Full text of DOI:10.1007/BF03018943

522
REPORTS OF INVESTIGATION
Postoperative pain man-
agement in patients
undergoing major
surgery after remifentanil
vs fentanyl anesthesia
Harold S. Minkowitz MD
and the Multicentre Investigator Group
Purpose: To determine if morphine sulphate was an effective transition analgesic in patients receiving a remifen-
tanil-based anesthetic regimen.
Methods: Open-label remifentanil or fentanyl was administered to 210 randomized patients undergoing inpa-
tient surgery. Isoflurane and nitrous oxide was administered to all patients. Thirty minutes before the end of
surgery, patients receiving remifentanil were randomized to receive morphine 0.15 mg·kg–1 (R/M15 group) or
0.20 mg·kg–1 (R/M20 group). Following extubation and prior to patient-controlled analgesia (PCA) initiation, 2 mg
boluses of morphine were administered for moderate/severe pain. Efficacy endpoints were total morphine used
in the post anesthesia care unit (PACU) and 24 and 48 hr postoperatively; postoperative pain; time to first mor-
phine bolus; time to first PCA administration; and time to recovery endpoints.
Results: Mean total morphine used in PACU was not different among groups (15.5 mg, 16.5 mg and 13.3 mg
in R/M15, R/M20 and F groups, respectively). Mean total 24 hr morphine use (58.1 mg, 56.93 mg and 53.6 mg
in R/M15, R/M20 and F groups) and mean total morphine used at 48 hr were not different (69.8 mg, 64.7 mg
and 62.1 mg in R/M15, R/M20 and F/I groups). Groups were similar with respect to pain severity ratings at all
postoperative times. Patients in the fentanyl arm experienced faster times to some recovery endpoints than
patients receiving either remifentanil regimen.
Conclusion: Morphine sulphate regimens of 0.15 or 0.20 mg·kg–1 administered 30 min before the end of
surgery are equally effective transition regimens for inpatient procedures.
Objectif : Déterminer si le sulfate de morphine constitue un analgésique de transition efficace chez les patients
qui reçoivent une anesthésie à base de rémifentanil.
Méthode : Des doses connues de rémifentanil ou de fentanyl ont été administrées à 210 patients de chirurgie
ambulatoire répartis au hasard. Tous ont reçu de l’isoflurane et du protoxyde d’azote. Trente minutes avant la fin
de l’opération, les patients qui recevaient du rémifentanil ont eu, de façon aléatoire, 0,15 mg·kg–1 (groupe R/M15)
ou 0,20 mg·kg–1 (groupe R/M20) de morphine. Après l’extubation, et avant l’analgésie contrôlée par le patient
(ACP), on a administré de la morphine en bolus de 2 mg pour contrer les douleurs de modérées à sévères. Les
paramètres d’efficacité étaient la quantité totale de morphine utilisée à la salle de réveil et 24 et 48 h après l’opéra-
tion, la douleur postopératoire, le temps écoulé avant l’administration du premier bolus de morphine, le temps
écoulé avant la première dose d’ACP et le temps nécessaire pour satisfaire aux paramètres de la récupération.
Résultats : La consommation moyenne totale de morphine à la salle de réveil n’a pas présenté de différence
intergroupe (15,5 mg, 16,5 mg et 13,3 mg pour les groupes R/M15, R/M20 et F, respectivement). La consom-
mation moyenne totale de morphine à 24 h (58,1 mg, 56,93 mg et 53,6 mg pour les groupes R/M15, R/M20 et
F) et à 48 h n’était pas différente entre les groupes (69,8 mg, 64,7 mg et 62,1 mg pour les groupes R/M15, R/M20
et F/I). Toutes les mesures postopératoires de la douleur ont montré des estimations similaires de sévérité. Les
patients du groupe fentanyl ont connu une récupération plus rapide, pour certains paramètres, que les patients
qui ont reçu l’un ou l’autre régime de rémifentanil.
Conclusion : Les doses de 0,15 ou de 0,20 mg·kg–1 de sulfate de morphine, administrées 30 min avant la fin de
l’opération, constituent des régimes de transition d’efficacité égale pour des patients de chirurgie ambulatoire.
Supported, in part, by Glaxo Wellcome Inc.
