British Journal of Anaesthesia, 0 (0): 1–8 (2017)

doi: 10.1093/bja/aex253
Clinical Investigation

CLINICAL INVESTIGATION

Intraoperative naloxone reduces remifentanil-induced

postoperative hyperalgesia but not pain: a randomized
controlled trial
C.-H. Koo1,†, S. Yoon2,†, B.-R. Kim2, Y. J. Cho2, T. K. Kim2, Y. Jeon2
and J.-H. Seo2,*
1
Department of Anaesthesiology and Pain Medicine, CHA Bundang Medical Center, CHA University, 59
Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13496, Korea and 2Department of Anaesthesiology and
Pain Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea

*Corresponding author. E-mail: eongpa@empal.com

†
These two authors equally contributed to this work as co-first authors.

Abstract
Background: Intraoperative use of a high-dose remifentanil may induce postoperative hyperalgesia. Low-dose naloxone can
selectively reverse some adverse effects of opioids without compromising analgesia. We thus hypothesized that the intrao-
perative use of a high-dose remifentanil combined with a low-dose naloxone infusion reduces postoperative hyperalgesia
compared with the use of remifentanil alone.
Methods: Patients undergoing elective thyroid surgery were randomly assigned into one of three groups, depending on the
intraoperative effect-site concentration of remifentanil, with or without a continuous infusion of naloxone: 4 ng ml1 remi-
fentanil with 0.05 lg kg1 h1 naloxone in the high-remifentanil with naloxone group, and 4 or 1 ng ml1 remifentanil with a
placebo in the high- or low-remifentanil groups, respectively. We measured the pain thresholds (primary outcome) to mech-
anical stimuli using von Frey filaments and incidence of hyperalgesia on the peri-incisional area 24 h after surgery. We also
measured pain intensity, analgesic consumptions and adverse events up to 48 h after surgery.
Results: The pain threshold presented as von Frey numbers [median (interquartile range)] was significantly lower in the
high-remifentanil group (n¼31) than in the high-remifentanil with naloxone (n¼30) and the low-remifentanil (n¼30) groups
[3.63 (3.22–3.84) vs 3.84 (3.76–4.00) vs 3.80 (3.69–4.08), P¼0.011]. The incidence of hyperalgesia was also higher in the high-
remifentanil group than in the other groups [21/31 vs 10/30 vs 9/30, P¼0.005]. Postoperative pain intensity, analgesic con-
sumptions and adverse events were similar between groups.
Conclusions: The intraoperative use of low-dose naloxone combined with high-dose remifentanil reduced postoperative
hyperalgesia but not pain.
Clinical trial registration: NCT02856087.

