Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine

ArticleinAnesthesiology 103(1):147-55 · July 2005with432 Reads
Impact Factor: 5.88 · DOI: 10.1097/00000542-200507000-00022 · Source: PubMed
Abstract

Remifentanil-induced secondary hyperalgesia has been documented experimentally in both animals and healthy human volunteers, but never clinically. This study tested the hypotheses that increased pain sensitivity assessed by periincisional allodynia and hyperalgesia can occur after relatively large-dose intraoperative remifentanil and that small-dose ketamine prevents this hyperalgesia. Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 microg x kg(-1) x min(-1) (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 microg x kg(-1) x min(-1) (large-dose remifentanil); or (3) intraoperative remifentanil at 0.40 microg x kg(-1) x min(-1) and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 microg x kg(-1) x min(-1) until skin closure and then 2 microg x kg(-1) x min(-1) for 48 h (large-dose remifentanil-ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h. Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P < 0.05) and allodynia to von Frey hair stimulation was greater (P < 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects. A relatively large dose of intraoperative remifentanil triggers postoperative secondary hyperalgesia. Remifentanil-induced hyperalgesia was prevented by small-dose ketamine, implicating an N-methyl-d-aspartate pain-facilitator process.

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Available from: Daniel Sessler
Anesthesiology 2005; 103:147–55 © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.
Remifentanil-induced Postoperative Hyperalgesia and Its
Prevention with Small-dose Ketamine
Vincent Joly, M.D.,* Philippe Richebe, M.D., Bruno Guignard, M.D.,* Dominique Fletcher, M.D., Pierre Maurette, M.D.,§
Daniel I. Sessler, M.D., Marcel Chauvin, M.D.#
Background: Remifentanil-induced secondary hyperalgesia
has been documented experimentally in both animals and
healthy human volunteers, but never clinically. This study
tested the hypotheses that increased pain sensitivity assessed
by periincisional allodynia and hyperalgesia can occur after
relatively large-dose intraoperative remifentanil and that small-
dose ketamine prevents this hyperalgesia.
Methods: Seventy-five patients undergoing major abdominal
surgery were randomly assigned to receive (1) intraoperative
remifentanil at 0.05
g kg
1
min
1
(small-dose remifentanil);
(2) intraoperative remifentanil at 0.40
g kg
1
min
1
(large-
dose remifentanil); or (3) intraoperative remifentanil at
0.40
g kg
1
min
1
and 0.5 mg/kg ketamine just after the
induction, followed by an intraoperative infusion of 5
g
kg
1
min
1
until skin closure and then 2
g kg
1
min
1
for
48 h (large-dose remifentanil–ketamine). Pain scores and mor-
phine consumption were recorded for 48 postoperative hours.
Quantitative sensory tests, peak expiratory flow measures, and
cognitive tests were performed at 24 and 48 h.
Results: Hyperalgesia to von Frey hair stimulation adjacent to
the surgical wound and morphine requirements were larger
(P < 0.05) and allodynia to von Frey hair stimulation was
greater (P < 0.01) in the large-dose remifentanil group com-
pared with the other two groups, which were comparable.
There were no significant differences in pain, pressure pain
detection threshold with an algometer, peak flow, cognitive
tests, or side effects.
Conclusion: A relatively large dose of intraoperative remifen-
tanil triggers postoperative secondary hyperalgesia. Remifen-
tanil-induced hyperalgesia was prevented by small-dose ket-
amine, implicating an N-methyl-
D-aspartate pain-facilitator
process.
OPIOIDS are potent analgesics and are often necessary
for treating moderate to severe pain. However, experi-
mental studies report that opioids may also elicit hyper-
algesia (increased sensitivity to noxious stimuli) and
allodynia (nociceptive responses to innocuous stimula-
tion). Animal studies have demonstrated the develop-
ment of opioid-induced hyperalgesia.
1–5
In some, opioid-
induced hyperalgesia was observed to follow analgesia
and lasted long after opioid exposure ended.
1,2,4
In oth
-
ers, though, there was evidence of opioid-induced hy-
peralgesia during continuous opioid exposure.
3,5
Opi
-
oid-induced processes that underlie hyperalgesia
decrease antinociception and contribute to opioid toler-
ance.
3,5,6
Similar phenomena are probably present when acute
opioid tolerance occurs in patients. For example, toler-
ance to analgesia during 4-h-long constant-rate remifen-
tanil infusions is profound in volunteers and develops
within 60–90 min.
7
Moreover, delayed hyperalgesia de
-
velops from short-acting opioid exposure,
8–10
and rela
-
tively large intraoperative opioid doses are associated
with greater postoperative opioid consumption and
higher pain scores.
11,12
However, unlike the experimen
-
tal conditions in which changes in baseline nociceptive
thresholds are measured in a controlled setting, it is
often difficult to determine whether pain sensitivity
changes in response to opioid administration in clinical
situations.
Mechanical hyperalgesia surrounding the wound in
postoperative patients shares the same central neuronal
mechanism as heat-induced secondary hyperalgesia and
confirms a degree of central sensitization.
13
Also, it is
possible to use periincisional mechanical allodynia and
hyperalgesia as objective measures of opioid-induced
hyperalgesia in clinical settings.
