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 COPYRIGHT 2017 EDIZIONI MINERVA MEDICA

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© 2016 EDIZIONI MINERVA MEDICA Minerva Anestesiologica 2017 February;83(2):200-13

Online version at http://www.minervamedica.it DOI: 10.23736/S0375-9393.16.11602-5

REVIEW

Analgesia/nociception monitoring
for opioid guidance:
meta-analysis of randomized clinical trials
Matthias GRUENEWALD 1*, Astrid DEMPFLE 2

1Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus
Kiel, Kiel, Germany; 2Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany
*Corresponding author: Matthias Gruenewald, Department of Anaesthesiology and Intensive Care Medicine, University Hospital
Schleswig-Holstein, Schwanenweg 21, 24105 Kiel, Germany. E-mail: matthias.gruenewald@uksh.de

A B STRACT
INTRODUCTION: The adequate suppression of nociception is, besides induction of unconsciousness and immobility,
the main objective during anesthesia. Analgesics, most commonly opioids, are usually titrated by established clinical
surrogates of nociception. Recently, monitoring techniques became available to evaluate analgesia/nociception during
anesthesia and provide better measures then clinical evaluation alone. They are primarily derived from autonomic re-
sponse on physiologic standard measures.
EVIDENCE ACQUISITION: A literature search and systematic review of randomized controlled trials was performed.
Trials enrolling patients undergoing general anesthesia and comparing the effects of opioids guided by analgesia/nocicep-
tion monitoring were considered. Studies were analyzed regarding the outcome effects of opioid therapy, intraoperative
events and postoperative pain. Meta-analyses were performed for each outcome separately using a fixed-effects model
and random effects models.
EVIDENCE ANALYSIS: Seven applicable randomized clinical trials using three different methods for analgesia/noci-
ception monitoring and opioid guidance during anesthesia were found. All but one trial were single centre studies, with
a high heterogeneity between the trials and differences in predefined primary outcome. This meta-analysis found that
the use of analgesia/nociception monitoring was associated with a significant reduction of movement events, a non-
significant trend towards reduction of intraoperative administered opioids and emergence time, but was inconclusive with
regard to effects on hemodynamic events, postoperatively reported pain and opioid consumption.
CONCLUSIONS: Monitoring analgesia/nociception is often reliant on regular physiologic conditions, like sinus rhythm.
Opioid guidance dependent on analgesia/nociception monitoring during anesthesia may have beneficial and clinically
relevant effects, however the number of currently available randomized controlled studies is low and conclusions are
hampered by heterogeneity. More studies with focussed clinical endpoints are therefore needed.
(Cite this article as: Gruenewald M, Dempfle A. Analgesia/nociception monitoring for opioid guidance: meta-analysis of
randomized clinical trials. Minerva Anestesiol 2017;83:200-13. DOI: 10.23736/S0375-9393.16.11602-5)
Key words: Analgesia - Nociception - Analgesics, opioid - Meta-analysis as topic.
or other proprietary information of the Publisher.

Introduction patients often request unconsciousness, amne-

sia or hypnosis in order to avoid any perception

A nesthesia prevents the patient from the

unpleasant perception of a surgical proce-
dure. Primarily, adequate analgesia is needed
to avoid pain and its consequences that are
induced by surgical stimulation. Additionally,
of the surgical procedure. Last but not least,
surgeons may require immobility for a number
of modern surgical procedures. Simplified, an-
esthesia can be described as a medication-in-
duced state of analgesia, unconsciousness and

