Eur J Anaesthesiol 2018; 35:165–172

ORIGINAL ARTICLE

Does the b-receptor antagonist esmolol have analgesic

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effects?
A randomised placebo-controlled cross-over study on healthy
volunteers undergoing the cold pressor test
Fredrik Ander, Anders Magnuson, Alex de Leon and Rebecca Ahlstrand

BACKGROUND Esmolol may attenuate the sympathetic res-
ponse to pain and reduce postoperative opioid consumption.
It is not clear whether esmolol has an analgesic effect per se.
OBJECTIVES The aim of this study was to evaluate the
analgesic effect of esmolol in the absence of anaesthetics
and opioids. We tested the hypothesis that esmolol would
reduce the maximum pain intensity perceived during the cold
pressor test (CPT) by 2 points on a 0 to 10 numeric pain
rating scale (NRS) compared to placebo.
DESIGN Randomised, placebo-controlled cross-over study.
SETTING Postoperative recovery area, Örebro University
Hospital. Study period, November 2013 to February 2014.
PARTICIPANTS Fourteen healthy volunteers. Exclusion cri-
teria included ongoing medication, pregnancy and breast-
feeding and participation in other medical trials.
INTERVENTIONS At separate study sessions, participants
received interventions: esmolol (0.7 mg kg1 bolus over 1 min
followed by infusion at 10 mg kg1 min1); 0.9% normal saline
bolus then remifentanil infusion at 0.2 mg kg1 min1 and
0.9% normal saline bolus and infusion according to a random
sequence. All infusions were administered over 30 min.
MAIN OUTCOME MEASURES Perceived maximum pain
intensity score, pain tolerance and haemodynamic changes
during CPT, and occurrence of side-effects to interventions
compared to placebo, respectively.
RESULTS Esmolol did not reduce perceived pain intensity or
pain tolerance during the CPT. The NRS-max score was
similar for esmolol, 8.5 (SD 1.4) and placebo, 8.4 (SD
1.3). The mean difference was 0.1 [95% confidence interval
(1.2 to 1.4)], P value equal to 0.83. Remifentanil signifi-
cantly reduced NRS-max scores, 5.4 (SD 2.1) compared to
placebo, [mean difference 3.1 (95% confidence interval
(4.4 to 1.8)), P < 0.001]. Side-effects were seen with
remifentanil but not with esmolol.
CONCLUSION No direct analgesic effect of esmolol could
be demonstrated in the present study. The postoperative
opioid-sparing effect demonstrated in previous studies, could
therefore be secondary to other factors such as avoidance of
opioid-induced hyperalgesia, synergy with coadministered
opioids or altered pharmacokinetics of those drugs.
TRIAL REGISTRATION European clinical trials database,
https://eudract.ema.europa.eu/, EudraCT no. 2011-005780-24.
Published online 15 September 2017

Introduction
and opioid requirements during surgery.12 The intraoper-
Esmolol is a b1-adrenoreceptor antagonist with a rapid
ative administration of esmolol may also reduce postoper-
onset and short duration.1–3 The drug is used to control
ative analgesic requirements,9–11,13,14 suggesting it could
hypertension and tachyarrhythmia,1 and in anaesthesia, to
possibly have an important perioperative role.
attenuate the sympathetic response to laryngoscopy and
tracheal intubation.4–6 Furthermore, new areas of use have Several animal studies have provided results suggesting
emerged7 including a reduction in volatile anaesthetic,8–11 that esmolol may possess inherent analgesic properties.15,16

From the Department of Anaesthesia and Intensive Care (FA, AldL, RA) and Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro,
Sweden (AM)
Correspondence to Fredrik Ander, MD, Department of Anaesthesia and Intensive Care, Örebro University Hospital, SE 701 82, Örebro, Sweden
Tel: +46 19 602 11 11; fax: +46 19 12 74 79; e-mail: fredrik.ander@regionorebrolan.se

0265-0215 Copyright ß 2018 European Society of Anaesthesiology. All rights reserved. DOI:10.1097/EJA.0000000000000711

Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.