Among the potential mechanisms leading to opioid-
induced hyperalgesia and antinociceptive tolerance, N-
methyl-
D-aspartate (NMDA) pain-facilitator processes
seem to play a key role.
14,15
Experimental studies per
-
formed in animals and volunteers have shown that
NMDA receptor antagonists such as ketamine inhibit
central sensitization and prevent opioid-induced hyper-
algesia.
1,2,8,16
Previously, we observed that small-dose
ketamine was a useful adjuvant to remifentanil-based
anesthesia by decreasing intraoperative remifentanil use
and postoperative morphine consumption.
17
However,
we did not study the action of ketamine and specially the
effects of ketamine on remifentanil-induced hyperalgesia
in the postoperative setting, which have yet to be eval-
uated. Therefore, we tested the hypothesis that relatively
This article is featured in “This Month in Anesthesiology.”
Please see this issue of ANESTHESIOLOGY, page 5A.
* Attending Anesthesiologist, Department of Anesthesia, Professor, # Profes-
sor and Chair, Department of Anesthesia and Institut National de la Sante´etdela
Recherche Médicale (INSERM) E 332, Hoˆpital Ambroise Pare, Assistance Pub-
lique Hoˆpitaux de Paris. Assistant Professor, § Professor and Chair, Depart-
ment of Anesthesia 3, Hoˆpital Pellegrin. Vice Dean for Research and Associate
Vice President for Health Affairs, Director O
UTCOMES RESEARCH Institute, and
Interim Chair and Lolita & Samuel Weakley Distinguished Professor of Anesthe-
siology, University of Louisville.
Received from the Department of Anesthesia and INSERM E 332, Hoˆpital
Ambroise Pare, Assistance Publique–Hoˆpitaux de Paris, Boulogne, France; the
Department of Anesthesia, Hoˆpital Pellegrin, Bordeaux, France; and the O
UTCOMES
RESEARCH Institute and Department of Anesthesiology & Perioperative Medicine,
University of Louisville, Louisville, Kentucky. Submitted for publication Novem-
ber 12, 2004. Accepted for publication March 15, 2005. Supported by a grant
from De´le´gation Re´gionale de la Recherche Clinique d’Ile de France for a Hospital
Clinical Research Project; grant No. GM 061655 from the National Institutes of
Health, Bethesda, Maryland; the Gheens Foundation, Louisville, Kentucky; the
Joseph Drown Foundation, Los Angeles, California; and the Commonwealth of
Kentucky Research Challenge Trust Fund, Louisville, Kentucky.
Address reprint requests to Dr. Chauvin: Assistance Publique–Hoˆpitaux de
Paris, 92100 Boulogne, France. Address electronic mail to: marcel.chauvin@apr.
ap-hop-paris.fr. On the World Wide Web: www.or.org. Individual article reprints
may be purchased through the Journal Web site, www.anesthesiology.org.
Anesthesiology, V 103, No 1, Jul 2005 147
Page 1
large intraoperative doses of remifentanil provoke post-
operative hyperalgesia as indicated by periincisional al-
lodynia and hyperalgesia and that small-dose ketamine
prevents hyperalgesia.
Materials and Methods
With approval of the Ethics Committee of the Hoˆpital
Ambroise Pare´, adult patients who were scheduled to
undergo open colorectal surgery lasting at least 2 h were
studied in two centers (Hoˆpital Ambroise Pare´, Bou-
logne, France, and Hoˆpital Saint Andre´, Bordeaux,
France). All had American Society of Anesthesiologists
physical status I–III.
Patients were excluded from the study when (1) im-
mediate extubation was not planned after surgery; (2)
they had chronic inflammatory disease including inflam-
matory bowel disease; (3) they regularly took analgesics
or had used opioids within 12 h of surgery; (4) they had
a history of drug or alcohol abuse, psychiatric disorder,
or obesity ( 130% of ideal body weight); (5) they had
contraindications to the self-administration of opioids
(i.e., unable to understand the patient-controlled analge-
sia [PCA] device); or (6) they had a condition, such as a
psychiatric disorder, acute cardiovascular disorder, or
unstable hypertension, for which the use ketamine was
contraindicated.
Protocol
During the preoperative anesthetic evaluation, the
evening before surgery, patients were instructed in the
use of quantitative sensory tests, the PCA pump (Master
PCA; Vial Fresenius, Brezins, France), the peak flow
monitor (Mini-Wright; Mediflux, Bry sur Marne, France),
a four-point verbal rating scale for pain (0 no pain, 1
slight pain, 2 moderate pain, 3 intense or severe
pain), the 100-mm visual analog scale (VAS) for pain (0
no pain to 100 worst pain), and an anxiety VAS (0
no anxiety to 100 worst imaginable anxiety). Control
measures of cognitive function, peak flow, and quantita-
tive sensory tests on skin area of surgery were also
performed during this visit. Patients were premedicated
with 1 mg lorazepam orally the night before surgery.
Anesthesia was induced with 6 mg/kg thiopental fol-
lowed by 0.5 mg/kg atracurium to facilitate orotracheal
intubation. Two minutes after the thiopental injection, a
1-
g/kg initial dose of remifentanil was given over 60 s.