200 Minerva Anestesiologica February 2017

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ANALGESIA/NOCICEPTION MONITORING FOR OPIOID GUIDANCE GRUENEWALD
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muscle paralysis, usually induced by particular
drugs. These drug effects often influence more
than one of the three aspects and are depend-
ent on numerous physiological, biochemi-
cal and pharmacological factors. The char-
acteristics of individual patients and specific
procedures make the titration of analgesics a
clinically challenging issue. Any over- or un-
derdosage during anesthesia carries additional
risks. Best monitoring for depth of anesthesia
is established for the drug induced neuromus-
cular blockade. Today, no patient should fear
unrecognized unwanted events induced by
neuromuscular blocking agents (NMBA) as
quantitative monitoring has become standard
in modern anesthesia. However, with respect
to analgesia and unconsciousness such a suf-
ficient measurement method does not exist
so far. The processed electroencephalogram
(EEG) is being widely used to monitor drug
induced hypnotic state. Despite some limita-
tions, there is growing evidence that moni-
toring depth of hypnosis is favourable during
anesthesia.1, 2 Nonetheless, awareness during
anesthesia cannot be fully excluded.
The development of monitoring the analge-
sia component of anesthesia is still in its early
stage. Whereas level of pain or effects of anal-
gesics is relatively easy to assess in awake pa-
tients, its measurement is highly sophisticated
during the state of anesthesia. The term “pain”
is per definition reserved for a conscious per-
ception of actual or potential tissue damage
and cannot be used during unconscious state
of general anesthesia.3 Therefore, the term
“nociception” was generally introduced and
describes the neural process of encoding nox-
ious stimuli.4 We have good evidence, that the
mechanisms to suppress the response to nox-
ious stimulation are located in subcortical re-
gions of the brain and in the spinal cord.5, 6 Im-
portantly “pain” and “nociception” may exist
or other proprietary information of the Publisher.
with and without each other in awake humans.
Anesthesia and analgesia suppresses nocicep-
tive pathways. Routinely, the anesthesiologist
uses physiological responses in order to as-
sess the suppression of nociceptive pathways,
such as movement, tachycardia, lacrimation
or sweating. Nonetheless, these symptoms oc-
Vol. 83 - No. 2 Minerva Anestesiologica 201
cur relatively late and are neither very sensi-
tive nor very specific, in case of movement
not even applicable during muscle paralysis.
Underdosage of opioids during anesthesia
may harm the patient by arousal and initia-
tion of awareness, inadequate and unexpected
movement during the surgical procedure, by
vegetative activation with tachycardia and hy-
pertension or additional neuroendocrine acti-
vation with potential effects on acute or chron-
ic postoperative pain.7, 8 On the other hand,
an inadequate overdose of opioids may not
be detected by using standard physiological
symptoms of nociception. Thus, opioid over-
dose may as well harm the patient by cardio-
vascular depression, constipation, prolonged
time of emergence and remarkably increased
postoperative pain (hyperalgesia).9, 10 Opioid
induced hyperalgesia effects immediate post-
operative recovery and seems to be associated
with high intraoperative opioid doses. It has
been suggested to limit intraoperative opioids
to the lowest possible dose.11 The role of in-
traoperative nociception/analgesia monitoring
in this regard still has to be investigated. The
effects of perioperative opioid administration
on immune regulation, angiogenesis or even
tumour growth are currently under intensive
debates.12-14 It is therefore of high clinical
interest to titrate analgesics, or more specific
perioperative opioids, individually and accord-
ing to the surgical induced stimulation in order
to avoid over- and underdosage. In this mean-
ing the term “nociception-antinociception bal-
ance” during anesthesia is being used. How-
ever, no general measurement of this balance
exists as it depends on a variety of different
influences within the peripheral and the central
nervous system. But, insufficient nociception-
antinociception balance during anesthesia is
characteristically reflected by an autonomic
activation (both sympathetic and parasym-
pathetic). Reactions such as changes in heart
rate or blood pressure, sweating, increase of
the pupil diameter, increasing breathing fre-
quency, lacrimation or patient movement may
be used for its quantification. Some of these
responses are pharmacologically suppressed
by co-medications (e.g. beta-blocker) and an-
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esthesia related drugs (e.g. muscle relaxants,
clonidine) or blunted by co-morbidities (e.g.
atrial fibrillation) and therefore not helpful to
be used during anesthesia.
Recently, a number of monitoring tech-
niques have been introduced to quantify the
autonomic activation as surrogate of analge-
sia or nociception/antinociception balance and
provide a possible guidance of analgesics. The
monitoring includes simple scoring systems,
as performed by Evans and coworkers, who
suggest the use of autonomic responses like
systolic blood Pressure, heart Rate, Sweating
and Tearing in order to quantify the respective
response to stimulation (Evans’ PRST score)
from 0 – 8.15 Further, medical devices have
been developed in order to quantify the auto-
nomic activation after noxious stimulation and
help to monitor analgesia/nociception. Most
techniques use the response of the cardiovas-
cular system. The measures include the heart
rate variability, heart frequency, vascular tone
or inhibition of the cardiac baroreflex. The
ANI (Analgesia Nociception Index, Mdolo-
ris Medical Systems, Loos, France) represents
an index, which is derived from ECG based
heart rate variability (HRV), defined as small
beat-to-beat oscillations of the regular sinus