 166 Ander et al.
However, only a few trials have addressed the possibility
of a direct analgesic effect of esmolol in men.17 – 19 In
these trials, pretreatment with esmolol was shown to
reduce the incidence of injection pain with propofol and
subparalysing doses of rocuronium, respectively. It has
also been suggested that the opioid-sparing effect may in
fact be related to secondary effects, such as synergism
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with, or altered pharmacokinetics of coadministered
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anaesthetics and opioids, or possibly through the avoid-
ance of opioid-induced hyperalgesia.9,12,20 – 25
Should esmolol have a specific analgesic action, it could
be used to complement existing multimodal analgesia
strategies to reduce the perioperative use of opioids and
possibly opioid-related complications.
The main objective of this study was to evaluate whether
esmolol, in the absence of opioids or anaesthetics, has an
analgesic effect during experimental pain testing using
the cold pressor test (CPT). We also aimed to evaluate
the effect of esmolol in attenuating the sympathetic stress
response during CPT, and whether or not esmolol pro-
duces any of the side-effects associated with remifentanil
treatment (swallowing difficulty, nausea, respiratory
depression and desaturation).
Methods
The study protocol was approved by the Regional Ethics
Committee in Uppsala, Stockholm, Sweden (Dnr 2012/
070) on 7 March 2012 (Chairperson Erik Lempert) and by
the Swedish Medical Products Agency on 23 March 2012
(No. 151 : 2012/12484) and registered in the European
Clinical Trials database (EudraCT no. 2011-005780-24,
https://eudract.ema.europa.eu/) prior to the start of enrol-
ment. It was conducted at the Department of Anaesthesia
and Intensive Care, University Hospital in Örebro,
Örebro, Sweden between November 2013 and February
2014. Volunteer recruitment was by advertisements on
the Örebro University notice boards, and the study
participants were included consecutively. The study
participants were fully informed of the details of the
study protocol prior to obtaining written informed con-
sent. Financial remuneration was provided.
Inclusion criteria were ASA classification I; men or
women; BMI less than 30 kg m2 and age 18 to 40 years.
Exclusion criteria were: ongoing treatment with cardio-
vascular medication, benzodiazepines or analgesics;
allergy to drugs used in the trial; pregnancy and breast-
feeding and participation in other medical trials.
Study protocol
After a brief physical examination and interview where
exclusion criteria were ruled out, study participants were
familiarised with the outline of the protocol, the CPT
and the numeric pain rating scale (NRS) used (range 0 to
10, 0 ¼ no pain, 10 ¼ worst pain imaginable).26,27 An
intravenous line for fluid and drug administration was
Eur J Anaesthesiol 2018; 35:165–172
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established and monitoring equipment applied [ECG,
pulse oximetry and noninvasive blood pressure (BP)].
Monitoring of the above parameters was performed
throughout each study session and documented at
5-min intervals. All study participants went through three
intervention sessions, each session being separated by at
least 3 days. During each study session, two infusion
pumps (Alaris CC syringe pump, Alaris Medical Nordic
AB, Solna, Stockholm County, Sweden) were used for
intravenous administration of the study drugs. In session
A, esmolol (Brevibloc; Baxter Healthcare Ltd., Thetford,
Great Britain) was administered by one of the pumps as a
bolus dose of 0.7 mg kg1 over 1 min followed by an
infusion of 10 mg kg1 min1 over 30 min administered
by the second pump. In session B, remifentanil (Remi-
fentanil Teva; TEVA Pharmaceuticals Works Private
Limited Company, Gödöllö, Pest County, Hungary)
was administered as an infusion of 0.2 mg kg1 min1
that was terminated without gradual withdrawal after
30 min. The infusion of remifentanil was preceded by
a bolus of saline over 1 min to resemble the bolus admin-
istration of esmolol. During session C, saline was admin-
istered by both syringe pumps as a 1-min bolus followed
by a 30-min infusion.
At the first study session, the study participants were
randomised to the sequence of intervention (A-B-C, A-C-
B, B-A-C, B-C-A, C-A-B or C-B-A) using sealed opaque
envelopes. Envelopes were prepared by departmental
staff who had no other part in the study. In preparation, a
note containing one of the six possible intervention
sequences was placed in each envelope, which were
sealed, mixed and numbered. The envelopes were then
used consecutively. The study participants were blinded
to the intervention sequence.
Experimental pain testing was performed using the
CPT.28,29 The device used for the CPT consisted of a
10-l plastic container that was two-thirds filled with tap
water and one-third crushed ice. Constant manual stirring
and temperature measurement ensured an even target
temperature of 0.0 to 1.08C. During each CPT, the right
hand was immersed in the ice water mixture above the
wrist. Pain intensity levels (NRS) and heart rate (HR)
were measured immediately before, and at 15 s intervals
during immersion. Noninvasive BP measurements were
performed as frequently as possible. Study participants
were informed that voluntary hand withdrawal was pos-
sible at any time during the test. The test was terminated
after 2 min if withdrawal had not already taken place.
Measures of cold pain intensity [NRS-max, NRS-area
under curve (AUC)]30,31 and cold pain tolerance were
used. NRS-max was defined as the maximum NRS
score during the CPT.31 The area under the NRS pain
curve was calculated using trapezoidal approximation
using the NRS-max to extrapolate the curve if withdrawal
had taken place before 2 min. Cold pain tolerance was
 Analgesic effect of esmolol 167