After tracheal intubation, the patients were ventilated to
normocapnia with 50% oxygen and without nitrous ox-
ide. An atracurium infusion was titrated to maintain one
twitch in response to a supramaximal train-of-four stim-
ulus at the orbicularis oculi; atracurium was discontin-
ued 15 min before the end of surgery. Anesthesia was
maintained with remifentanil per randomized dosing de-
scribed below and desflurane at an initial end-tidal con-
centration of 0.5 minimum alveolar concentration
(MAC), adjusted to age.
18
Patients were randomly assigned, in a double-blinded
fashion, to one of three groups (25 patients/group).
Before the study began, a random-number table was
generated, specifying the group to which each patient
would be assigned upon entry into the trial. For each
patient, an envelope containing the group assignment
was prepared, sealed, and sequentially numbered. On
the morning of surgery and before induction of anesthe-
sia, a nurse not involved in the evaluation of the patient
opened the patient’s envelope and prepared remifen-
tanil and ketamine or saline solution syringes. None of
the other investigators involved in patient management
or data collection were aware of the group assignment.
In case of emergency, the attending anesthesiologist was
able to break the code. The three treatment groups were
as follows:
1. Small-dose remifentanil: Patients were given an
intraoperative infusion of remifentanil at a rate of
0.05
g kg
1
min
1
, which has been demon
-
strated not inducing hyperalgesia in volunteers,
9
and
a saline placebo infusion.
2. Large-dose remifentanil: Patients were given an
intraoperative infusion of remifentanil at a rate of
0.4
g kg
1
min
1
, an amount that has been
shown to maximally reduce anesthetic requirement
during abdominal surgery,
19
and a saline placebo in
-
fusion.
3. Large-dose remifentanil–ketamine: Patients were
given an intraoperative infusion of remifentanil at a
rate of 0.4
g kg
1
min
1
and ketamine. The dos
-
ing scheme for the ketamine infusion was calculated
using published pharmacokinetic variables
20
to
achieve target plasma concentrations of 250 ng/ml
intraoperatively and 100 ng/ml postoperatively.
These ketamine concentrations, especially 100 ng/ml,
are in the range known to counteract hyperalgesia
while producing minimal side effects.
21
The initial
loading dose of ketamine, given just after induction,
was 0.5 mg/kg; this was followed by a maintenance
infusion of 5
g kg
1
min
1
intraoperatively until
skin closure and subsequently by an infusion of 2
g kg
1
min
1
during the initial 48 postoperative
hours.
Insufficient anesthesia was defined as a heart rate that
exceeded preinduction values by 15%, systolic arterial
blood pressure exceeding baseline values by 20% for at
least 1 min, and/or a Bispectral Index of 70 or greater.
Patient movement, coughing, tearing, and sweating
were also considered signs of inadequate anesthesia.
Inspired desflurane concentration was increased step-
wise by 1% when insufficient anesthesia was suspected.
Hypotension, defined by a systolic arterial pressure less
than 80 mmHg or a mean arterial pressure less than
148 JOLY ET AL.
Anesthesiology, V 103, No 1, Jul 2005
Page 2
60 mmHg, prompted stepwise 1% reductions in desflu-
rane concentration for Bispectral Index values that re-
mained less than 70. Additional intravenous fluids were
also given as deemed appropriate by the responsible
anesthesiologist. Similarly, atropine or intermittent bo-
luses of ephedrine were given as required to treat bra-
dycardia or persistent hypotension.
Thirty minutes before the anticipated end of surgery, a
0.15-mg/kg bolus dose of morphine was given intrave-
nously. After skin closure, desflurane and remifentanil
were discontinued, and residual neuromuscular block-
ade was antagonized with 40 60
g/kg intravenous
neostigmine and 15–20
g/kg intravenous atropine. The
trachea was extubated when patients responded to the
verbal commands, spontaneous respiratory rate ex-
ceeded 12 breaths/min, and end-tidal carbon dioxide
partial pressure was less than 45 mmHg.
Patients were transferred to the postanesthesia care
unit (PACU) within 5 min of tracheal extubation. They
remained in the unit for at least 4 h and were given
oxygen via a facemask at a rate of 5 l/min throughout
this period. Postoperative pain was initially treated with
morphine chlorohydrate, which was titrated as required
by nurses who were unaware of patients’ group assign-
ments. Boluses of morphine (3 mg) were given at 5-min
intervals until the behavioral pain score (defined in the
Measurements section) was less than 1 or the verbal
rating scale score for pain was less than 2. However,
morphine administration was discontinued in patients
when the sedation score (defined in the Measurements
section) was greater than 2 or the respiratory rate was
less than 12 breaths/min. Subsequently, within 4 h after
tracheal extubation, patients were connected to a PCA
device set to deliver 1 mg morphine as an intravenous
bolus with a 5-min lockout interval; continuous infusion
was not allowed. This PCA regimen was continued for
48 h after tracheal extubation.
Measurements
Baseline heart rate and systolic arterial pressure were
defined as the mean of the two lowest measurements
recorded during a 3- to 5-min interval immediately be-
fore induction of anesthesia. Values from all routine
anesthetic monitors, including Bispectral Index monitor-
ing (Aspect A-2000
®
EEG monitor; Aspect Medical Sys
-
tems, Natick, MA), were recorded at 5-min intervals
during surgery.