rhythm. These fluctuations are dependent on
sympathetic and/or parasympathetic tone,
which influence different parts of the spectral
analysis of HRV. During stable anesthesia the
variation of beat-to-beat interval is small and
increases by stimulation like surgical skin inci-
sion. The high frequency component of HRV
is related to the parasympathetic tone, whereas
the shift towards sympathetic tone moves the
spectrum of HRV towards the low frequency
component. As ANI is derived from the area
under the curve of the high frequencies, it
yields a numerical value from 100 to 0 strong-
ly related to the parasympathetic tone.16, 17 The
or other proprietary information of the Publisher.
CARDEAN Index (CARdiovascular DEpth
of ANalgesia, Alpha-2, Lyon, France) uses
stimulus induced increases of blood pressure
and heart rate (somato-sympathetic reflex) by
non-invasive blood pressure measurement.
The cardiac baro-reflex actually decreases
heart rate in case of hypertension in order to
202 Minerva Anestesiologica February 2017
maintain blood pressure. During noxious stim-
ulation and inadequate analgesia, this reflex is
inhibited and hypertension is accompanied by
tachycardia. Because these effects would not
be measureable at intermittent blood pressure
measurement a non-invasive continuous beat-
to-beat blood pressure monitor is being used.18
The algorithm has been adopted, but calculated
index is displayed as numerical value between
0 and 100. A threshold value of >60 is being
used as indicator of inadequate suppression of
nociception.19 The SPI (Surgical Pleth Index,
GE Healthcare, Helsinki, Finland) is based on
normalized plethysmografic derived heart rate
and pulse wave amplitude. Therefore this in-
dex reflects the activation of the autonomous
system by noxious stimulation, as increase in
sympathetic tone decreases heart rate interval
and pulse wave amplitude. Correspondingly,
the index values vary between 0 and 100,
whereas higher values represent the insuffi-
cient suppression of nociception. The devel-
opers of SPI could demonstrate that the index
correlates with stimulus intensity and opioid
concentration.20, 21 Further developments in-
clude the skin conductance, based on the prin-
ciple of electrodermal activity (Stress Detector;
Med-Storm Innovation AS, Oslo, Norway).22
Simplified, activation of sympathetic nervous
system evokes the filling of eccrine palmar and
plantar sweat glands. All the abovementioned
monitors use the autonomous response to stim-
ulation in order to evaluate adequate analgesia/
antinociception. It represents the humeral an-
swer of noxious stimulation, which then needs
to be measured and analyzed. Therefore these
monitoring variables are — unless they use
some pre-emptive test-stimulation — delayed
in response. However, it is of high interest to
measure the activation or suppression of noci-
ceptive pathways directly. Following this idea,
spinal reflexes have been the focus of research.
Whereas first trials using monosynaptic reflex-
es were encouraging but limited to an experi-
mental setup,23 today the measurement of spi-
nal polysynaptic reflex pathways has become
commercially available. The NFTS (Nocicep-
tive Flexion reflex ThreShold, Dolosys GmbH,
Berlin, Germany) can be recorded from with-
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means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
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drawal reflex (also known as RIII-reflex) and
has been proposed as a possible pathway for
monitoring responsiveness to noxious stimula-
tion.24 The threshold value represents the re-
spective intensity of stimulation eliciting the
reflex response. The RIII-reflex threshold in-
creases after administration of analgesics and
decreases after activation of sensory neurons
by capsaicin. The superiority of the RIII-reflex
threshold for prediction of movement in com-
parison to EEG-processed variables has been
previously demonstrated.24 Another reflex
pathway being used represents the reflex pupil-
lary dilatation (RPD) also known as ciliospinal
reflex. Increase in sympathetic tone leads to an
increase in pupil diameter. The mechanisms
are not fully understood, but pathways seem
to be dependent on supraspinal modulation, as
they are diminished in brain dead organ do-
nors.25 The pupil diameter and its change after
electrical noxious stimulation can be automati-
cally measured (AlgiScan, IDMED, Marseille,
France). RPD may be measured intermittently
during anesthesia and correlates with plasma
concentrations of opioids.26 RPD was superior
to heart rate or blood pressure in detection of
inadequate suppression of nociception.27 Fur-
thermore, it has to be mentioned, that EEG
based variables may also add information
about the nociception balance. The CVI (Com-
posite Variability Index, Covidien, Mansfield
MA, USA), which includes the variability of
bispectral index (BIS) and the frontal electro-
myogram, is presented as numerical value be-
tween 0 and 10, whereas 0 presents a low and
10 a high nociceptive level.28 There are con-
troversies about the usefulness of EEG based
variables in detection of nociception balance.
Some of the studies show a high depend-
ency on the EMG signal, whereas others re-
port high influences of the hypnotic state.29, 30
Very interesting is the modelling of EEG by
or other proprietary information of the Publisher.
autoregressive moving average (ARMA) and
dividing the signal by characteristics of sub-
cortical (thalamic) input into the cortical State
as measure of hypnotic and cortical Input as
measure of nociceptive activation.31 All these
monitoring variables have been examined
during anesthesia and application of various
Vol. 83 - No. 2 Minerva Anestesiologica 203
noxious stimulation, however, their clinical
usefulness needs to be evaluated within rand-
omized clinical trials.
Objectives
The aim of this review and meta-analysis is
to summarize the available data regarding in-
traoperative opioid guidance by measurement
