general, most of the articles documented that AOT
and OIH were induced when remifentanil was infused
at $0.1 mg$kg21$min21 and after stopping infusion of
opioids.21,31,36,43,55,57,63,69,71 Cabanero et al55 suggested
that remifentanil induced dose-dependent pronociceptive effects, and calculated ED50s of 1.7 (95%
confidence interval, 1.3–2.1) and 1.26 (1.0–1.6)
mg$kg21$min21 for thermal and mechanical hyperalgesia, respectively, in a mouse model. During infusion
of remifentanil, acute tolerance was documented that it
was profound and developed very rapidly when
remifentanil was infused continuously at 0.1
mg$kg21$min21.63,71 Whereas in a placebo-controlled
and double-blind study, they suggested that infusion
of remifentanil at a rate of 0.08 mg$kg21$min21 could
not induce tolerance to analgesic opioid effects in the
cold pressor test and in models of electrical and
heat pain.69 After stopping infusion of remifentanil,
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Remifentanil-Induced Tolerance and Hyperalgesia
Angst et al31 documented that the mechanical hyperalgesia was enlarged within 30 minutes of stopping
a 90-minute infusion with remifentanil of 0.1
mg$kg21$min21. Koppert et al57 also suggested that
mechanical hyperalgesia was more profound after discontinuation of remifentanil when administered at
a rate of 0.10 mg$kg21$min21 but not at a rate of 0.05
mg$kg21$min21. When compared with different doses
of remifentanil, the patients receiving the intraoperative remifentanil of 0.3 6 0.2 mg$kg21$min21 required
morphine significantly earlier, and needed nearly twice
more morphine in the first 24 postoperative hours than
remifentanil kept constant at 0.1 mg$kg21$min21.
Higher pain scores were observed in the remifentanil
group despite higher morphine requirement.21 Joly
et al36 suggested that large dose of remifentanil (0.4
mg$kg21$min21) triggered a larger hyperalgesia as well
as a larger morphine consumption compared with
small doses of remifentanil (0.05 mg$kg21$min21) for
48 postoperative hours. Therefore, acute tolerance of
rescue opioids as well as OIH might be induced by
the acute exposure to large doses of opioids.
In several reports, the authors infused remifentanil
as well as other opioids using CI mode. However,
recently TCI mode has been recommended for achieving more precise effectiveness because TCI mode has
been shown not only to improve intraoperative hemodynamic stability but also to decrease intraoperative
remifentanil requirements.72,73 In studies on AOT and
hyperalgesia, although most authors have used the CI
mode, there are a few reports using the TCI
mode.43,58,74,75 Hood et al58 showed that areas of hyperalgesia continuously enlarged 4 hours after remifentanil (targeted concentration of 3.1 6 1.2 ng/mL) was
stopped, to 180% 6 47%. Shin et al74 suggested that
remifentanil using TCI at 4 ng/mL induced the more
increased cumulative morphine consumption and postoperative hyperalgesia than that at 1 ng/mL during
sevoflurane anesthesia. This result is similar with that
of previous studies using CI mode, higher dose of opioid, and higher development of AOT and OIH. Angst
et al43 also suggested that target remifentanil concentrations corresponding to infusion rates of 0.65 and 1.3
mg$kg21$min21 did not induce tolerance in any of their
pain models. There are reports assuming which rate is
closely fit with TCI rate. A bolus of remifentanil
1 mg/kg followed by infusion 0.2 mg$kg21$min21 will
produce stable plasma concentrations of 4–5 ng/mL
within a few minutes.72 The infusion rate for remifentanil 0.1 mg$kg21$min21 can achieve a stable plasma
concentration ranging between 2.7 and 2.9 ng/mL during the infusion.31 Remifentanil concentrations of 1.6
and 3.2 ng/mL correspond to steady-state concentrations achieved when infusing remifentanil at a constant
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e67
rate of about 0.065 and 0.13 mg$kg21$min21.71 Such
rates are commonly used in a clinical setting to provide
analgesia during surgery. Therefore, according to these
references, $0.1 mg$kg21$min21 using CI mode
and $2.7 ng/mL using TCI mode seem to be sufficient
to develop hyperalgesia.