The total dose of remifentanil given in the operating
room was recorded, as was the age-adjusted desflurane
dose in MAC/h.
18
Complications including laryngo
-
spasm, bronchospasm, respiratory depression, muscular
rigidity, agitation, and shivering were recorded. Pain was
evaluated for the first 15 min after extubation with a
behavioral score (0 calm patient with no verbal or
behavioral manifestation of pain, 1 behavioral or ver-
bal expression of pain, 2 intense behavioral or verbal
manifestation [crying or extreme agitation]). This behav-
ioral pain scale was performed 5, 10, and 15 min after
tracheal extubation.
Patients assessed pain intensity by giving both VAS and
verbal rating scale scores at 15-min intervals during the
first hour and then hourly for 3 h. Subsequently, pain
was evaluated only with the VAS at 4-h intervals for an
additional 44 h.
The pain threshold for mechanical static (punctuate)
stimuli was assessed using calibrated von Frey hairs
(0.057–178 g/mm
2
). The patients were instructed to
close their eyes during the procedure. Care was taken to
avoid stroking the skin with the hair and to apply only a
pressure stimulus. Filaments were applied to the desig-
nated point on the skin for approximately 1 s. Von Frey
hair applications were separated by at least 30 s to
reduce the likelihood of anticipatory responses. The von
Frey filaments were applied in ascending order of stiff-
ness. Tactile pain threshold was defined as the smallest
force (g/mm
2
) necessary to bend a von Frey hair, which
was just perceived as painful. Three determinations with
an interval of 30 s were made at each assessment, and a
mean was calculated. If tactile pain threshold exceeded
hair number 19 (178 g/mm
2
), the sensitivity was cen
-
sored at number 20.
A handheld electronic pressure algometer (Somedic
AB, Stockholm, Sweden) with a 0.28-cm
2
probe area was
used to determine pressure pain threshold. The patients
were instructed to immediately activate a push button,
which freezes the digital display, when pain was per-
ceived. The average of three measurements with an
interstimulus interval of 60 s was defined as pressure
pain threshold value. Values were expressed in kPa.
Tactile and pressure pain thresholds were measured in
an area 2–3 cm from the incision at three levels (top,
middle, and bottom) and on the inner forearm. A mean
value for the three periincisional regions was calculated
and used for statistical comparisons.
The extent of mechanical static (punctuate) hyperal-
gesia to von Frey hair stimulation proximal to the surgi-
cal wound was assessed with von Frey hair No. 16
(pressure 122 g/mm
2
) according to the methods de
-
scribed by Ilkjaer et al.
22
Hyperalgesia was determined
by stimulating along three linear paths at right angles to
the top, middle, and bottom sides of the surgical incision
in steps of 5 mm at 1-s intervals, starting well outside the
hyperalgesic area. During the first test, the regions were
marked. Stimulations continued toward the incision un-
til patients reported a clear change in sensation (e.g.,
burning, tenderness, or more intense pricking). The dis-
tance (in cm) from the incision to where sensations
changed was measured, and a sum of the three assess-
ments (top, middle, and button) was calculated and used
for statistical comparisons.
Dynamic allodynia was investigated using a soft brush
2–3 cm from the incision. Allodynia was considered to
149KETAMINE PREVENTS REMIFENTANIL-INDUCED HYPERALGESIA
Anesthesiology, V 103, No 1, Jul 2005
Page 3
be present if stroking the skin evoked a clear sensation
of pain. We repeated this test three times at 24 and 48 h
after surgery. Peak flow (l/min) was determined the
evening before surgery. Postoperative pain scores on a
VAS scale during peak flow measurement were also
assessed.
Anesthetic-related complications were recorded, in-
cluding nausea, vomiting, pruritus, dysphoria, hallucina-
tions, and diplopia. Nausea and vomiting were treated by
intravenous bolus of 0.5 mg droperidol. Sedation was
monitored using the following four-point rating scale:
0 patient fully awake, 1 patient somnolent and
responsive to verbal commands, 2 patient somnolent
and responsive to tactile stimulation, 3 patient asleep
and responsive to painful stimulation. Postoperative re-
spiratory depression was defined by the combination of
a sedation score greater than 1 and a respiratory rate less
than 10 breaths/min.
We assessed short-term memory and working memory
using the Digit Span Backward Test (DSBT).
23
For this
test, subjects were asked to repeat a string of digits in the
original order (digit span forward, maximal score 7)
and in the reverse order (digit span backward, maximal
score 7). To measure cognitive and perceptual speed,
patients were asked to take a Digit Symbol Substitution
Test (DSST).
23
DSBT, DSST, and anxiety VAS were per
-
formed preoperatively the evening before surgery, and
postoperatively at 24 and 48 h.
Patients were asked to complete a written question-
naire on the first and second postoperative days to eval-
uate psychopharmacologic effects that have been re-
ported after ketamine; these included altered color
perception, reduced visual acuity, changes in hearing,
hallucinations, altered body image, feelings of unreality,
anxiety, aggression, altered physical strength, dizziness,
discomfort, illness, and nausea.