of analgesia/nociception during anesthesia.
Therefore, a search for appropriate random-
ized clinical trials should be performed and it
has to be elucidated by meta-analysis whether
the use of these technologies leads to a reduc-
tion of intraoperative opioid use, reduction of
unwanted intraoperative events like movement
or cardiovascular signs of inadequate anesthe-
sia, reduction of emergence time or reduction
of postoperatively reported pain and opioid
consumption.
Evidence acquisition
Methods
The methodology for this meta-analysis was
adapted from PRISMA statement (Preferred
Reporting Items for Systematic Reviews and
Meta-Analyses) and PICOS Approach.32 An
electronic data and article search was per-
formed through PubMed by M.G. in order to
identify appropriate studies, that have per-
formed an intraoperative opioid guidance de-
rived by variables from analgesia/nociception
measurement technologies and discard irrel-
evant trials. Keywords included “anesthesia”
and “randomized” with respective monitoring
variables “analgesia nociception index”, “car-
dean”, “nociception level”, “nociceptive flex-
ion reflex”, “pupillary dilatation reflex”, “skin
conductance”, “surgical pleth index” and “sur-
gical stress index”. The search was restricted
to controlled, randomized clinical trials that
are published in English (last search: April
2016). Population included patients (adults or
children) who received general anesthesia in-
cluding opioid analgesia. The intervention was
guidance of opioids performed by usage of an-
algesia/nociception monitoring in comparison
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means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
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to a control group, where no additional moni-
toring was used to monitor analgesia/nocic-
eption (only clinical judgement, i.e. treatment
as usual). The following outcomes or study
endpoints were defined: intraoperative opioid
consumption, occurrence of movement, occur-
rence of cardiovascular events (summarized
in two groups: hypertension/tachycardia and
hypotension/bradycardia), time to emergence
from anesthesia, reported pain in the postop-
erative period and postoperative opioid con-
sumption. Methodological quality was classi-
fied by using Jadad Scale.33
Statistical analysis
Meta-analyses were performed for each
outcome separately using a fixed-effects
model (only if between-study heterogene-
ity was not significant at a level of 0.05) and
random effects models, each with standard
inverse variance weighting. For continuous
outcomes (intraoperative opioid consump-
tion, time to emergence, reported pain in the
postoperative period and postoperative opi-
oid consumption), standardised mean differ-
ences (SMD, based on Hedges’ g) 34 between
intervention and control groups were used as
effect measures. Absolute values of opioid
consumption would not be comparable be-
tween trials since different opioids were used
in different trials. No censoring was present
in time to emergence data, therefore it was
also used as a continuous variable. Different
definitions of time to emergence, from either
end of surgery or end of anesthesia to either
extubation or eye opening required again the
use of SMDs. For one study,35 SDs were cal-
culated from reported 95% confidence inter-
vals (CIs) of means, using a normal approxi-
mation. Postoperative pain was reported on
numerical rating scales (or visual analogue
or other proprietary information of the Publisher.
scales) with a range of 0 to 10. Three studies
reported mean and SD 35-37 of one pain rat-
ing per patient at different postoperative time
points, one study reported mean and SD of
the sum of four ratings per patient on a scale
from 0 to 100, of which the mean and SD for
one rating was estimated and transformed
204 Minerva Anestesiologica February 2017
to a 0 to 10 scale.38 Two studies did not re-
port mean and SD for pain rating but rather
reported median pain ratings together with
range 39 or interquartile range (IQR).40 Since
a formal meta-analysis requires estimates of
the same variables for each study, we used for
these studies the value of the median instead
of the mean (imputation) and imputed SD by
IQR/1.35 or range/4 (which may be very un-
reliable since the original data was of small
sample sizes and probably skewed). There-
fore we report meta-analysis results for all six
studies and additionally for only those four
studies reporting mean and SD (Supplemen-
tary Figure 1, online content only).
For events that might occur more than once
to any patient during one surgery (intraopera-
tive movements, intraoperative cardiovascular
events), incidence rate ratios (IRR) between
treatment and control groups were used as ef-
fect measures, since only the total count over
all surgeries but not the exact distribution of
these events was available from publications.
For counts of zero in one group, a correction
of 0.5 was added. Cardiovascular events were
aggregated; the sum of hypertensive events
and tachycardia was used as an indicator of
low levels of analgesia, and the sum of hypo-
tensive events and bradycardia as an indicator
of high levels of analgesia. One study 35 re-
ported tachycardia, bradycardia, hypertension
and hypotension as “percent of time” which
was used instead of a count. For illustration,
forest plots including individual study results
and fixed- as well as random-effects meta-
analyses were prepared. All statistical analy-
ses were performed using the package meta
in R.41, 42
Evidence synthesis
A flowchart of the data search, including
the reasons for exclusion is presented in Fig-
ure 1. Finally, seven trials could be identified
as randomized controlled trials that used an-
algesia/nociception monitoring for guidance
of intraoperative opioids. All studies were
published between 2010 and 2015 and in-
cluded a total number of 683 patients. They
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include usage of three different monitoring