Presented at the International Anesthesia Research Society, 1998
Address correspondence to: Harold Minkowitz MD, Memorial Hospital; Memorial City, Department of Anesthesiology, 920 Frostwood,
Houston, TX 77024 USA. Phone: 713-932-3438; Fax: 713-932-3664; E-mail: mink@houston.rr.com
Accepted for publication on 14 February, 2000.
CAN J ANESTH 2000 / 47: 6 / pp 522–528

Minkowitz et al.: POSTOPERATIVE ANALGESIA AFTER REMIFENTANIL
523
Multicentre Investigator Group:
ments during the post-anesthesia care unit (PACU)
period through patient-controlled analgesia (PCA)
discontinuation.
Harold S. Minkowitz MD,* Joel M. Yarmush MD,
H George W. Rung MD, I Tim I. Melson MD,'
Jonathan H. Weiss DO, & Lawrence G. Kushins MD,2
Joel O. Johnson MD PhD,** Louis E. Claybon MD,
HH Steven A. Fiamengo MD, II Stephanie B. Jones MD,''
James D. Kindscher MD, & Michael W. Colopy PhD,22
Alison L. Wentz PHARMD,22
From the UT Medical School - Houston,*
Houston, TX; UMDNJ Medical School,H Newark,
NJ; Penn State Geisinger Health System,I Hershey, PA;
Helen Keller Hospital,' Sheffield, AL; Cooper
Hospital,& Camden, NJ; Robert Wood Johnson
University Hospital,2 New Brunswick, NJ; University
of Utah,** Salt Lake City, UT; Mercy Hospital
Anderson,HH Cincinnati, OH; Oregon Health
Sciences University,II Portland, OR; Washington
University School of Medicine,'' St. Louis, MO;
University of Kansas Medical Center,&& Kansas City,
KS; Glaxo Wellcome Inc.,22 Research Triangle Park,
NC, USA.
Materials and methods
This multicentre (12 sites) study consisted of an open-
label, randomized, parallel-group anesthesia phase;
followed by a double-blind, randomized, parallel-
group, active-control analgesia phase. Eligible patients
were at least 18 yr old with American Society of
Anesthesiologists I-III physical status. In addition,
patients were eligible if they were scheduled for inpa-
tient surgery under general anesthesia of at least one
hour duration which required treatment with par-
enteral analgesics for postoperative pain and at least a
24 hr hospitalization. Written informed consent was
obtained from eligible patients during the screening
period at which time physical examination and med-
ical history were evaluated.
Anesthetic protocol
ANESTHESIA PHASE. Study evaluation began upon the
patient’s arrival in the preoperative area. At this time,
standard ASA monitors, including lead II ECG, finger
pulse oximeter, and non-invasive BP cuff were placed.
After baseline measurements were obtained, patients
were premedicated with 0.025 mg·kg– 1midazolam iv.
A second dose of 0.025 mg·kg–1 midazolam was
administered if further sedation was required.
Intraoperative heart rate (HR), oxyhemoglobin sat-
uration (SPO2), end-tidal carbon dioxide partial pres-
sure (PETCO2), and systolic and diastolic blood pressure
(SBP and DBP) were measured by an automated mea-
suring device were continuously monitored. During
induction anesthesia, patients’ lungs were ventilated
with oxygen 100% for three minutes. Patients random-
ly received either open label remifentanil or fentanyl
(2:1 randomization). Patients in the remifentanil arm
received 2 mg·kg– 1 thiopental iv bolus followed by 1
µg·kg–1·min– 1remifentanil infusion, whereas patients in
the fentanyl arm received 4 µg·kg– 1 fentanyl iv bolus
followed by 2 mg·kg–1 thiopental iv bolus. Patients in
both arms were treated with additional thiopental doses
as needed until loss of consciousness (LOC).
OTENT opioids possessing shorter durations
of action have recently been added to the
therapeutic armamentarium available to the
P
anesthesiologist. Remifentanil hydrochloride
is the latest short-acting synthetic opioid to be intro-
duced. Remifentanil is a selective µ-opioid receptor
agonist having a methyl-ester linkage that makes it sus-
ceptible to metabolism by esterases in blood and other
tissues.1–3 The pharmacokinetic and pharmacodynamic
profile of remifentanil suggests that this agent is highly
titratable with a predictable offset of action.3 Indeed,
the rapid metabolism of remifentanil results in an ultra-
short effective biological half-life of 10 min or less.2
The short-acting nature of remifentanil, which pro-
vides rapid recovery from anesthesia, also results in the
potentially rapid appearance of postoperative pain.