Key words: hyperalgesia; naloxone; remifentanil

Editorial decision: June 29, 2017; Accepted: July 4, 2017

C The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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 2 | Koo et al.
Editor’s key points
• Remifentanil has been associated with postoperative
hyperalgesia.
• Von Frey filaments are used to measure mechanical
nociceptive thresholds.
• Hyperalgesia is but one component influencing postop-
erative pain intensity.
• Low-dose naloxone can reduce remifentanil-induced
hyperalgesia.
Remifentanil is a l-opioid receptor agonist, which is widely
used for intraoperative analgesia.1–5 Remifentanil has unique
pharmacokinetic properties with rapid onset and offset, thus
higher doses can also be safely used without delaying postoper-
ative recovery.2 4 6 7 However, exposure to high doses of remi-
fentanil may paradoxically reduce the pain threshold after its
discontinuation.1 2 4–6 8–10 The postoperative hyperalgesia is
known to be associated with acute and persistent pain.11–13
Naloxone is a l-opioid receptor antagonist commonly used
to reverse several side-effects of opioids.14 15 Low doses of
naloxone can selectively eliminate adverse effects of opioids
without compromising analgesia.1 8 16–18 However, the effects of
naloxone on remifentanil-induced hyperalgesia have not yet
been investigated in surgical patients although its effects were
suggested in an animal study.5 Therefore, we conducted a
randomized trial to test the hypothesis that the intraoperative
use of a high-dose remifentanil combined with a low-dose
naloxone reduces postoperative hyperalgesia compared with
the use of remifentanil alone.
Methods
Design
This prospective, double-blind, single-centre, parallel-group,
randomized controlled trial was approved by the Institutional
Review Board of Seoul National University Hospital (Seoul,
Korea) and registered at ClinicalTrials.gov (NCT02856087). After
obtaining written informed consent, we enrolled patients with
ASA physical status I–II, aged 20–75 yr, and undergoing elective
thyroid surgery under general anaesthesia using desflurane and
remifentanil from November 2014 to April 2015. We excluded
patients with an allergy to anaesthetic drugs, a history of
thyroid surgery, current analgesic medications, drug or alcohol
dependence, neurological or psychiatric disorders, severe hep-
atic or renal dysfunction, pregnancy and a BMI of >30 kg m2.
Patients were randomly assigned in a 1:1:1 ratio with a
computer-generated random sequence and the sealed envelope
method by an assistant not involved in the trial. All investiga-
tors and patients were blinded to the group assignment.
Anaesthesia
Nurses not involved in the study prepared remifentanil with na-
loxone or normal saline according to the group assignment, which
was blinded to the investigators. Two investigators (C.-H.K. and
B.-R.K.) performed anaesthetic management according to a
predetermined protocol. Without premedication, patients were
monitored with non-invasive blood pressure, pulse oximetry, elec-
trocardiography, bispectral index (A-2000 XP; Aspect Medical
Systems, Newton, MA, USA) and acceleromyography (TOF-watch
SX; MSD, Haarlem, the Netherlands), and received forced-air
warming. Remifentanil (Ultiva; GlaxoSmithKline, Brentford,
Middlesex, UK) was administered intravenously via effect-site tar-
get-controlled infusion (Base Primea; Fresenius Vial, Brézins,
France) with Minto pharmacokinetic model, and naloxone (Samjin
Pharm, Seoul, Korea) or normal saline were given at a constant
infusion rate according to the group assignment. Patients were
randomly assigned to one of three groups depending on the
effect-site concentration of remifentanil with or without a
continuous infusion of naloxone during anaesthesia: 4 ng ml1
of remifentanil with 0.05 lg kg1 h1 of naloxone in the
high-remifentanil with naloxone group; and 4 or 1 ng ml1 of remi-
fentanil with placebo in the high- and low-remifentanil groups,
respectively. The study drugs were administered from anaesthetic
induction until skin closure after surgery. The infusion devices
were blinded to the investigators.
General anaesthesia was induced by i.v. propofol 1.5–2 mg kg1
and rocuronium 0.6–0.8 mg kg1. At a bispectral index of <60
and train-of-four count¼0, the patient’s trachea was intubated
with a direct or video (UEscope; UE Medical Devices, Newton, MA,
USA) laryngoscope. Reinforced tracheal tubes (Medtronic,
Minneapolis, MN, USA) with an inner diameter of 7.0 and 7.5 mm
were used for women and men, respectively. The intracuff
pressure of the tube was adjusted to less than 25 cm H2O with a
cuff pressure monitor (VBM Medizintechnik GmbH, Sulz am
Neckar, Germany). Core temperature was monitored in the
nasopharynx.
Anaesthetic depth was maintained at a bispectral index of
40–60 by adjusting the end-tidal concentration of desflurane.
The patient’s lungs were ventilated (Primus; Dragger, Lubeck,
Germany) with a tidal volume 6–8 ml kg1 of predicted body
weight, a positive end-expiratory pressure 5 cm H2O, and an
inspired oxygen fraction 0.5 with a fresh gas flow 2 litres min1
of oxygen and air. The respiratory rate was set to obtain an
end-tidal carbon dioxide tension of 4.7–5.3 kPa. Rocuronium
0.2–0.3 mg kg1 was intermittently administered at a train-of-
four count 1. At a mean blood pressure of <60 mm Hg, lactated
Ringer’s solution 200 ml, ephedrine 5 mg or phenylephrine 30 lg
were given as appropriate.
At skin closure after surgery, administration of desflurane,
remifentanil and naloxone or placebo was stopped, and ramose-
tron 0.3 mg and ketorolac 30 mg were given intravenously. At a
train-of-four ratio of >90%, pyridostigmine 300 lg kg1 and gly-
copyrrolate 10 lg kg1 were administered to reverse the residual
neuromuscular block. Confirming adequate spontaneous
breathing and responses to verbal commands, the patient was
transferred to the post-anaesthesia care unit after tracheal
extubation. The patient was discharged from the unit at a modi-
fied Aldrete score of 9 or 10.
Outcomes
We collected baseline data on patients, surgery and anaesthe-
sia. We checked amounts of anaesthetic drugs or fluid and re-
quirements for inotropes during surgery. We also recorded
mean blood pressure, heart rate and end-tidal concentrations of
desflurane at six time points: before induction and intubation,
one minute after intubation, skin incision, skin closure, and
extubation. An investigator (S.Y.) evaluated pain intensity using
an 11-point numeric rating scale (0, no pain; 10, worst pain im-
aginable) at six time points: 30 min, 1, 6, 12, 24, and 48 h after
surgery. Patients with the pain score higher than 4 received i.v.
or i.m. ketorolac 30 mg and the number of rescue analgesic
 Naloxone reduces remifentanil-induced hyperalgesia | 3