devices (ANI, CARDEAN and SPI), which
have basically been compared to standard
clinical care. All studies used EEG based
monitoring (either bispectral index or state
entropy) as depth of anesthesia monitor for
measurement of hypnosis component. A sum-
mary of characteristics of all selected studies
is given in Table I.
A summary of the results of this meta-anal-
ysis with regard to the investigated endpoints
is presented in Table II. Further the results are
presented as forest plots in Figures 2-8. For
most of the considered outcome measures, het-
erogeneity between studies is high and statisti-
cally significant.
All studies reported on the intraoperative
opioid administration guided by nociception
measurement. We detected a non-significant
trend towards intraoperative opioid reduction.
With respect to effects on unwanted intraop-
erative events, we could detect a significant
reduction of movement events by almost one
half in the intervention groups. Beyond this,
the available data is still insufficient to draw
definite conclusions with regard to hemody-
namic events. Intraoperative guidance of opi-
oids may reduce the time to emergence from
anesthesia, however this effect was not sig-
nificant. With regard to postoperative reported
pain and opioid consumption, a clinically rel-
evant effect of intraoperative analgesia/noci-
ception monitoring can neither be confirmed
nor refuted.
Discussion
With regard to intraoperative analgesia/
nociception monitoring and opioid guidance,
we found a limited number of available stud-
ies with a high heterogeneity. The main results
of this meta-analysis are that intraoperative
or other proprietary information of the Publisher.
Figure 1.—Flowchart of the data search.
to the influence of intraoperative analgesia/no-
ciception monitoring on intraoperative cardio-
vascular events, or reported postoperative pain
and opioid use, studies are inconclusive.
There are numerous studies for a high num-
ber of analgesia/nociception monitoring tech-
niques that show the effect of noxious stimu-
lation during differing states of anesthesia on
the measurement variable itself. These studies
may be considered “proof of principle” and
demonstrate that these measures have advan-
tages in detecting nociception in comparison
to clinical standard.17, 20, 21, 43 However, its
clinically usefulness still has to be proven in
randomized controlled trials. We found only
seven RCTs regarding the intraoperative guid-
ance of opioids by described analgesia/noci-
ception monitoring techniques. These studies
differ in their primary outcomes and we could
detect a high heterogeneity between them,
which limits the ability to draw final conclu-
sions.
One major goal of intraoperative analgesia/
nociception monitoring would be a precise
adaptation of opioid administration on the