FACTORS THAT LEAD TO
DISCREPANCIES REGARDING AOT
AND OIH
The clinical relevance of above-mentioned results is
questionable, and there are some limitations in negative results concerning AOT and OIH (Table 2). These
discrepancies can be explained by multiple methodological issues, including the administrated dose and
duration of opioids administration, the different infusion mode, the coadministrated anesthetic drug’s
effect, method assessing pain sensitivity, and the repetitive and potentially tissue damaging nature of the
stimuli used to determine the threshold during opioid
infusion.16,18,46,78
First, we can explain these discrepant results by differences in exposed opioid doses and administration
duration. Studies reporting positive results have shown
that acute tolerance to opioid-mediated analgesia develops in dose-dependent fashion and only becomes
evident when total opioid exposure is quite high, which
was supported by many animal and clinical research.
The nonsignificant increase of postoperative pain and
opioid consumption in studies reporting negative results may be noticed because of lower total intraoperative opioid exposure when compared with the positive
results,21,44,79 suggesting a dose-dependent effect of
opioids on the development of OIH. Acute tolerance
is typically investigated during CI over 2–3 hours,
whereas hyperalgesia is usually assessed within 1 hour
postinfusion.21,23,32,34,62,64,80–82 Cabanero et al55 agreed
that remifentanil induced dose-dependent pronociceptive effects for thermal and mechanical hyperalgesia,
which lasted longer with higher doses, but they suggested that the duration of infusion did not alter the
pronociceptive effects of remifentanil. This negative
result might be explained by the shorter exposed duration, just over 30 or 60 minutes, than the positive results. In the recent animal study, they showed that
intravenous remifentanil infusion alone induced transient hyperalgesia associated with the duration of exposure to remifentanil.82 Although 30-minute remifentanil
infusion did not induce hyperalgesia, 120-minute remifentanil infusion induced the hyperalgesia regardless of
dose. However, hyperalgesia was not sustained more
than 60 minutes. Other study also documented that
American Journal of Therapeutics (2015) 22(3)
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e68
Kim et al
Table 2. Factors that lead to discrepancies regarding AOT and OIH by remifentanil.
Study
Crawford
et al40
Guignard
et al21
Joly et al36
Schmidt et al41
Shin et al74
Song et al42
Vinik and
Kissin63
Yalcin et al76
Angst et al43
Cortinez et al44
Echevarria
et al77
Gustorff et al69
Hansen et al45
Lahtinen
et al46
Schraag et al70
Yeom et al47
Exposed time
(min)
Observed
time
QST
Anesthetics
N2O
Infusion
mode
460
24 h
X
Propofol [173 or 91 (R) mg$kg21$min21]
No
CI
260
24 h
X
Desflurane [0.7 or 0.5 (R) MAC]
No
CI
270
70
245
110
240
48 h
90 min
24 h
48 h
—
O
O
X
O
X
Desflurane [0.8 (SD) or 0.5 (LD) MAC]
Isoflurane [0.62 (SD) or 0.52 (LD) MAC]
Sevoflurane or propofol
Sevoflurane (1.6 vol%)
—
No
No
No
No
—
CI
CI
TCI
CI
CI
71
180
100
182
48 h
—
24 h
18 h
O
X
X
X
Desflurane, 0.5 MAC
No
Sevoflurane [1.75% (SD) or 0.5% (LD)]
Propofol
No
No
Yes (50%)
Yes (70%)
CI
TCI
CI
CI
180
223
180
—
24 h
48 h
O
X
X
—
Sevoflurane [1.0 or 0.8 (R) MAC]
Propofol
—
—
—
CI
CI
CI
360
240
—
48 h
X
X
Propofol
Propofol (2–4 mg$kg21$h21) or
sevoflurane
—
Yes (50%)
TCI
CI
LD, large-dose group; MAC, minimal alveolar concentration; R, remifentanil group; SD, small-dose group.