defined as the time (s) from immersion to spontaneous
withdrawal,32 or termination of the test whichever was
the case.
During each study session, a cold pressure test was
performed prior to intervention, at the very end of the
30-min intervention period, and 20 min after the infusion
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vs. placebo and remifentanil vs. placebo), correction for
multiple testing was performed using the Bonferroni–
Holm method.33 Corrected P values less than 0.05 were
considered statistically significant. Mean differences with
95% confidence intervals (CI) were used as association
measures. Statistical analyses were performed using SPSS
version 22.0 (IBM Corp., Armonk, New York, USA)

had been stopped.

and STATA release 14 (College Station, Texas, USA:
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The primary end point was the perceived maximum pain StataCorp LP).
intensity score (NRS-max). Secondary end points were
The manuscript adheres to the applicable equator guide-
the pain intensity score NRS-AUC and pain tolerance.
lines (Fig. 1, CONSORT flow diagram) and the Helsinki
Haemodynamic changes (BP, HR) during CPT, and the
declaration.
occurrence of side-effects defined as oxygen saturation
92% or less, respiratory rate 8 min1 or less, subjective
swallowing difficulty and nausea were also measured. Results
Initially, we aimed to evaluate the degree of swallowing All 14 study participants completed the study sessions
difficulty, and nausea each on a four-point scale. How- without any unexpected incidents. Demographic data are
ever, as few volunteers had difficulty with swallowing or presented in Table 1.
nausea, only the occurrence of swallowing difficulty or The mean pain intensity scores, measured as NRS-max,
nausea, regardless of severity, are reported in the results were similar with esmolol 8.5 (SD 1.4) and placebo 8.4
section. Comparisons were made between esmolol and (SD 1.3); mean difference 0.1 [95% CI (1.2 to 1.4)],
placebo and between remifentanil and placebo. P ¼ 0.83 (Table 2). Remifentanil, on the other hand,
significantly reduced the pain intensity score, 5.4
Statistical analysis (SD 2.1), compared to placebo; mean difference 3.1
As no study similar to the present one, on the analgesic [95% CI (4.4 to 1.8)], P < 0.001. Similar findings were
effect of esmolol, had been performed before, it was observed when the pain intensity score was measured as
difficult to perform a sample size estimation. In theory, NRS-AUC (Table 2). NRS-max and NRS-AUC values
during intervention with esmolol compared to placebo, showed a very high correlation (r ¼ 0.9). Furthermore,
with a SD of 2, a sample size of 10 paired comparisons mean pain intensity scores (NRS-max and NRS-AUC)
should have been sufficient to demonstrate a reduction in were similar in the CTPs performed after interventions,
NRS-max of 2 points on the NRS scale given the power of as in the CPTs performed before (Table 2).
0.8 and a type 1 error probability of 0.05. In the present
study 14 study participants were enrolled. Fig. 1
Pain intensity scores (NRS-max, NRS-AUC) data were
evaluated using a linear mixed model with unstructured
Assessed for eligibility (n = 14)
covariance structure, which showed the best model fit
from Akaike Information Criteria. Intervention (esmolol/
remifentanil/placebo), time of CPT (before, during and
after drug administration), sequence of intervention and
the interaction variable intervention by time, were cate-
gorical independent variables in the mixed model. Anal- Allocated to randomised intervention (n = 14)
ysis of haemodynamic data was performed in a similar
manner, except that it was adjusted for baseline values.
The Shapiro–Wilk test was used to verify the normality
assumption of the residuals from the mixed model. The
correlation between NRS-max and NRS-AUC was mea-
sured using Pearson’s correlation coefficient (r). Completed intervention A, B, and C (n = 14)