guidance of opioids by analgesia/nociception
monitoring significantly reduces the number of
unwanted movement events. Possibly, it is also
accompanied by less intraoperative opioid use
and shorter emergence time from anesthesia,
however this trend was not statistically signifi-
cant with currently available data. With regards
individual need of the patient and the surgi-
cal procedure/stimulus. It could be expected
that opioid administration guided by clinical
evaluation and experience may increase the
overall consumption due to fixed application
algorithms or even pre-emptive dosing. In
this meta-analysis, we found a trend towards

Vol. 83 - No. 2 Minerva Anestesiologica 205

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Table I.—Characteristics of selected studies.

Patients
Study Year N. Design Maintanance of anaesthesia (hypnotic/opioid)
ASA-Score
Martinez et al.19 2010 Adults 146 Prospective RCT, Propofol/alfentanil
(ASA I-II) single center

Chen et al.39 2010 Adults 80 Prospective RCT, Propofol/remifentanil

(ASA I-II) single center
Bergmann et al.36 2013 Adults 151 Prospective RCT, Propofol/remifentanil
(ASA I-III) single center

Gruenewald et al.35 2014 Adults 82 Prospective RCT, Sevoflurane/sufentanil

(ASA I-II) single center
Colombo et al.37 2015 Adults 60 Prospective RCT, Propofol/remifentanil
(ASA I-II) single center

Szental et al.38 2015 Adults 119 Prospective RCT, Sevoflurane or desflurane or propofol/
(ASA not reported) two centers fentanil and morphine

Park et al.40 2015 Children 45 Prospective RCT, Sevoflurane and nitrous oxide/fentanil
(ASA I) single center
ASA-ASA: Physical Status Classification System; N.: number of studied patients; RCT: randomized controlled trial; ENT: ear-nose and
throat; BIS: Bispectral Index; SE: state entropy; CARDEAN: cardiovascular depth of anaesthesia index; SPI: Surgical Pleth Index; ANI:
Analgesia Nociception Index; Jadad score: score for methodological quality.

Table II.—Summary of meta-analysis.

Number Between study Fixed effect Random ef-
Endpoint of studies heterogeneity model P value fects model P value
(k) (P value) (95%CI) (95%CI)
Intraoperative opioid consumption 7 <0.0001 NA NA SMD=-0.34 0.058
[-0.87; 0.01]
Intraoperative movement 4 0.07 IRR=0.56 0.0002 IRR=0.54 0.049
[0.41; 0.76] [0.29; 1.0]
Intraoperative hypertension and/or tachycardia 4 <0.0001 NA NA IRR=0.65 0.46
[0.21; 2.03]
Intraoperative hypotension and/or bradycardia 3 <0.0001 NA NA IRR=0.45 0.22
[0.13; 1.62]
Time to emergence 5 0.0005 NA NA SMD=-0.30 0.17
[-0.71; 0.12]
Postoperative pain 6 0.03 NA NA SMD=0.14 0.30
[-0.13; 0.42]
Postoperative opioid consumption 4 0.16 SMD=0.15 0.25 SMD=0.18 0.33
[-0.10; 0.40] [-0.17; 0.53]
NA: not applicable.

less opioid use in the intervention group, monitoring may therefore equilibrate for this
which just missed statistical significance. effect and leads to a reduction of opioid use
Three studies described a significant reduc- under rather deep level of hypnosis and pos-
or other proprietary information of the Publisher.

tion effect on intraoperative opioids.36, 39, 40
On the other hand one study even described
an increased use of opioids in the interven-
tion group.19 Therefore it seems that reported
results deviate. But, it has to be taken into ac-
count, that opioid requirement is influenced
by hypnotic level.44 Analgesia/nociception
sibly increase the use of opioids at rather light
level of hypnosis.
We detected a significant reduction in
movement events in the intervention groups
that have been treated by analgesia/nocicep-
tion monitoring. Intraoperative movement is
clinically the most important outcome meas-

206 Minerva Anestesiologica February 2017

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Type of procedure/surgery Guidance of Intervention Primary outcome Jadad Funding Country

hypnotic effect score
Colonoscopy ± gastroscopy BIS CARDEAN Movement 2 Declared France
(40-60) (≥60 + conventional signs)

ENT surgery BIS SPI Unwanted 2 Declared Germany

(40-60) (20-50) events
Orthopaedic surgery SE SPI Emergence and 3 Declared Germany
(40-60) (20-50 or Δ10) consumption
of anaesthetics
Orthopaedic and BIS SPI Movement 3 Declared Germany
gynaecological surgery (40-60) (> 50 or movement)
Laparoscopic cholecystectomy SE SPI Sympathetic 3 Declared Italy
(40-60) (> 50) modulation by
HRV
Laparoscopic cholecystectomy BIS ANI Severe 3 Declared Australia
(not defined) (< 50) postoperative
pain
Adenotonsillectomy SE SPI Intraoperative 3 Declared South Korea
(40-60) (20-50) opioid

Figure 2.—Forrest plots representing the effects of intervention (opioid guided by analgesia/nociception monitoring) in com-
parison to control groups on intraoperative opioid administration.

ure, as it represents the most evident effect of traoperative movement by use of analgesia/
or other proprietary information of the Publisher.

inadequate anesthesia/analgesia balance. It is nociception monitoring is therefore of high

part of the still used MAC concept, which
has been described decades ago.45 The sup-
pression of movement during anesthesia is
linked to spinal and subcortical pathways
and movement is not necessarily associated
with cerebral arousal.46 The reduction of in-
clinical importance. Possibly the monitor-
ing allows earlier detection of inadequate
nociception/antinociception balance than
using clinical evaluation alone. This allows
faster interaction and titration of opioids with
subsequent prevention of inadequate anal-

Vol. 83 - No. 2 Minerva Anestesiologica 207

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means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
or other proprietary information of the Publisher.