Assessed for eligibility (n =95)

Excluded (n =4)
Not meeting inclusion criteria (n =2)
Declined to participate (n=2)

Randomized (n = 91)

Allocated to high-remifentanil Allocated to high-remifentanil Allocated to low-remifentanil

with naloxone group (n = 30) group (n = 31) group (n = 30)

Lost to follow-up (n = 0) Lost to follow-up (n =0) Lost to follow-up (n =0)

Analysed (n= 30) Analysed (n =31) Analysed (n =30)

Fig 1 CONSORT diagram.

medications was recorded. We checked lengths of stay in the
post-anaesthesia care unit and hospital.
The investigator (S.Y.) assessed pain thresholds to mechan-
ical stimuli on the peri-incisional area of thyroid surgery and
the forearm preoperatively, at 24 and 48 h after surgery as
described in previous studies.4 19 20 The pain threshold was
measured with von Frey filaments (Touch TestTM Sensory
Evaluators; Stoelting Co., Wood Dale, IL, USA) and presented as
von Frey numbers logarithmically transformed from the mech-
anical force produced by the filament.21–23 The lower von Frey
number indicates the lower threshold and more sensitization to
pain.21–23 On the peri-incisional area, the pain threshold was
defined as the average of three measurements at 2 cm below the
bilateral edges and middle of the skin incision. The incision
length was 5–6 cm in all patients. The threshold was also ob-
tained on the non-dominant forearm by averaging three meas-
urements at 3, 6 and 9 cm distal to the antecubital crease. We
checked numbers of patients with lower, higher and same post-
operative pain thresholds compared with the preoperative val-
ues on the peri-incisional area and forearm. Postoperative
hyperalgesia was defined as a decrease in the postoperative
pain threshold compared with the preoperative one.
The primary outcome was the pain threshold on the
peri-incisional area 24 h after surgery. Secondary outcomes were
the other pain thresholds and incidence of hyperalgesia on the
peri-incisional area or forearm; postoperative rescue analgesic
requirements, pain intensity and adverse events; and intraopera-
tive haemodynamic variables and amounts of drugs or fluid.
Statistical analysis
In our pilot study (n¼10), the mean (SD) von Frey number on the
peri-incisional area was 3.1 (0.8) at 24 h after thyroid surgery
using desflurane and 4 ng ml1 effect-site concentration of
remifentanil. For a clinically significant 20% difference in the
pain threshold by adding naloxone, 27 patients were needed in
each group with a risk of type-I error of 0.05 and power of 0.8 for
two-tailed statistical analysis.
Continuous variables were presented as mean (SD) or median
(interquartile range) after checking the normality with the
Shapiro–Wilk test. Outcomes collected sequentially were ana-
lysed with repeated-measures analysis of variance (ANOVA) or
the Friedman test for entire time points, and then with one-way
ANOVA or Kruskal–Wallis test, unpaired or paired t-tests, and
Mann–Whitney U or Wilcoxon signed-rank tests at each time
point as appropriate. Categorical variables were the number of
patients compared with Fisher’s exact test. Effect sizes with 95%
confidence interval (CI) were calculated if necessary. All ana-
lyses were conducted in an intention-to-treat manner. A P-value
<0.05 was considered statistically significant. STATA software
(Stata Corporation, College Station, TX, USA) was used for all
statistical analyses, sample size calculation and randomization.
Results
After screening 95 patients, 91 eligible patients were included,
30 in the high-remifentanil with naloxone group, 31 in the high-
remifentanil group and 30 in the low-remifentanil group (Fig. 1).
Characteristics of patients, surgery and anaesthesia were com-
parable between groups except doses of remifentanil and nalox-
one (Table 1). The end-tidal concentrations of desflurane were
similar during anaesthesia (P¼0.28 by repeated-measures
ANOVA). However, the mean blood pressure (Fig. 2A; P¼0.001 by
repeated-measures ANOVA) and heart rate (Fig. 2B; P¼0.004) at
tracheal intubation and skin incision were significantly higher
in the low-remifentanil group than in the high-remifentanil
 4 | Koo et al.