The Kaplan–Meier method was used to visualise cold

pain tolerance, and the log-rank test was used to compare
times to hand withdrawal between placebo and esmolol
and remifentanil, respectively.
Analysed (n = 14)
Fisher’s exact test was used to analyse categorical side-
effect data (presence of swallowing difficulty, oxygen
saturation 92%, respiratory rate 8 and nausea). As CONSORT flow diagram.
two interventions were compared with placebo (esmolol

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 168 Ander et al.

Table 1 Demographic data trigeminal nucleus of the substantia gelatinosa,36 suggest-

Volunteers (n U 14)
ing attenuating of afferent signals and facilitation of the
Age (years) 23 (3)
pain inhibitory system in the spinal cord. Finally, nor-
Sex (Female/Male) 3/11 adrenaline increases heat-induced hyperalgesia in skin
Weight (kg) 75 (14) that has been sensitised by capsaicin,37 which implies
Height (cm) 178 (9)
that b-receptor antagonists could be used to modify
BMI (kg m-2) 23.5 (2.8)
peripheral inflammatory reactions. The postulated anti-
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Data presented as mean (SD) or numbers when applicable. nociceptive action of esmolol could thus be explained by
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modulation of pain signals at central, spinal and periph-

The Kaplan–Meier figure shows the cumulative propor-
tion of hand withdrawals because of pain during CPT
(Fig. 2). No significant difference between esmolol and
placebo regarding pain tolerance was demonstrated,
P ¼ 1.0. When remifentanil was administered, however,
all study participants were able to tolerate the 120 s CPT,
(P < 0.05 compared to placebo).
Compared to placebo, remifentanil caused significantly
more episodes of respiratory depression than esmolol
(Table 3). Otherwise, no significant differences in side-
effects (Table 3) and haemodynamic changes (Table 4)
were demonstrated.
Discussion
It is well established that the sympathetic system is
involved in nociception, and numerous studies on the
possible involvement of b-blockers in pain management
have been performed.9–11,13,14 With its short onset and
duration, esmolol is a b-receptor antagonist suitable for
intraoperative use,3 and some reports have indicated that
it may possess antinociceptive properties per se.15–19 The
possibility of an inherent analgesic effect is, however,
controversial, and the exact mechanism of action
remains unknown.
It has been suggested that b-receptor antagonists could
attenuate stress-related secretion of noradrenaline in the
hippocampus,34 a process possibly involved in antinoci-
ception. Furthermore, esmolol has been shown to block
tetrodotoxin-resistant sodium channels in dorsal root
ganglia,35 and to modulate neurotransmission in the
eral levels. The hydrophilic nature of esmolol, however,
means that it does not readily cross the blood–brain
barrier,3 thus making an action at the central level
unlikely.
In addition to the postulated direct action on pain, it has
also been suggested that the opioid-sparing effect of
esmolol could be related to the secondary effects men-
tioned in the introduction section.9,12,13,20,23–25,38 As little
is known about the mechanisms involved in the opioid-
sparing effect of esmolol, the aim of the present study was
to establish whether or not the very low dose of esmolol
used during anaesthesia for postoperative opioid spar-
ing,10–13 has an analgesic effect when administered alone.
Our main finding was that esmolol had no inherent
analgesic properties when evaluated with the CPT. Mean
NRS-max pain intensity scores during intervention with
esmolol and placebo were similar. The CI limit of the
primary end point (difference in NRS-max between
esmolol and placebo) was nowhere near the hypothesised
2-point reduction used to estimate the sample size,
suggesting that the nonsignificant result was not because
of the sample size being too small.
Remifentanil on the other hand, produced a significant
decrease in the mean NRS-max pain intensity score
compared to placebo, which was expected.39 When CPTs
were repeated 20 min after termination of the remifen-
tanil infusion, maximum intensity pain scores were simi-
lar as in the CPTs performed before initiation of the
intervention, implying that development of hyperalgesia
did not occur (Table 2).