remifentanil-induced hyperalgesia started from 2 hours
after surgery and reached its peak at 24–48 hours after
surgery.83
Also, it is not sufficient to explain the cause of these
discrepancies by using the dose and duration of remifentanil infusion. Although some authors used remifentanil infusion rate that was enough to develop
hyperalgesia, they have reported the negative results
on development of hyperalgesia after CI. It can be partially explained by the effect of coadministrated anesthetic drugs, such as propofol, sevoflurane, and nitrous
oxide, which might affect the development of AOT
and/or OIH. In a clinical case report, Fodale et al84
suggested that the development of AOT due to remifentanil was not encountered when it was coadministered with propofol or sevoflurane, which produced an
inhibiting effect at NMDA receptors neutralizing the
remifentanil stimulation on these receptors. However,
sevoflurane has only a minimal inhibitory effect on
NMDA receptors,85 which are considered to be
involved in the development of opioid-related hypersensitivity.86 Relatively low sevoflurane concentrations
(1.0%) reverse OIH, but there was the lack of effect of
sevoflurane concentrations of 1.0% and 1.5% to oppose
American Journal of Therapeutics (2015) 22(3)
hyperalgesia after high-dose opioids.85,87 Shin et al74
also suggested that remifentanil-induced hyperalgesia
was not apparent during propofol anesthesia compared with the effect produced during sevoflurane
anesthesia, although dosage was increased from 1.0
to 4.0 ng/mL. This results can be supported by several
observations; propofol inhibits the NMDA subtype of
the glutamate receptor,88,89 which is one of the potential mechanisms that induced the OIH. Recent evidence
suggests that propofol may have some modulatory
effect on OIH, possibly through interactions with
gamma-aminobutyric acid (GABA-A) receptors at the
supraspinal level.90,91 Specifically, propofol was shown
to have analgesic effects at subhypnotic doses, and it
delayed the onset of antianalgesia after remifentanil
infusion in a small clinical study of healthy human
volunteers.90 However, it actually aggravated postremifentanil infusion secondary hyperalgesia in the intradermal electrical stimulation pain model, suggesting
a facilitation of pronociceptive pathways, possibly
through modulation of descending inhibition by receptor binding to the GABA-A ionophore.91 The clinical
significance of these findings, especially in higher dosages used in the intraoperative setting, remains to be
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Remifentanil-Induced Tolerance and Hyperalgesia
studied. In addition, some authors ignored the impact
that nitrous oxide might have against the AOT and
hyperalgesia.44,47 Echevarria et al77 reported that the
group using the 70% nitrous oxide with remifentanil
of 0.3 mg$kg21$min21 showed a greater decreased
mechanical threshold than the group without nitrous
oxide at postoperative 12–18 hours, although the postoperative pain scores and cumulative morphine consumption was similar between the groups. Lee et al79
suggested that 70% nitrous oxide showed comparable
effect on the postoperative opioid consumption similar
to remifentanil at mean 0.17 mg$kg21$min21.
Next, different infusion mode also can influence the
development of acute tolerance and hyperalgesia,
although they have an equipotential effect on the pain
control. TCI has been shown not only to improve intraoperative hemodynamic stability but also to decrease
intraoperative remifentanil requirements.72,73 Interestingly, Richebe et al75 evaluated whether the use of TCI
mode also would lead to decrease in early postoperative period hyperalgesia after cardiac surgery. They
suggested that an infusion of intraoperative remifentanil using TCI mode (target: 7 ng/mL) reduced postoperative hyperalgesia, compared with that using CI
mode (0.3 mg$kg21$min21), and this decrease in postoperative hyperalgesia was sustained and lasted
throughout the first postoperative week. The conclusion of the study was supported by the difference of
intraoperative infused total remifentanil dose, which
was greater in CI than in TCI group, despite the initial
expectation that TCI of remifentanil at 7 ng/mL was
equivalent to a CI rate at 0.3 mg$kg21$min21.72,92
Then, when nociceptive thresholds are repeatedly
measured in a situation in which protective withdrawal reflexes are impaired or abolished by opioid
administration, the possibility of cumulative tissue
injury manifesting as AOT or OIH should be carefully
excluded.93 This is especially likely to occur with repetitive testing protocols. In the study by Luginbuhl
et al,38 they exposed volunteers to significantly higher
nociceptive input during remifentanil versus during
saline placebo administration. It cannot be excluded
that postinfusion hyperalgesia resulted from more
intense noxious stimulation during the remifentanil
infusion rather than the opioid administration itself.