Table 1 Characteristic of patients, surgery and anaesthesia. Data are number of patients or mean (SD) except age [mean (range)].
*Significantly lower in the low-remifentanil group than in the other groups by one-way analysis of variance (ANOVA) and unpaired t-test.
†
Only given in the high-remifentanil with naloxone group

High-remifentanil High-remifentanil Low-remifentanil P-value

with naloxone group (n¼31) group (n¼30)
group (n¼30)

Age (yr) 50 (24–71) 44 (24–75) 52 (22–75) –

Sex (male/female) 8/22 12/19 9/21 –
Weight (kg) 63 (11) 63 (13) 61 (11) –
Height (cm) 160 (8) 165 (10) 161 (8) –
BMI (kg m–2) 24.4 (3.4) 23.1 (3.2) 23.4 (2.9) –
ASA physical status (I/II) 25/5 25/6 20/10 –
Medical conditions (hypertension/diabetes/pulmonary disease) 4/3/3 6/1/5 8/2/3 –
Type of surgery (thyroidectomy/lobectomy) 25/5 21/10 26/4 –
Amount of anaesthetic drugs and a fluid
Propofol (mg) 105 (28) 100 (21) 114 (23) 0.095
Rocuronium (mg) 49 (9) 49 (11) 47 (7) 0.64
Remifentanil (lg)* 1029 (334) 1101 (451) 321 (202) <0.001
Naloxone (lg)† 5.562.4 0 0 <0.001
Lactated Ringer’s solution (ml) 417 (167) 405 (165) 455 (259) 0.60
Patients receiving inotropes 19 22 19 0.76
Duration of surgery (min) 92 (21) 89 (41) 94 (37) 0.86
Duration of anaesthesia (min) 122 (24) 124 (42) 124 (41) 0.96

A High-remifentanil with naloxone B

High-remifentanil
Low-remifentanil

140 * 120
‡

120 100 §
Blood pressure (mm Hg)

†
Heart rate (beats min–1)

100 80

80 60

60 40

0 0
Before Before Intubation Skin Skin Extubation Before Before Intubation Skin Skin Extubation
induction intubation incision closure induction intubation incision closure

Fig 2 Mean blood pressure (A) and heart rate (B) during anaesthesia. Data are mean and SD. *Mean difference (95% CI) 20 (5–35) mm Hg, P¼0.008 and 19 (5–34) mm Hg,
P¼0.010 compared with the high-remifentanil with and without naloxone groups, respectively, by unpaired t-test; †14 (5–24) mm Hg, P¼0.005 and 17 (8–26) mm Hg,
P<0.001; ‡10 (1–20) beats min1, P¼0.043 and 15 (5–25) beats min1, P¼0.003; §14 (5–24) beats min1, P¼0.001 and 14 (4–26) beats min1, P¼0.002.