Table 2 Numeric pain rating scale-max and numeric pain rating scale-area under curve during the cold pressor tests before, during and after
interventions

Placebo n U 14 Esmolol n U 14 Remifentanil n U 14 Esmolol vs. Placebo Remifentanil vs. Placebo

Mean (WSD) Mean (WSD) Mean (WSD) Mean difference (95% CI) P value Mean difference (95% CI) P value
NRS-max
Before 8.6  1.3 8.6  0.6 8.2  1.5
During 8.4  1.3 8.5  1.4 5.4  2.1 0.1 (1.2 to 1.4) 0.83 3.1 (4.4 to 1.8) <0.001
After 8.6  1.3 8.5  1.2 8.4  1.5
NRS-AUC
Before 864  165 871  117 818  165
During 824  196 824  187 494  200 0.5 (161 to 160) 1.0 340 (501 to 179) <0.001
After 833  166 843  163 813  184

During each study session, cold pressor tests were performed before, during and after interventions. NRS-max and NRS-AUC denote maximal values registered during
cold pressor tests, and are expressed as mean (SD). Effects of esmolol and remifentanil (NRS-max, NRS-AUC) during cold pressor tests are compared to placebo and
adjusted for sequence of intervention using linear mixed model, see statistics section for details. Measures of effect are expressed as mean difference, 95% CI. P values are
corrected for multiple testing using the Bonferroni–Holm method. AUC, Area under curve; CI, confidence interval; NRS, numeric ration scale.

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 Analgesic effect of esmolol 169

Fig. 2

1.0
Cumulative proportion of withdrawal
Placebo Esmolol vs. Placebo: P = 1.0
Esmolol Remifentanil vs. Placebo: P < 0.05

0.8
Remifentanil
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0.6
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0.4
0.2
0.0

0 30 60 90 120
Time in seconds
Number of patients
Placebo 14 14 10 8 8
Esmolol 14 14 11 9 8
Remifentanil 14 14 14 14 14

Cold pain tolerance (s) during the 120 s cold pressor test. The Kaplan–Meier figure shows the cumulative proportion of hand withdrawal, because of
pain. The log-rank test was used to compare time to withdrawal for the primary and secondary hypothesis (esmolol and remifentanil vs. placebo). P
values are corrected for multiple testing using the Bonferroni–Holm method.