However, Ishii et al80 documented that neither acute
tolerance nor hyperalgesia was observed even in the
setting when they used a tapered remifentanil infusion
to rapidly attain maximum analgesic effect of remifentanil and tried to minimize the repetitive and potentially tissue damaging nature of the stimuli.
Finally, it remains unclear whether OIH contributed
to increased postoperative opioid requirements and/or
pain in studies exposing patients to high intraoperative
www.americantherapeutics.com
e69
opioid doses because pain sensitivity was not formally
assessed before and after surgery. As noted previously
in this review, the need for dose escalation to maintain
analgesia can be owing to the development of analgesic
tolerance, OIH, or simultaneous expression of both
phenomena. No causal relationship between acute
perioperative opioid exposure and development of
OIH can be established without direct measurement
of pain sensitivity. If patients have a comorbidity
affecting sensory thresholds preoperatively, this condition could distort postoperative measures on OIH. The
German Network on Neuropathic Pain established
a standardized QST protocol to investigate the somatosensory thresholds in healthy subjects and in patients
with neuropathic pain.94 Reference values from healthy
subjects could be used to establish normal sensory
functioning in patients before anesthesia. In a clinical
setting, this direct measure could be used for distinguishing between OIH and AOT, because of clinical
importance, as AOT can be overcome by dose increase,
while OIH may be aggravated by the same intervention. Without direct measures to assess hyperalgesia,
such as QST, the results are not easy to distinguish
from acute tolerance.63 Clinical studies examining
remifentanil-induced hyperalgesia by QST showed that
at a relatively high-dose remifentanil decreased the
pain threshold.36,41,42,69,76 These studies used remifentanil infusions at clinically standard rates, and all of
them showed clear hyperalgesia either shortly after
discontinuing infusion or 1 and 2 days postoperatively.
However, most studies confirmed the reality of this
phenomenon using indirect evidence, such as greater
postoperative pain and morphine consumptions
instead of using QST.21,95 Therefore, we think that a further study is needed to reveal the development of AOT
and OIH using QST.
IMPORTANCE OF AOT AND/OR OIH
IN CONSIDERING THE REDUCTION
OF REMIFENTANIL DOSAGE AND
ADOPTING PREVENTIVE
MODULATIONS
Of note, 41% of all surgical patients still experience
moderate-to-severe acute postoperative pain and that
24% experience inadequate pain relief.96 According to
previously mentioned reports, when opioid is used
alone with high infusion rate, the OIH may be seen
during 1–5 hours after stopping infusion and can last
anywhere from 2 to 10 days.21,29,53,97,98 In a recent
cohort study on postoperative remifentanil-induced
hyperalgesia, its incidence was reported 16.1% of
American Journal of Therapeutics (2015) 22(3)
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e70
patients undergoing general anesthesia with remifentanil and whose length of operative incision was less
than 4 cm.99 They also suggested that the relevant
influencing factors were age less than 16 years, operative duration of above 2 hours, and more than 30
mg/kg of remifentanil. Increased pain sensitivity has
been increasingly recognized as a paradoxical and
undesirable effect of opioid, OIH, to combat surgical
pain, and nociception.37 The presence of hyperalgesia
in the acute postoperative period is likely to increase
the amount of pain experienced. This, in turn, potentially increases the effects that carry the risk of more
complications, impaired mobilization, prolonged hospital stay, and many other undesirable outcomes after
surgery. More pain frequently results in more analgesia use, leading to an increase in analgesia-associated
side effects, well documented for opioids and respiratory, gastrointestinal, and urologic function. Hyperalgesia itself may make opioid analgesic titration more
difficult. Eventually, hyperalgesia and increased pain
in the postoperative period is now considered a major
candidate mechanism for the development of chronic
pain.48–50 It has recently been highlighted that chronic
pain as a direct result of surgery is more common than
previously recognized.48 Therefore, less postoperative
hyperalgesia results in better acute postoperative pain
control,36 and interventions associated with alterations
of postoperative hyperalgesia are also associated with
changes in acute postoperative pain outcomes.21,95