24
Quantitative sensory tests were performed in each
center by the same experienced investigator (V. J. or
P. R.) preoperatively the evening before surgery and
postoperatively at 24 and 48 h. The study ended after
48 h.
Statistical Analysis
The extent of hyperalgesia to von Frey hair stimulation
proximal to the surgical wound was considered our
primary endpoint. The secondary endpoints were other
results of quantitative sensory tests, VAS pain scores, and
morphine consumption. Our sample-size estimate was
based on the expected differences in the extent of hy-
peralgesia to von Frey hair stimulation proximal to the
surgical wound at 48 h between the large- and small-dose
remifentanil groups. In a preliminary study of 20 pa-
tients, we observed that the extent of hyperalgesia for
punctuate mechanical stimuli around a xiphopubic inci-
sion was 7 cm with a SD of 4 cm. A sample size estimate
indicated that 21 patients/group would give a power of
80% at an
level of 0.05 for detecting a difference in
50% in the extent of hyperalgesia to von Frey hair stim-
ulation proximal to the surgical wound. The study size
was thus prospectively set to 75 patients (25 patients/
group).
Age, weight, height, duration of procedures, tempera-
ture at end of the study, and cumulative postoperative
morphine consumption at 48 h were compared with an
unpaired Student t test. The relative frequencies of sex,
American Society of Anesthesiologists physical status,
ephedrine use, psychopharmacologic effects, nausea,
and vomiting were compared with the Fisher exact test.
Hemodynamic variables, Bispectral Index, pain thresh-
olds, peak flow, and VAS scores for 48 h were analyzed
with two-way analysis of variance for repeated measures.
DSBT and DSST scores were analyzed with the nonpara-
metric Kruskal-Wallis test. Statistical analysis was per-
formed with Statview for Windows (version 5.0; SAS
Institute Inc, Cary, NC). Results are presented as mean
SD or median (interquartile range); P 0.05 was con-
sidered statistically significant.
Results
Seventy-five patients were enrolled in the study. One
patient was excluded from the large-dose remifentanil–
ketamine group because of respiratory depression that
occurred postoperatively in the PACU and was treated
with a 0.4-mg injection of naloxone. This patient arrived
in the PACU with a VAS pain score of 100 mm. He
received a morphine dose of 21 mg by intravenous
titration, which corresponded to a total dose of 33 mg,
including the intraoperative bolus of 0.15 mg/kg. Respi-
ratory depression occurred 1 h after the last morphine
injection. It was attributed to excessive perioperative
morphine administration.
Morphometric and demographic characteristics, dura-
tion of surgery and anesthesia, and types of surgical
procedures were comparable in the three treatment
groups (table 1). Desflurane requirement was signifi-
cantly greater in the small-dose remifentanil group than
in the other two groups (P 0.05; table 2). The times
from the remifentanil discontinuation until awakening
and tracheal extubation were comparable in the three
groups (table 2).
Bispectral Index values were comparable in the large-
and small-dose remifentanil groups but greater in the
large-dose remifentanil–ketamine group (P 0.05; table
3). Intraoperatively, systolic and diastolic pressures were
similar in the three groups; however, heart rate was
generally higher (P 0.05; table 3) in the small-dose
remifentanil group. More ephedrine was required in the
large-dose remifentanil– ketamine group than in the two
other groups to maintain hemodynamic stability (P
0.05; table 2).
150 JOLY ET AL.
Anesthesiology, V 103, No 1, Jul 2005
Page 4
Tactile pain thresholds adjacent to the incision were
significantly less at 24 and 48 postoperative hours in the
large-dose remifentanil group than in the other groups
(P 0.01; fig. 1). However, there were no significant
differences among the groups for pressure pain thresh-
old determined with the algometer at 2–3 cm from the
incision (table 4). Moreover, no clear sensation of pain
could be evoked in any patient by stroking the skin with
a brush adjacent to the incision.
Extent of hyperalgesia to von Frey hair stimulation
proximal to the surgical incision was easily detected in
all patients and was significantly larger at 24 and 48 h in
the large-dose remifentanil group than in the other two
groups (P 0.03; fig. 2).
Tactile and pressure pain thresholds measured on the
forearm did not differ preoperatively versus postopera-
tively in any group (data not shown).
Visual analog scale (fig. 3) and verbal rating scale (data
not shown) pain scores at rest and after peak flow (table
3) did not differ among the three groups. Peak flow
values were also comparable (table 4).
Although the mean time to first morphine administra-
tion and the cumulative amount of intravenous mor-
phine given by nurses in the PACU did not differ among
the three groups (table 2), postoperative morphine con-
sumption, including morphine titrated in the PACU, was
significantly greater throughout the 48-h postoperative
period in the large-dose remifentanil group than in the
other groups (P 0.05; table 2).