208
©

parison to control groups on intraoperative movement events.

parison to control groups on intraoperative hypotension and/or bradycardia.

parison to control groups on intraoperative hypertension and/or tachycardia.

Minerva Anestesiologica
COPYRIGHT 2017 EDIZIONI MINERVA MEDICA

GRUENEWALD ANALGESIA/NOCICEPTION MONITORING FOR OPIOID GUIDANCE

Figure 5.—Forrest plots representing the effects of intervention (opioid guided by analgesia/nociception monitoring) in com-
Figure 4.—Forrest plots representing the effects of intervention (opioid guided by analgesia/nociception monitoring) in com-
Figure 3.—Forrest plots representing the effects of intervention (opioid guided by analgesia/nociception monitoring) in com-

February 2017
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means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
or other proprietary information of the Publisher.

Vol. 83 - No. 2
parison to control groups on emergence time.
©

parison to control groups on postoperative pain rating.

parison to control groups on postoperative opioid adminstration.

Minerva Anestesiologica
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209
Figure 8.—Forrest plots representing the effects of intervention (opioid guided by analgesia/nociception monitoring) in com-
Figure 7.—Forrest plots representing the effects of intervention (opioid guided by analgesia/nociception monitoring) in com-
Figure 6.—Forrest plots representing the effects of intervention (opioid guided by analgesia/nociception monitoring) in com-
ANALGESIA/NOCICEPTION MONITORING FOR OPIOID GUIDANCE GRUENEWALD
 ©
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not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
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gesia. However, prediction of movement is
still challenging and most monitoring vari-
ables were unable to predict movement in
advance.47 Maybe the use of spinal reflex
pathways as monitoring tool allows further
advantages, but has not yet been elucidated
within a RCT.24
With regard to hemodynamic stability we
could not detect an effect of opioid guid-
ance by analgesia/nociception monitoring.
Neither hypertension/tachycardia as pos-
sible signs of underdosing opioids nor hy-
potension/bradycardia as possible signs of
overdosing opioids differed in comparison
to standard care. This is surprising since an-
algesia/nociception monitors have previous-
ly shown to be predictors of hemodynamic
reactivity during anesthesia.48 And one of
the studies has shown that opioid guidance
by analgesia/nociception monitoring led to
more stable sympathetic modulation, without
clinically relevant advantages.37 Only one of
the studies detected a significant reduction in
hemodynamic events.39 However, the results
of this meta-analysis are based on only a lim-
ited number of studies and confidence inter-
vals in the random effect model are too large
to allow final conclusions.
Overall, the reduction of unwanted events
like movement or hemodynamic events can be
considered as an important clinical goal and
possible motivation for the use of intraopera-
tive analgesia/nociception monitoring. Recent
developments for analgesia/nociception moni-
toring combine some of the existing monitor-
ing techniques using nonlinear methods and
reported very promising results with regard to
discrimination of noxious and non-noxious pe-
riods.49 Thus, new developments may provide
further advantages with regard to reduction of
unwanted events.
Five of the selected studies reported on an-
or other proprietary information of the Publisher.
esthesia emergence times. Bergmann et al.
selected “emergence” as primary outcome
and could report a clinically relevant advan-
tage of analgesia/nociception monitoring in
outpatient anesthesia as emergence was sig-
nificantly shortened.36 One study reported a
trend towards prolonged emergence time in
210 Minerva Anestesiologica February 2017
the intervention group.38 However, the au-
thors did not describe a procedure of hypno-
sis adoption at the end of surgery, assuming
that short emergence time was not much in-
tended. In this meta-analysis we could detect
a tendency towards shorter emergence times
in the fixed effect model but significance was
missed in the random effect model. Therefore
it remains uncertain whether emergence time
can be shortened by use of intraoperative an-
algesia/nociception monitoring.
Further this meta-analysis examined, wheth-
er the intraoperative guidance of opioids by
analgesia/nociception monitoring has an im-
pact on pain and opioid consumption reported
in the post-operative period. There are recent
studies that reported a possible link between
analgesia/nociception monitoring at the end of
surgery and postoperative pain.50
Therefore one of the selected studies used
the level of postoperative pain as primary out-
come, and could not find a reduction of pain.38
This meta-analysis comes to the same consist-
ent result; there is currently no evidence that
intraoperative guidance of opioids by analge-
sia/nociception monitoring affects the level
of postoperatively reported pain. Possibly, the
present results even point to a higher level of
pain and increased postoperative opioid need.
Nonetheless, it has to be considered that in
the future analgesia/nociception monitoring
may provide information regarding to predict-
ed postoperative pain and early intervention
based on the monitoring prevents the patient
from the bad experience after surgery.
In this analysis, we only identified rand-
omized clinical trials that used analgesia/noci-
ception monitoring devices taking into account
cardiovascular variables as surrogates for au-
tonomic responses. The use of these variables
is hampered during arrhythmia or pharmaco-
logical alteration of the cardiovascular system
and limits its utility for monitoring critical ill
patients. Maybe new developments including
monitoring spinal reflex pathways or process-
ing of nociception and analgesia within the
central nervous system are resolving these
clinically important challenges. Taken together
our findings and experience, the use of existing
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means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
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monitoring tools for intraoperative guidance of