with and without naloxone groups: 108 (31) vs 88 (25) vs 89 On the peri-incisional area, the pain thresholds presented as
(25) mm Hg, P¼0.007 and 91 (21) vs 81 (18) vs 76 (18) beats min1, von Frey numbers (Fig. 3A; P¼0.046 by Friedman test) were sig-
P¼0.008 at intubation; 91 (21) vs 76 (17) vs 74 (14) mm Hg, P<0.001 nificantly lower in the high-remifentanil group than in the high-
and 78 (18) vs 65 (11) vs 65 (12) beats min1, P<0.001 at incision remifentanil with naloxone and the low-remifentanil groups at
by one-way ANOVA. 24 and 48 h after surgery: 3.63 (3.22–3.84) vs 3.84 (3.76–4.00) vs
3.80 (3.69–4.08), P¼0.011 at 24 h; 3.61 (3.22–3.84) vs 3.84 (3.76–4.00)

A High-remifentanil with naloxone
High-remifentanil
Low-remifentanil
4.5 † ‡
*
4.0
von Frey number
3.5
3.0
2.5
Before surgery 24 h after surgery
Fig 3 Pain thresholds to mechanical stimuli presented as von Frey numbers on the peri-incisional area of thyroid surgery (A) and the forearm (B). P¼0.007 (*),
0.016 (†) and 0.004 (‡) by Mann–Whitney U-test.
vs 3.90 (3.69–4.08), P¼0.004 at 48 h by Kruskal–Wallis test. In the
pairwise comparisons within each group, the postoperative pain
thresholds were significantly lower than the preoperative one in
the high-remifentanil group (P¼0.006 at 24 h; P¼0.005 at 48 h by
Wilcoxon signed-rank test), but comparable in the other groups.
The incidence of postoperative hyperalgesia on the peri-
incisional area was also significantly higher in the high-
remifentanil group than in the other two groups (Table 2).
However, the postoperative pain threshold (Fig. 3B; P¼0.345 by
Friedman test) and the incidence of hyperalgesia (Table 2) on the
forearm were comparable between and within groups. In add-
ition, there were no significant differences in the postoperative
pain intensity expressed as numeric rating scales (Fig. 4), rescue
analgesic requirements, adverse events and lengths of stay in
the post-anaesthesia care unit or hospital (Table 2).
Discussion
Remifentanil provides sufficient intraoperative analgesia attenu-
ating haemodynamic fluctuations during surgery.1–3 6 Because
of its short context-sensitive half-time of less than 9 min,7 high
doses of remifentanil can be safely given intraoperatively
with little risk of delayed recovery or adverse effects postopera-
tively.2 4 6 7 In our study, the intraoperative use of the high-dose
remifentanil (4 ng ml1 of effect-site concentration) compared
with the low-dose (1 ng ml1) attenuated increases in the mean
blood pressure and heart rate induced by noxious stimuli such
as tracheal intubation or skin incision. The requirements for ino-
tropes or the fluid, length of stay in the post-anaesthesia care
unit or hospital, and adverse events were similar regardless of
the intraoperative dose of remifentanil. Therefore, the 4 ng ml1
effect-site concentration of remifentanil seems to be effective
for adequate intraoperative analgesia in relatively healthy
patients, although caution should be taken in cardiovascular-
compromised patients.24 25
However, the intraoperative use of remifentanil can lead to
postoperative hyperalgesia.2 4 6 The hyperalgesia is known to be
Naloxone reduces remifentanil-induced hyperalgesia | 5
B
‡ 4.5
4.0
3.5
3.0
2.5
48 h after surgery Before surgery 24 h after surgery 48 h after surgery
induced by an effect-site concentration of remifentanil higher
than 2.7 ng ml1,2 and its underlying mechanisms are likely to
be associated with upregulation or alteration of N-methyl-D-as-
partate (NMDA)8 26–28 or l-opioid receptors.5 29 In our study, the
intraoperative use of the high-dose remifentanil compared with
the low dose decreased the pain thresholds and increased the
incidence of hyperalgesia on the peri-incisional area, in agree-
ment with previous studies.30 31
Our study showed that adding the low-dose naloxone
(0.05 lg kg1 h1) to the high-dose remifentanil during anaesthe-
sia significantly reduced postoperative hyperalgesia on the peri-
incisional area compared with using remifentanil alone. This
anti-hyperalgesic effect of naloxone is likely to be produced by
antagonizing or modifying NMDA4 8 26 32 and l-opioid receptor
activities5 17 33 34 related to the opioid-induced hyperalgesia, al-
though our study did not investigate its precise mechanisms.
Naloxone can reverse the analgesic effects of opioids as well
as the side-effects in doses higher than 0.06 lg kg1 h1,17
thus lower doses may be preferable to selectively obtain anti-
hyperalgesic effects without affecting analgesia.
The intraoperative opioids and nociceptive stimuli may have
synergistic effects on postoperative hyperalgesia.4 13 23 This
might explain no difference in the pain threshold on the fore-
arm unrelated to surgical insult in our study, in accordance with
previous findings.4 23 35 36 Furthermore, hyperalgesia is known
to be more associated with pain evoked by coughing or move-
ments rather than resting pain.4 37 In addition, although hyper-
algesia may aggravate postoperative pain,6 10 the association
was reported to be low between the pain threshold objectively
measured by von Frey filaments and the pain intensity subject-
ively assessed by the Likert-type scale.19 31 38 They might
explain the similar pain intensity presented as the numeric
rating scale despite the difference in the pain threshold.19 31 38
Our study has some limitations. As mentioned above, we
only checked the pain intensity in a resting state but not during
coughing or movements. We also only collected outcomes for
intraoperative and acute postoperative periods although
 6 | Koo et al.