Thus, a transition analgesic regimen is needed before
discontinuation of a remifentanil infusion. In an effort
to define a better transition analgesic regimen, this
study compared the analgesic efficacy and safety of
two loading doses of morphine sulphate administered
30 min prior to the end of surgery in patients receiv-
ing remifentanil. Since fentanyl is a widely used opioid
in balanced anesthesia with inhalational agents, this
study also compared the anesthesia recovery profiles
and morphine requirements of patients receiving
remifentanil vs traditional fentanyl anesthesia with
isoflurane and nitrous oxide. This is the first study to
use fentanyl as a direct comparator with remifentanil
and the first to evaluate transition analgesic require-
After LOC, all patients received 0.15 mg·kg– 1
cisatracurium to facilitate tracheal intubation.
Following intubation, the remifentanil infusion rate was
decreased to 0.5 µg·kg–1·min–1. In both arms, isoflurane
was started to achieve an end-tidal concentration of
0.25%, and nitrous oxide 67%/oxygen 33% was initiat-
ed. Sustained responses to intubation were treated with
a 1 µg·kg–1 remifentanil bolus administered over 30 sec
in the remifentanil arm and a 1 µg·kg– 1 fentanyl bolus

524
CANADIAN JOURNAL OF ANESTHESIA
in the fentanyl arm also administered over 30 sec. If the
anticipated time between intubation and skin incision
was >15 min and stimulation was not present, the
remifentanil infusion rate could be decreased to 0.25
µg·kg–1·min–1. The rate was increased to 0.5
µg·kg–1·min– 1at the time of skin incision.
severe pain before PCA initiation, 2 mg morphine iv,
was administered and repeated as needed. Subsequent
pain was managed with PCA morphine.
Efficacy assessment
ANALGESIA. The primary efficacy endpoint was the
mean total amount of morphine sulphate used in the
24 hr postoperative period. The mean total amount of
morphine included PCA morphine and any additional
morphine used after extubation and before PCA mor-
phine initiation. Measures of secondary efficacy
included the mean total amount of morphine used in
the PACU and the mean total morphine used in the
48 hr postoperative period.
RECOVERY. The level of postoperative pain was
assessed by patient questioning utilizing a four-point
scale (0 = none; 1 = mild; 2 = moderate; 3 = severe).
Pain was assessed upon PACU arrival, then every 15
min during the initial two hours following PACU
entry, then every 30 min for the next two hours, then
every four hours until 24 hr after PACU entry, then
every four hours until discontinuation of PCA mor-
phine or 48 hr after PACU entry (whichever occurred
first). Additional endpoints were time to first postop-
erative morphine bolus (if given) and time to first
administration of PCA morphine. Postoperative
Aldrete scores,4 were assessed at 5, 10, 15, 30, 45, and
60 min after PACU entry, then every 30 min until
PACU discharge.
During maintenance, patients in the remifentanil
arm continued to receive 0.5 µg·kg–1·min–1 remifen-
tanil, while patients in the fentanyl arm received a 1
µg·kg–1 maintenance bolus of fentanyl every hour.
Signs of light anesthesia (i.e., hypertension, somatic or
autonomic responses) in the remifentanil arm were
treated with infusion rate increases (0.125-0.25
µg·kg–1·min–1 increments) and/or 30 sec infusions of
1 µg·kg–1 remifentanil at two-five minute intervals. If
signs of light anesthesia remained after two boluses or
infusion rate increases, the end-tidal concentration of
isoflurane was increased (0.2% increments) up to
1.2%. After the response was controlled for five min-
utes, the end-tidal isoflurane concentration was
decreased to 0.25%. Signs of light anesthesia in
patients in the fentanyl arm were treated with increas-
es in end-tidal isoflurane (0.2%) increments up to
1.2%. After the response was controlled for five min-
utes, the end-tidal isoflurane was decreased to 0.5%.
If signs persisted, patients in the fentanyl arm also
received 1 µg·kg–1 fentanyl bolus, unless signs of light
anesthesia were present within 20 min before the
anticipated end of surgery.
In both arms, hypotension was initially treated with
iv fluid administration and decreasing isoflurane (0.2%
decrements). The remifentanil infusion rate could also
be reduced in the remifentanil arm. If hemodynamic
instability persisted in either arm, additional pharma-
cologic agents could be administered at the investiga-
tor’s discretion.