opioids offers clinical advantages in relatively
healthy patients, like often seen in an ambula-
tory setting.
Limitations of the study
Some limitations of this analysis have to be
considered when interpreting the data. First of
all, the number of studies is rather small as this
field of research is very new and there is a high
heterogeneity. Except for one study, all studies
are single centre studies and may be influenced
by reporting and/or publication bias. The fo-
cus and primary outcome definitions within
the different studies are inconsistent and surgi-
cal interventions widely differ (Table I), that
may explain some of the heterogeneity within
studies. Another limitation is concerning the
blinding of assessors in these trials, which is
not possible for most of the assessed oucomes.
It would be of high interest to agree on stan-
dards with regard to clinical endpoints, when
conducting studies with analgesia/nociception
 1. Mashour GA, Shanks A, Tremper KK, Kheterpal S,
guided opioid titration as well as conducting
more multicentre RCTs.
 2. Lobo FA, Schraag S. Limitations of anaesthesia depth
Conclusions
 
In conclusion, this meta-analysis enabled
the detection of seven studies with intraop-  
erative guidance of opioids performed by an-
 
algesia/nociception monitoring techniques.
The studies show a high heterogeneity. Inter-
 
vention in comparison to standard care led to
a reduction of movement events as well as
 
a trend towards reduction of intraoperative
opioid consumption and shorter emergence
from anesthesia. No definite effects with
respect to hemodynamic events or pain and  
opioid consumption reported postoperatively
or other proprietary information of the Publisher.
Key messages
—— There are numerous recent develop-
ments with regard to monitoring analgesia/
nociception during anesthesia. However,
randomized clinical trials are rare and show
a high heterogeneity.
—— Monitoring analgesia/nociception
during anesthesia can prevent movement
and may lead to a reduction in opioid ad-
ministration.
—— Intraoperative guidance of opioids
does not have an effect on postoperative
reported pain or opioid need.
—— Clinical endpoints for intraopera-
tive analgesia/nociception monitoring are
heterogeneous and maybe a consensus on
these endpoints would facilitate planning
and performing larger studies.
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(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other

45. Eger EI, 2nd, Saidman LJ, Brandstater B. Minimum al-
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Funding.—None.
Conflicts of interests.—MG has performed research in the field of analgesia monitoring and was an author/co-author in two of the
selected studies. He has held honorary lectures for GE Healthcare the manufacturer of SPI. AD reports no conflict of interest.
Article first published online: November 3, 2016. - Manuscript accepted: November 2, 2016. - Manuscript revised: October 3, 2016.
- Manuscript received: July 25, 2016.
For supplementary materials, please see the online version of this article.
or other proprietary information of the Publisher.

Vol. 83 - No. 2 Minerva Anestesiologica 213

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SUPPLEMENTARY MATERIALS
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itoring) in comparison to control groups on postoperative pain ratings in studies that reported mean and SD (no imputation).
GRUENEWALD ANALGESIA/NOCICEPTION MONITORING FOR OPIOID GUIDANCE

Supplementary Figure 1.—Forrest plots representing the effects of intervention (opioid guided by analgesia/nociception mon-

February 2017