Table 2 Postoperative outcomes. Data are number of patients or mean (SD). *Numbers of patients with lower, higher and same postopera-
tive pain thresholds compared with the preoperative values. †P¼0.016 and 0.007 and ‡P¼0.001 and <0.001 compared with the high-remi-
fentanil with naloxone and the low-remifentanil groups, respectively, by Fisher’s exact test

High-remifentanil High-remifentanil Low-remifentanil P-value

with naloxone group (n¼31) group (n¼30)
group (n¼30)

Patient receiving analgesics 9 13 8 0.46

Pain threshold on the peri-incisional area* (lower/higher/same)
24 h after surgery 10/7/13 21/5/5† 9/6/15 0.018
48 h after surgery 10/5/15 23/5/3‡ 8/7/15 0.001
Pain threshold on the forearm* (lower/higher/same)
24 h after surgery 7/3/20 10/6/15 6/6/18 0.56
48 h after surgery 7/5/18 11/5/15 6/4/20 0.63
Adverse events
Nausea 5 5 2 0.47
Dizziness 5 3 9 0.13
Headache 5 6 5 >0.99
Drowsiness 2 2 2 >0.99
Shivering 2 3 0 0.36
Length of stay
Post-anaesthetic care unit (min) 44 (6) 46 (7) 45 (3) 0.38
Hospital (days) 4.1 (0.7) 4.0 (0.7) 4.3 (0.9) 0.40

High-remifentanil with naloxone

10
High-remifentanil
Low-remifentanil
9

7
Numeric rating scale

0
30 min 1h 6h 12 h 24 h 48 h
Postoperative period

Fig 4 Postoperative pain intensity assessed by an 11-point numeric rating scale (0, no pain; 10, worst pain imaginable). Data are mean and SD. There were no
significant differences between groups [P¼0.23 by repeated-measures analysis of variance (ANOVA)].

hyperalgesia is known to be associated with chronic pain.12 13
Therefore, further research is needed to investigate the effects
of intraoperative naloxone on acute and chronic postoperative
pain.
In conclusion, the intraoperative use of low-dose naloxone
combined with high-dose remifentanil reduced postoperative
hyperalgesia compared with the use of remifentanil alone, al-
though it seemed to have no clinical benefits in reducing post-
operative pain.
Authors’ contributions
Study design: C.-H.K, S.Y., T.K.K., Y.J., J.-H.S.
Study conduct and data collection: C.-H.K., S.Y., B.-R.K.
Data analysis: Y.J.C., T.K.K., Y.J.
Writing paper: C.-H.K., S.Y., Y.J.C., J.-H.S.
Revising paper: all authors
Acknowledgements
We thank the American alumni association of our depart-
ment for the support of this study.
Declaration of interest
None declared.
Funding
This work was supported by the Department of
Anaesthesiology and Pain Medicine, Seoul National
University Hospital.
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Handling editor: Paul Myles