The incidences of nausea and vomiting and of droperi-
dol consumption (table 2), the distribution of sedation
and anxiety scores (data not shown), and the responses
to the written questionnaire evaluating postoperative
ketamine psychopharmacologic effects were similar in
all groups. However, one patient in the large-dose
remifentanil–ketamine group reported hallucinations at
24 and 48 h after surgery and altered body image at 24 h,
and another patient in the same group reported altered
color perception, dizziness, and reduced visual activity
at 24 h. Eight patients in the small-dose remifentanil
group, five in the large-dose remifentanil group, and six
in the large-dose remifentanil–ketamine group declined
to take the DSST postoperatively. All patients performed
the DSBT at 24 and 48 h, however. No intergroup dif-
ferences were found in the results of the DSBT or DSST.
The DSBT score (mean scores between 12 and 17) was
Table 2. Anesthetic Characteristics, Postoperative Morphine
Use, and Nausea and Vomiting
Small-dose
Remifentanil
(n 25)
Large-dose
Remifentanil
(n 25)
Large-dose
Remifentanil–
Ketamine
(n 24)
Remifentanil dose,
mg
0.9 0.3* 6.7 3.1 6.5 3.4
Desflurane, MAC/h 0.8 0.2* 0.5 0.2 0.6 0.2
Ephedrine, No. of
doses/No. of
patients
9/17 10/13 50/15†
Final intraoperative
temperature, °C
36.6 0.7 36.3 0.8 36.3 0.9
Awakening time,
min
14 613 514 6
Extubation time,
min
16 614 615 4
Time to first
postoperative
morphine, min
35 (28–46) 24 (20–33) 41 (32–52)
Morphine given in
PACU, mg
16 (10–24) 20 (17–27) 20 (14–23)
0–48 h cumulative
postoperative
morphine
consumption,
mg
68 (50–91) 86 (59–109)‡ 62 (48–87)
Postoperative
nausea and
vomiting, No. of
patients
78 8
Droperidol, No. of
doses/No. of
patients
8/7 8/8 8/8
Times (awakening, extubation, first morphine administration) were defined
from remifentanil discontinuation. The cumulative postoperative morphine
consumption excluded the dose of 0.15 mg/kg given 30 min before the end
of surgery. Values are presented as mean SD, median (interquartile range),
or number of patients.
* P 0.05 vs. large-dose remifentanil and large-dose remifentanil–ketamine
groups. P 0.05 vs. small-dose remifentanil and large-dose remifentanil
groups. P 0.05 vs. small-dose remifentanil and large-dose remifentanil–
ketamine groups.
MAC minimum alveolar concentration; PACU postanesthesia care unit.
Table 1. Morphometric and Demographic Data, Surgical
Procedures, and Duration of Surgery and Anesthesia
Small-dose
Remifentanil
(n 25)
Large-dose
Remifentanil
(n 25)
Large-dose
Remifentanil–
Ketamine
(n 24)
Age, yr 58 13 56 12 59 13
Weight, kg 67 13 69 12 67 13
Height, cm 164 10 168 9 167 7
Sex, M/F 10/15 9/16 9/16
ASA status, I/II/III 10/12/3 12/10/3 9/12/4
Procedure, No. of
patients
Right
colectomy
53 5
Colectomy with
colorectal
anastomosis
11 15 12
Colectomy with
coloanal
anastomosis
76 7
Total
colectomy
21 0
Duration of
anesthesia, h
4.4 (3.3–5.7) 4.3 (3.1–4.6) 4.4 (3.3–5.0)
Duration of
surgery, h
3.5 (2.6–4.5) 3.5 (2.5–3.8) 3.5 (2.6–4.2)
Values are presented as mean SD, median (interquartile range), or number
of patients. There were no statistically significant differences among the
groups.
151KETAMINE PREVENTS REMIFENTANIL-INDUCED HYPERALGESIA
Anesthesiology, V 103, No 1, Jul 2005
Page 5
not impaired postoperatively in any group; however, the
mean DSST scores, which were between 41 and 47
preoperatively, were significantly decreased by 22–34%
at 24 h after surgery and returned to baseline at 48 h in
all three groups.
Discussion
We confirmed our hypothesis that a relatively large
dose of intraoperative remifentanil increases pain sensi-
tivity as evidenced by a reduction of the postoperative
tactile pain threshold proximal to the surgical wound
and an extension of periincisional hyperalgesia in our
large-dose remifentanil group. This phenomenon lasted
throughout both postoperative days and was associated
with an increase in morphine administered by PCA. We
also found that giving a small dose of ketamine during
and after surgery completely prevented the increase in
postoperative pain sensitivity and punctuate hyperalge-
sia that otherwise resulted from large-dose remifentanil
administration. Moreover, patients who received a large
dose of remifentanil with ketamine had significantly less
postoperative morphine requirements than those receiv-
ing the large dose of remifentanil only; in fact, the dose
was comparable to that of the small-dose remifentanil
patients.
The differences in postoperative morphine require-
ments between the small- and large-dose remifentanil
groups were less marked than we observed in a previous
study.