The experiments in this study were performed in a
controlled environment where the CPT was used as a
surrogate for perioperative pain. For obvious reasons, the
experimental setting cannot be fully compared with the
clinical setting of surgery and anaesthesia, where many
external and internal factors affect the patient. However,
it enabled us to study the postulated analgesic effect of
esmolol per se, without the interference of other factors.
The failure to demonstrate an analgesic effect may imply
that the opioid-sparing effect of esmolol, when used as an
adjunct to anaesthesia, could instead be because of one,
or several of these secondary factors, rather than a direct
analgesic effect. This suggestion is further supported
when taking into account the pharmacokinetic properties
of esmolol, whose postoperative effect on pain otherwise
should reach a point far beyond that where the drug has
been fully eliminated.3
Remifentanil-induced episodes of low respiratory rate
and desaturation, whereas esmolol, like placebo, had
no such negative side-effects. This was expected as
remifentanil is known to cause dose-dependent respira-
tory depression.39 In addition, our research group has
demonstrated that remifentanil may impair swallowing
function40 and cause pulmonary aspiration in healthy
volunteers.41 We, therefore, wanted to explore whether
esmolol could cause subjective swallowing difficulties.
No such side-effects were demonstrated. In contrast,
even though not statistically significant, remifentanil
caused more volunteers to experience swallowing diffi-
culties than did placebo in this setting.
The result of the present study raises some issues that
need to be addressed. The dose of esmolol was chosen to
resemble the clinical studies demonstrating an opioid-
sparing effect of esmolol when administered as adjunct to
anaesthesia, rather than a dose that cause HR reduction.
In those studies, an initial bolus dose of 0.5 to 1 mg kg1
in conjunction with induction of anaesthesia, followed by
a maintenance dose of between 5 and 15 mg kg1 min1
was used.10–13 Given the short elimination half-life of
esmolol, the plasma concentration should be very low

Table 3 Side-effects of interventions

Placebo Esmolol Remifentanil Esmolol vs. Remifentanil vs.

n U 14 n U 14 n U 14 placebo P value placebo P value
SpO2 92% 0 0 9 NA <0.001
Respiratory rate 8/min 3 3 13 1.0 <0.001
Swallowing difficulty 1 1 7 1.0 0.07
Nausea 0 0 4 NA 0.20

Data are presented as number of study participants suffering from the indicated side-effects, on at least one occasion during interventions. Side-effects of esmolol and
remifentanil were compared to placebo using Fisher’s exact test. P values are corrected for multiple testing using the Bonferroni–Holm method. NA, not applicable; SpO2,
oxygen saturation.

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 170 Ander et al.

Table 4 Blood pressure and heart rate changes during the cold pressor tests before, during and after interventions

Placebo n U 14 Esmolol n U 14 Remifentanil n U 14 Esmolol vs. Placebo Remifentanil vs. Placebo

Mean (SD) Mean (SD) Mean (SD) Mean difference Mean difference
Baseline Max Baseline Max Baseline Max (95% CI) P value (95% CI) P value
SBP (mmHg)
Before 133  11 153  20 131  10 150  20 133  14 154  21
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During 126  13 149  16 124  9 146  22 135  20 150  26 1.6 (12.5 to 9.2) 0.76 7.0 (18.1 to 4.1) 0.41
129  146  15 128  12 147  20 131  15 146  23
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After 10
DBP (mmHg)
Before 76  8 92  11 78  8 93  12 78  8 94  12
During 75  11 93  11 74  8 91  12 75  14 86  11 2.1 (9.3 to 5.1) 0.55 7.2 (14.4 to 0.1) 0.10
After 75  7 94  11 75  7 91  15 78  8 87  10
Heart rate (BPM)
Before 67  10 91  13 68  11 84  10 67  11 92  14
During 67  10 82  8 62  8 79  8 71  25 88  25 0.4 (8.7 to 7.9) 0.93 4.1 (4.3 to 12.4) 0.66
After 65  10 81  10 65  13 78  11 72  19 85  17

During each study session, cold pressor tests were performed before, during and after interventions. Baseline registrations were recorded immediately before initiation of
the cold pressor test, whereas max values denote maximal values measured during cold pressor tests. Baseline and maximal values are expressed as means (SD). Effects
of esmolol and remifentanil on haemodynamic variables during cold pressor tests are compared to placebo and adjusted for sequence of intervention using linear mixed
model. Measures of effect are expressed as mean difference, 95% CI. See statistics section for details. P values are corrected for multiple testing using the Bonferroni–
Holm method. BPM, beats per minute; CI, confidence interval.