However, there is a lack of good-quality clinical
research in this area, despite the fairly extensive basic
science evidence. In a structured evidence-based
review for all levels of evidence on OIH in humans,18
10 hypotheses have been used to test for the possibility of OIH. Among them, 3 hypotheses are of interest:
(1) opioid infusion in normal volunteers or chronic
pain patients will decrease pain threshold and/or tolerance; (2) opioid infusion in normal volunteers will
increase secondary hyperalgesia as measured by allodynia or hyperalgesia; and (3) perioperative opioids
will increase postoperative pain and/or opioid requirements. They suggested that there was no sufficient evidence to support or refute the existence of
OIH in humans except in the case of normal volunteers receiving opioid infusions. There was consistent
evidence that opioid infusion in normal volunteers
induced either an increase in secondary hyperalgesia
or allodynia, and there was inconsistent evidence on
pain threshold and tolerance in normal volunteers or
chronic pain patients although the threshold
decreased with opioid infusion. They also documented that using opioid in perioperative period
increased the postoperative pain or opioid requirements with inconsistent evidence.
American Journal of Therapeutics (2015) 22(3)
Kim et al
There are some questions regarding the importance
of the drug use to prevent AOT and OIH in postoperative patients and whether the assessment of OIH at
immediate postoperative period is suitable. Clinical
studies assessing the preventive effect of drugs on
OIH in the immediate postoperative period showed
that the clinical benefit is either absent,77 limited to
a moderate opioid-sparing effect,36,74 or a slight reduction in pain scores.42,74 According to these results,
Martinez and Fletcher19 suggested that the immediate
postoperative period may not be the optimal period to
detect the preventive effects on OIH, although additional clinical data need to confirm it.
Furthermore, Simonnet and Rivat56 suggested that
OIH should be considered as a normal adaptive
response counteracting the perturbations caused by
administration of analgesic opioids. However, it is
tempting to speculate that the long-lasting hyperalgesia induced by endogenous or exogenous opioids may
still facilitate learning processes and memorization of
drives so that environmental changes which might
lead to pain may be better avoided. From a medical
viewpoint, OIH after a first opioid administration is
not a passive response but it might be considered as
the first step of an active process leading to pain sensitization. This suggests that opioids have reinforced
a nociceptive memory, which could contribute to pain
chronicization.
CONCLUSIONS
Current experimental and clinical data generally support the development of AOT and OIH in specific settings, such as acute remifentanil exposure in human
volunteer and postsurgical pain cohorts, when remifentanil was infused at $0.1 mg$kg21$min21 either
alone or with inhalation anesthetics. Therefore, in
these situations, clinicians need to be cautious for the
possibility of the development of AOT and OIH,
which may impair treatment of pain or even aggravate
preexisting pain. Clinicians should suspect manifestation of OIH when opioid treatment effect seems to
decline in the absence of disease progression, with
unexplained pain reports or allodynia unassociated
with the site of injury. According to the previous reported results, coadministrated anesthetic drugs, such
as propofol and nitrous oxide, and using of TCI model
seem to be helpful to modulate the development of the
AOT and OIH. However, there are no sufficient data to
support evidence of modulatory effect of them.
Finally, we also cannot find any strong consistent evidence to support the need to reduce the dose of remifentanil or apply the modalities for preventing the
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Remifentanil-Induced Tolerance and Hyperalgesia
AOT and the OIH. Consequently, further studies will
need to investigate whether remifentanil induce the
AOT and the OIH after general anesthesia using propofol, nitrous oxide, or TCI mode through high-quality
prospective trials. And the development of the AOT
and the OIH should be evaluated with direct measures, such as QST. It is also important to investigate
if remifentanil-induced hyperalgesia may contribute to
the development of chronic pain, and if this contribution can be attenuated or even reversed through pharmacologic modulation.
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