12
The reasons are likely related to differences in
the design of these two studies. In the current study, we
gave remifentanil a constant rate throughout the intraoper-
ative period, whereas in the previous study, remifentanil
was titrated to patient responses. Consequently, in the
previous study,
12
the remifentanil infusion rate frequently
exceeded our current limit of 0.4
g kg
1
min
1
. This
difference in the rate of infusion may account for the
differences observed in postoperative morphine require-
ments in the large-dose remifentanil groups in the two
Table 3. Intraoperative Heart Rate, Mean Arterial Blood Pressure, and Bispectral Index of the Electroencephalogram
Small-dose Remifentanil (n 25) Large-dose Remifentanil (n 25)
Large-dose Remifentanil–Ketamine
(n 24)
HR, beats/
min
MAP,
mmHg BIS
HR,
beats/min
MAP,
mmHg BIS
HR,
beats/min
MAP,
mmHg BIS
Before induction 75 13 72 14 96 473 14 76 14 97 281 18 76 13 95 5
After induction 74 13 65 15 59 21† 70 12 70 17 57 22 78 14 70 10 48 18
OTI 80 16 83 21 65 15 74 21 75 20 67 12 78 16 76 20 67 16
Incision 69 15*† 67 19 53 14 59 14 53 12 50 10‡ 59 750 960 12
Piece 74 13† 58 13 43 10† 67 957 12 50 12‡ 68 14 50 12 57 10
Skin closure 86 18* 63 17 56 15† 67 18 67 18 64 14 84 20 69 16 67 14
Extubation 84 11 78 12 92 389 11 86 13 96 3‡ 86 16 90 12 89 9
Values are presented as mean SD.
* P 0.05 vs. large-dose remifentanil group. P 0.05 vs. large-dose remifentanil–ketamine group. P 0.05 vs. large-dose remifentanil–ketamine group.
BIS Bispectral Index of the electroencephalogram; HR heart rate; MAP mean arterial blood pressure; OTI orotracheal intubation.
Fig. 1. Tactile pain thresholds (g/mm
2
) determined with von
Frey hair 2–3 cm proximal and perpendicular to the top, mid-
dle, and bottom of the surgical incision. Solid bars small-dose
remifentanil group; gray bars large-dose remifentanil group;
open bars large-dose remifentanil– ketamine group. Results
are expressed as mean SD. * Statistical difference from small-
dose remifentanil and large-dose remifentanil– ketamine
groups (P < 0.01).
Table 4. Peak Flow, VAS Pain Scores during Peak Flow, and
Pressure Pain Threshold with Algometer Preoperatively and
Postoperatively
Small-dose
Remifentanil
(n 25)
Large-dose
Remifentanil
(n 25)
Large-dose
Remifentanil–
Ketamine
(n 24)
Preoperative
Peak flow, l/min 380 (280–450) 360 (300–450) 320 (275–400)
Algometer, kPa 180 73 177 90 187 79
24 h postoperative
Peak flow, l/min 100 (15–120) 100 (70–150) 100 (55–150)
VAS, mm 42 26 44 21 36 20
Algometer, kPa 66 36 74 50 60 38
48 h postoperative
Peak flow, l/min 100 (95–155) 120 (80–150) 95 (60–150)
VAS, mm 43 20 37 23 33 18
Algometer, kPa 64 41 72 45 67 45
Values presented as median (interquartile range) or means SDs. No signif-
icant difference was found among the groups.
VAS visual analog scale.
152 JOLY ET AL.
Anesthesiology, V 103, No 1, Jul 2005
Page 6
studies because acute opiate tolerance seems to be dose
dependent.
1,9,11,25
Previous studies clearly demonstrated that there is an
area of mechanical hyperalgesia around a surgical inci-
sion.
22,26–28
However, the current study is the first to
evaluate to what extent intraoperative opioid use con-
tributes to this hyperalgesia. Koppert et al.
9
reported
that, in volunteers, the area of hyperalgesia surrounding
a transcutaneous electrical stimulation at a high current
density increased after discontinuation of remifentanil
when administered at a rate of 0.10
g kg
1
min
1
but
not at a rate of 0.05
g kg
1
min
1
. It would also be
reasonable to assume that periincisional hyperalgesia ob-
served in the small-dose remifentanil group was mainly
induced by surgery, whereas 0.40
g kg
1
min
1
remifentanil used in the large-dose remifentanil group
triggered approximately half of the observed mechanical
hyperalgesia.
As in animal experiments,
25
it is possible to imagine
that postoperative morphine potency was reduced in
the large-dose remifentanil patients in whom allodynia
proximal to the wound was most profound and ex-
tended, which accounts to greatest total postoperative
PCA morphine consumption in these patients—possibly
resulting from an acute tolerance to the analgesic effects
of morphine.
In contrast to static mechanical allodynia triggered
with von Frey filaments, we were unable to detect dy-
namic mechanical allodynia triggered by brushing as in
experimental models of secondary mechanical hyperal-
gesia.
9
One reason may be that these two types of allo
-
dynia have dissimilar origins. Punctuate allodynia is elic-
ited by input from high-threshold A-
fibers,
29
whereas
mechanical dynamic allodynia is elicited from low-
threshold A-
fibers.
30
Despite the differences between the large-dose
remifentanil group and the other groups in tactile pain
threshold proximal to the surgical wound and in extent
of hyperalgesia tested by von Frey hair filament, pressure
pain thresholds tested by algometer and VAS pain scores
at rest and during peak flow were comparable in the
three groups. These results are difficult to explain; how-
ever, they support those of other studies using the same
measurements.