ANALGESIA PHASE. Thirty minutes before the end of
surgery, patients in the remifentanil arm randomly
received either a double-blind bolus of 0.15 mg·kg– 1
morphine or 0.20 mg·kg– 1 morphine (1:1 randomiza-
tion). Twenty minutes before the end of surgery, end-
tidal isoflurane concentration was reduced to 0.25%
and fentanyl boluses were discontinued. Ten minutes
before the end of surgery isoflurane administration
was discontinued, and glycopyrrolate and neostigmine
were administered if neuromuscular blockade reversal
was required. At the end of surgery, the remifentanil
infusion and nitrous oxide were discontinued.
The times from the end of surgery to the following
recovery parameters were evaluated for each patient:
adequate respiration, tracheal extubation, operating
room discharge, and response to verbal command.
The times to qualification for PACU discharge (first
two consecutive Aldrete score 9 and pain and nau-
sea/emesis controlled), actual PACU discharge, and
hospital discharge were also recorded. In addition, an
Anesthesiologist’s Satisfaction Assessment form,
which assessed the predictability of patient response
and overall quality of the study drug, was completed.
INTRAOPERATIVE RESPONSES. An assessment of
intraoperative responses during the maintenance
phase, including responses to light anesthesia,
hypotensive and bradycardic responses, and responses
to intraoperative stimuli (i.e., intubation, skin incision,
skin closure and extubation) was conducted.
Intraoperative responses were defined as one or more
of the following occurring within five minutes of an
event: hypertension (SBP >15 mmHg above preoper-
ative baseline one minute), tachycardia (HR >90 bpm
for one minute), somatic (movement, swallowing,
grimacing, eye opening), or autonomic (tearing,
sweating, mydriasis) response.
All patients received PCA morphine for postopera-
tive analgesia. Prior to morphine PCA initiation, all
patients were asked to assess their pain level according
to a four-point rating scale (0 = none; 1 = mild; 2 =
moderate; 3 = severe). If the patient had moderate or

Minkowitz et al.: POSTOPERATIVE ANALGESIA AFTER REMIFENTANIL
525
Safety assessment
included only doses for patients who had completed a
given time period.
Safety was assessed by monitoring adverse events, vital
signs (SBP and DBP, HR, RR), electrocardiography,
respiratory parameters (SPO2 and PETCO2), and
response to surgical stimuli. All observed adverse
events were categorized by treatment group and with-
in treatment groups by drug-related status.
Analysis of postoperative pain was based on calcu-
lating an average pain score for each patient, weighted
by the number of minutes that pain (0-4) was
endured. This average pain score, called an area under
the curve (AUC), was calculated for each patient for
time intervals of 2, 4, 12, 24, 36 and 48 hr. Patients
discharged before reaching a given time interval were
not included in the calculation for that mean AUC.
Mean AUCs were compared among groups using
analysis of variance, adjusting for investigator.
The time from the end of surgery to first morphine
bolus (2 mg) and the time from the end of surgery to
the first administration of PCA morphine were com-
pared using the Cox proportional hazards model;
stratified by investigator. The Cox proportional haz-
ards model, stratified by investigator, was also used to
assess treatment differences in the time to the first of
two consecutive 9Aldrete scores, and times to recov-
ery endpoints between two treatment groups. Finally,
a logistic regression model was used to assess treat-
ment differences in the proportion of patients with
responses to surgical stimuli between the two groups.
Statistical analysis
This study was 90% powered to detect a 10 mg differ-
ence in total amount of PCA morphine sulphate used
in the 24 hr postoperative period, between two treat-
ment groups at the 5% statistical significance level.
The total amount of morphine used 24 hr postopera-
tively was compared between groups using analysis of
variance (ANOVA), adjusting for investigator and age
(=65 yr and >65 yr). The total amount of morphine
used 48 hr postoperatively and in the PACU was com-
pared between groups using analysis of variance,
adjusting for investigator.
Morphine use was summarized in two ways. In the
analysis above, mean total amount included all doses,
regardless of when the patients were discharged.