when the CPT is performed toward the end of the 30-min
infusion. This assertion is supported by the failure of
esmolol to reduce the HR prior to the CPT, and to
attenuate the sympathetic response (rise in BP and
HR) during the CPT, compared to placebo. Contrary
to the low continuous dose of esmolol used in the present
study, esmolol was administered in considerably higher
doses in animal studies demonstrating possible direct
analgesic properties.35,36 It would, therefore, be interest-
ing to perform a study using a dose titration design to
evaluate the possible analgesic effect of esmolol.
Apart from the question of dosage, there are a few other
limitations that need to be addressed. The short elimi-
nation half-times of esmolol (approximately 7 to 9 min)1,3
and remifentanil (approximately 3 min)42,43 exclude any
carryover effect between study sessions. However, even
though a very low dose of esmolol was used, the wash out
period of 20 min within each study session may be
somewhat short to rule out any remaining effect of
esmolol during the CPT performed after drug adminis-
tration. However, as the b-blocking effect of esmolol has
been shown to be short lived, with complete recovery of
HR 20 min after termination of a 300 mg kg1 min1
infusion,1 the wash out period in the present study was
considered to be long enough to avoid clinical carryover
effects considering the much lower continuous dose that
was used (10 mg kg1 min1).
In the present study, we managed to enrol only three
women (Table 1). The skewed sex distribution may be
considered a weakness as men and women perceive
noxious stimuli differently.44 However, as the cross-over
design allows each volunteer to act as his/her own control,
the uneven sex distribution should not have affected the
result and is of limited concern.
Finally, various tests of experimentally induced pain
sometimes exhibit low intermodality correlation.45,46
The study may, therefore, have benefitted from the
addition of another experimental pain modality. The
CPT, however, is considered a reliable method for exper-
imental testing of nociceptive pain,30,47,48 and is a stan-
dardised well documented procedure that offers good test
reliability.29,49–51 Furthermore, the autonomic response
to the CPT is well documented.28,52
The study also has several strengths worth mentioning.
The two pain intensity scores (NRS-max and NRS-AUC)
correlated highly (r ¼ 0.9), suggesting that they truly
represented the intended parameter to be measured.
The pain tolerance parameter was also in agreement.
Furthermore, during the ‘placebo session’ the maximum
pain intensity scores were very similar in the before,
during and after test sessions, suggesting consistent sta-
bility of the test method, and the unlikelihood of test-to-
test conditioning,53 temporal summation54 or effect of
learning. The cross-over design reduced the risk for
confounding issues. To compensate for the slight imbal-
ance in the numbers of study participants randomised to
each intervention sequence, the mixed model analysis
was adjusted for the sequence of intervention. This
adjustment had little impact and did not alter the study
findings.
Contrary to our hypothesis, no sign of a direct analgesic
effect of esmolol was seen during CPTs when adminis-
tered as a single drug in a dose similar to that previously
shown to cause intra and postoperative opioid sparing.
This could possibly be because of the low dose, and could
be clarified by a dose titration study.
However, our study indicates that the opioid-sparing
effect of esmolol, more likely, is secondary to other

Eur J Anaesthesiol 2018; 35:165–172

Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.

factors such as synergy with opioids, or prevention of
opioid-induced hyperalgesia, rather than a direct analge-
sic effect of the drug.
Acknowledgements relating to this article
Assistance with the study: we thank Professor Magnus Wattwil for
his contributions to this study and to MD Stefan Enbuske for the
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help with data acquisition.
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Financial support and sponsorship: the work was supported by the
Medical Research Fund, Örebro County Council, Örebro, Sweden.
Conflicts of interest: none.
Presentation: preliminary data from this study were presented in a
lecture at the American Society of Anesthesiologists Annual Meet-
ing, ‘Anesthesiology 2014’, 11 to 15 October 2014, New Orleans,
Louisiana, USA.
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