26,28,31
One explanation would be that
the potential increase in pain scores was counteracted
by increased PCA morphine use. Moreover, the lack of
differences in postoperative peak flow values between
the groups in the current study may be due to the
dependence of this measurement on pain after abdomi-
nal surgery.
32
Although the clinical implication of the area of periin-
cisional hyperalgesia remains poorly understood, hyper-
algesia proximal to the wound was found to be present
3 months after surgery in patients recovering from ab-
dominal hysterectomy,
22
and long-term incisional pain at
1 month, 6 months, and 1 yr after open colorectal sur-
gery was more frequent in patients who experienced the
most extended hyperalgesia surrounding the surgical
wound during the initial 72 postoperative hours.
28
Therefore, our results suggest that relatively large doses
of intraoperative remifentanil without concomitant
small-dose ketamine might be deleterious in patients at
risk for chronic postoperative pain such as those under-
going thoracotomy and amputation.
33
Further studies
are necessary though to confirm whether the extension
of periincisional hyperalgesia may be considered a prog-
nostic factor of chronic postsurgical pain.
Many mechanisms may explain remifentanil-induced
hyperalgesia observed in the current study;
15
these in
-
clude extensive internalization and thereby inactivation
of
-opioid receptors by remifentanil,
34
opioid-induced
up-regulation of the cyclic adenosine monophosphate
pathway,
35
spinal dynorphin release,
3,36
and activation
of central NMDA nociceptive systems.
15,25
That the
Fig. 2. Extent of hyperalgesia to von Frey hair number 16 (pres-
sure 122 g/mm
2
) stimulation proximal to the surgical wound
(distance from wound in cm). Solid bars small-dose remifen-
tanil group; gray bars large-dose remifentanil group; open
bars large-dose remifentanil– ketamine group. Results are
expressed as mean SD. * Statistical difference (P < 0.03) from
small-dose remifentanil and large-dose remifentanil– ketamine
groups.
Fig. 3. Visual analog pain scores (VAS) at rest during 48 postop-
erative hours. Closed triangle small-dose remifentanil group;
open triangle large-dose remifentanil group; open circle
large-dose remifentanil– ketamine group. Results are expressed
as mean SD. There were no statistically significant differences
among the three groups.
153KETAMINE PREVENTS REMIFENTANIL-INDUCED HYPERALGESIA
Anesthesiology, V 103, No 1, Jul 2005
Page 7
NMDA receptor antagonist ketamine was able to prevent
the increase in postoperative hyperalgesia triggered by a
large dose of remifentanil is consistent with the hypoth-
esis that pronociceptive processes involving NMDA re-
ceptor activation account for opioid-induced hyperalge-
sia and acute opioid tolerance. In accord with this
hypothesis, it was recently reported that remifentanil
stimulates different NMDA receptor subunit combina-
tions (NR1A/2A, NR1A/2B).
37
The ability of ketamine to
reduce both hyperalgesia and postoperative morphine
consumption supports the possibility that the effect of
ketamine on opioid-induced hyperalgesia results in the
reduction of opioid consumption.
2,25,33
Few side effects were noted in the large-dose remifen-
tanil–ketamine group. The case of severe respiratory
depression requiring naloxone was likely caused by the
large dose of morphine that was administered periopera-
tively (33 mg), as we have previously observed.
38
Effec
-
tively, according to studies evaluating respiratory inter-
actions between opioids and ketamine,
39,40
it seems
unlikely that this case of respiratory depression was
related to ketamine. Two patients in the large-dose
remifentanil–ketamine group had ketamine-induced
central nervous system side effects at the specific writ-
ten questionnaire, albeit without significant differences
in patient responses among the three groups. However,
we did not detect any effect of small dose ketamine
on DSBT or DSST. The results of the current study seem
consistent with a quantitative systematic reviews
in which small-dose ketamine ( 2.5
g kg
1
min
1
)
given postoperatively did not specifically increase
the incidence of hallucinations or impair cognitive
functioning.
33,41–43
Because the patients in the small-dose remifentanil
group received larger doses of desflurane, an alternative
explanation for our findings would be that the larger
doses of desflurane prevented surgery-induced hyperal-
gesia, compared with the smaller doses received by the
patients in the large-dose remifentanil group. Indeed,
halogenated anesthetics have been shown to decrease
hyperexcitability of spinal dorsal horn neurons after tis-
sue injury.
44
Volatile anesthetics, including desflurane,
seem to block NMDA receptors.
45
However, volatile
anesthetics do not prevent subsequent hyperexcitability
of spinal dorsal horn neurons even though they suppress
evoked responses to incision.
44
Furthermore, response
of NMDA receptors expressed in oocytes to glutamate
are suppressed only 20% at 0.5 MAC and 40% at 1.0 MAC
desflurane. This suggests that the small 0.3% difference
in desflurane concentration does not account for the
exaggerated hyperalgesia in the large-dose remifentanil
group.
In summary, intraoperative administration of a rela-
tively large dose of remifentanil increased postoperative
pain sensitivity, specifically periincisional hyperalgesia.
A small dose of ketamine prevented hyperalgesia, impli-
cating NMDA receptors in remifentanil-induced hyperal-
gesia and confirmed the benefits of administering small-
dose ketamine when relatively large intraoperative
remifentanil doses are required.
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