Another summary statistic, mean cumulative amount,
Results
Patient demographics
TABLE I Patient demographic data
R/M15
Group
n=71
R/M20
Group
n=68
F/I
Group
n=71
All 210 patients who received study drug (164
women, 46 men) were included in the efficacy analy-
ses. Groups were similar with regard to demographics
and baseline parameters (Table I). The median dura-
tions of anesthesia were 132, 135 and 124 min in the
R/M15, R/M20 and F/I groups, respectively. The
majority of patients were ASA II (67%), female (78%)
and Caucasian (80%). Urogenital procedures account-
ed for the majority of the procedures performed.
Sex – n
Female / Male 53 / 18 56 / 12
55 / 16
45.2 14.0
75.2 18.3
Mean age – yr SD
47.6 12.3
43.9 13.4
74.5 18.0
Mean weight – kg SD 75.5 16.2
Median duration
of anesthesia
– min (range)
132
(43-412)
135
(53-351)
124
(56-300)
Efficacy evaluations
TABLE II Mean total morphine sulphate during first 24 hr, dur-
ing PACU, and during 48 hr postoperative period
ANALGESIA. Analysis of primary efficacy data showed
that the mean total amounts of morphine used in the
24 hr postoperative period were 58.1 mg, 56.9 mg and
53.6 mg in the R/M15, R/M20 and F/I groups,
respectively (Table II, Figure 1). Statistical comparisons
between treatment groups showed no differences with
respect to mean total amount of morphine (R/M15 vs
F/I, P=0.391; R/M20 vs F/I, P=0.427). Patients >65
yr required less morphine than patients 65 yr.
Efficacy Endpoint
Treatment Group
R/M20
R/M15
F/I
During PACU
Mean – mg S.E.
95% C.I.
15.52 1.19 16.48 1.46 13.30 0.98
13.19-17.86 13.61-19.35 11.38-15.22
24 hr Post-Op
Mean – mg SEM.
95% C.I.
58.07 3.67 56.93 4.45 53.58 2.95
50.88-65.26 48.19-65.67 47.80-59.37
Secondary efficacy analyses indicated that the differ-
ences among the remifentanil groups and the fentanyl
group in 48 hr mean total morphine requirements were
not statistically significant. Likewise, the mean total
amount of PACU morphine was similar between
remifentanil and fentanyl groups (Table II).
Mean (# 65 yr) – mg 60.97
Mean (>65 yr) – mg 31.57
48 hr Post-Op
59.61
43.54
53.83
50.90
Mean – mg S.E.
95% C.I.
69.76 5.25 64.70 5.09 62.12 4.20
59.46-80.05 54.72-74.69 53.88-70.37
Note: All statistical comparisons resulted in P > NS

526
CANADIAN JOURNAL OF ANESTHESIA
Longer median times were observed between both
the R/M15 and the R/M20 vs the F/I group for the
following recovery endpoints: adequate respiration,
extubation, response to verbal command, and actual
PACU discharge (Table III). There was a difference
between the R/M20 and F/I groups with respect to
median time to discharge from the operating room
and median time to qualification for PACU discharge.
However, the difference between the R/M15 and F/I
groups was not significant for these parameters.
The median time to the first of two consecutive 9
Aldrete scores was similar between remifentanil and
fentanyl groups (20, 20 and 17 min in the R/M15,
R/M20 and F/I groups, respectively). Additionally,
the time to hospital discharge was not different
between the R/M15 and F/I groups or the R/M20
and F/I groups.
FIGURE 1 Mean cumulative amount of morphine sulphate
(included patients that completed time period)
The results of the Anesthesiologist’s Satisfaction
Assessment indicated that anesthesiologists rated the
predictability of response as either very good or excel-
lent in 80%, 86% and 78% of the R/M15, R/M20 and
F/I patients, respectively. Overall study opioid perfor-
mance was rated as good, very good or excellent in
97%, 99% and 87% of the R/M15, R/M20 and F/I
patients, respectively.
INTRAOPERATIVE RESPONSES. There were differences
between both remifentanil groups and the fentanyl
group when responses to intubation, skin incision and
skin closure were analyzed. Patients receiving remifen-
tanil regimens experienced fewer responses to these
intraoperative stimuli (Table IV). Response to extuba-
tion was not different between treatment groups. A
review of intraoperative hemodynamic data indicated
that the most common responses to all intraoperative
stimuli were hypertension and tachycardia.
FIGURE 2 Weighted mean postoperative pain scores
Safety evaluations
RECOVERY. Comparisons between postoperative
AUC of pain scores of remifentanil groups and the
fentanyl group were not different at 2, 4, 12, 24, 36,
or 48 hr following PACU entry (Figure 2). Treatment
groups were similar with respect to pain severity rat-
ings at all postoperative time points.
There were 43, 40 and 38 patients in the R/M15,
R/M20 and F/I groups, respectively, who required at
least one morphine bolus prior to PCA initiation. The
median time from the end of surgery to the first mor-
phine bolus was similar in each group (20, 20 and 19
min in the R/M15, R/M20 and F/I groups, respective-
ly) (Table III). Likewise, the median time from the end
of surgery to first PCA morphine use was similar among
remifentanil and fentanyl groups (42, 49 vs 40 min in the
R/M15, R/M20 and F/I groups, respectively).
All 210 patients who received study drug were includ-
ed in the safety analyses. The overall incidence of
patients experiencing at least one adverse event was
87% in the R/M20 group and 85% in the R/M15 and
F/I groups. Of these adverse events, 48% in the
R/M15 group, 47% in the R/M20 group and 37% in
the F/I group were drug-related (Table V). Nausea
was the most prevalent adverse event with an occur-
rence rate of 65%, 60% and 62% in the R/M15,
R/M20 and F/I groups, respectively. The incidence
decreased to 31%, 26% and 27%, respectively, for nau-
sea considered to be drug-related. All reports of nau-
sea occurred during the postoperative period.
The overall incidence of emesis was 11%, 21% and
17% in the R/M15, R/M20 and F/I groups, respec-
tively, whereas the incidence of drug-related emesis

Minkowitz et al.: POSTOPERATIVE ANALGESIA AFTER REMIFENTANIL
527
TABLE III Recovery endpoints
Efficacy Endpoint
Time to:
Treatment Group
R/M20
R/M15
F/I
Adequate Respiration
Response to Verbal Commands
Extubation
Discharge from Operating Room
First Morphine Bolus Dose
First PCA Morphine Dose
First of Two Consecutive Aldrete Scores ($ 9)
Qualification for PACU Discharge
Actual Discharge from PACU
Hospital Discharge
Median – min (range)
Median – min (range)
Median – min (range)
Median – min (range)
Median – min (range)
Median – min (range)
Median – min (range)
Median – min (range)
Median – min (range)
Median – hrs (range)
7 (-3-19)*
7 (0-27)*
9 (1-23)*
12 (6-26)
20 (7-41)
42 (9-232)
20 (7-140)
74 (14-315)
6 (-2-26)*
6 (1-28)*
8 (2-28)*
14 (4-30)*
20 (6-49)
49 (12-145)
20 (9-108)
72 (19-625)
3 (-17-47)
5 (0-46)
5 (0-49)
11 (4-51)
19 (8-48)
40 (9-385)
17 (6-108)
70 (11-165)
112 (74-536)*
70 (24-215)
125 (66-1705)* 101 (62-492)
54 (2-266)
74 (19-433)
* P < 0.05 for comparison with F/I
was 21% (R/M15), 19% (R/M20) and 4% (F/I).
However, 27% of R/M15 patients, 15% of R/M20
patients and 48% of F/I patients did not experience
any hypotensive or bradycardic responses. There were
no differences in mean RR, SPO2, or PETCO2 at any
time point among the groups.
TABLE IV Percentage of patients with one or more responses to
intraoperative stimuli
Intraoperative Stimuli
Treatment Group
R/M15 R/M20 F/I
Intubation
Patients with $ 1
response – %
Patients with $ 1
response – %
Patients with $ 1
response – %
37*
6*
29*
4*
69
21
77
84
Skin Incision
Skin Closure
Extubation
Discussion
Remifentanil hydrochloride is a potent ultrashort-act-
ing µ-opioid agonist that may be useful in clinical sit-
uations where rapid recovery is desirable. The
disadvantage of the short-acting nature of remifentanil
is the need for a transition analgesic regimen before
discontinuation of the infusion in surgery with mod-
erate to severe postoperative pain. Without such a
transition analgesic, patients may experience greater
than average pain in the PACU and require increased
doses of morphine to be comfortable postoperatively.
The present study found that the mean total amount
of morphine used in the PACU, and the 24 and 48 hr
postoperative periods in both remifentanil groups and
the fentanyl group were not different; indicating that
the transition analgesic was effective.
The mean individual postoperative morphine
requirements in this study are within the ranges
reported by White5 and Tamsen.6 This study also con-
firmed previous studies indicating that elderly patients
require less analgesic medication.7 The mean total
morphine requirement in the 24 hr postoperative peri-
od was almost halved in patients older than 65 yr com-
pared with patients 65 yr of age or less.
35*
82
46*
90
Patients with $ 1
response – %
* P < 0.05 for comparisons with F/I
TABLE V Percent of patients experiencing drug–related adverse
events
Treatment Group
R/M 15 R/M 20 F/I
Percentage of patients with any event 48%
47%
31%
26%
7%
26%
19%
7%
1%
1%
1%
1%
1%
0
37%
28%
27%
8%
6%
4%
3%
3%
3%
0
0
0
1%
1%
Gastrointestinal
Nausea
Emesis
Cardiovascular
Hypotension
Bradycardia
Musculoskeletal
Muscle rigidity
Infusion site reactions
Erythema at study iv site
Pruritis at study iv site
Respiratory
34%
31%
4%
21%
21%
3%
0
0
0
0
0
0
Respiratory depression
0
0
Other measurements that support the effectiveness
of the transition analgesic include similar times from
the end of surgery to the first morphine bolus and first
PCA morphine administration between treatment
groups. In addition, the differences between the
weighted mean postoperative pain scores of the
was 4%, 7%, and 8%, respectively. The second most
prevalent adverse event was hypotension with an
occurrence rate of 23% (R/M15), 21% (R/M20) and
7% (F/I). The incidence of drug-related hypotension

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CANADIAN JOURNAL OF ANESTHESIA
remifentanil groups and the fentanyl group were not
significantly different at any time points following
PACU entry.
administered 30 min prior to discontinuation of a
remifentanil infusion are equally effective transition
analgesic regimens for inpatient procedures lasting one
hour or more. Postoperative analgesic requirements of
morphine sulphate in the PACU and 24 and 48 hr post-
operatively were similar between all regimens studied.
Generally, patients in the fentanyl arm experienced
faster times to various recovery endpoints than patients
receiving remifentanil and morphine as a transition
analgesic. The longer times to recovery endpoints in the
remifentanil groups observed in this study are probably
due to morphine, which achieves peak effect approxi-
mately 5 - 20 min following iv administration.9 The
timing of anesthetic agent discontinuation may also
have contributed to longer times to recovery endpoints
experienced by remifentanil patients. The remifentanil
infusion was discontinued at the end of surgery, where-
as the median time of last bolus dose of fentanyl in the
fentanyl arm was 44 min (range, -4 to 118) prior to the
end of surgery. Although the usual duration of action of
the analgesic effect of fentanyl is 30 to 60 min after a
single iv dose of up to 100 µg,10 the timing of the
administration of fentanyl meant that patients in the
fentanyl arm had an opportunity to emerge from anes-
thesia sooner than remifentanil patients.
Despite the generally longer times to recovery end-
points, no difference was detected between remifen-
tanil groups and the fentanyl group when Aldrete
scores, the major eligibility criteria for PACU dis-
charge, were compared. Furthermore, as evidenced by
the Anesthesiologist’s Satisfaction Assessment, clini-
cians did not feel the difference in the recovery profile
impacted patient response or quality of study opioid
performance.
Opioids may decrease arterial blood pressure and
heart rate.11 Remifentanil produces hemodynamic
effects typical of potent opioids with a rapid onset of
action and short time to peak effect. Opioid-based
anesthesia may also prevent episodic tachycardia and
hypertension which may occur intraoperatively in
response to varying levels of surgical stimulation.
Remifentanil is potent in this regard because higher
doses may be given intraoperatively without fear of
prolonging recovery. Patients in this study who
received remifentanil-based regimens experienced
fewer responses to intraoperative stimuli and had a
more stable anesthetic course.
Generally, remifentanil was well tolerated with sim-
ilar adverse events profiles observed between remifen-
tanil- based and traditional fentanyl-based anesthetic
regimens. Nausea was the most prevalent drug-related
adverse event experienced by patients during the post-
operative period. Nausea and vomiting are common
side effects of emergence from general anesthesia.
In conclusion, this study demonstrated that mor-
phine sulphate regimens of 0.15 or 0.20 mg·kg–1
Acknowledgments
Statistical review performed by:
Michael W. Colopy PhD, Glaxo Wellcome Inc., 5
Moore Drive, Research Triangle Park, NC 27707,
USA.
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