Comparative Clinical Effects of Hydromorphone and Morphine

A Meta-analysis
L. Felden; C. Walter; S. Harder; R.-D. Treede; H. Kayser; D. Drover; G. Geisslinger; J.
Ltsch
Authors and Disclosures
Posted: 09/22/2011; Br J Anaesth. 2011;107(3):319-328. 2011 Oxford University
Press

Abstract and Introduction
Abstract
We have conducted a meta-analysis of the clinical effects of morphine and hydromorphone to
compare their benefit in analgesia. Embase and Medline were searched with an end-date of June 2009
for randomized, controlled trials or observational studies that addressed comparative analgesic and side-
effects or particular side-effects. Two researchers independently identified included studies and extracted
the data. Estimates of opioid effects were combined by using a random-effects model. Meta-analysis of
eight studies suggested that hydromorphone (494 patients) provides slightly better (!0.012) clinical
analgesia than morphine (510 patients). The effect-size was small (Cohen's /0.266) and disappeared
when one study was removed, although the advantage of hydromorphone was more evident in studies of
better quality (Jadad's rating). Side-effects were similar, for example, nausea (!0.383, nine studies, 456
patients receiving hydromorphone and 460 morphine); vomiting (!0.306, six studies, 246 patients
receiving hydromorphone and 239 morphine); or itching (!0.249, eight studies, 405 patients receiving
hydromorphone, 410 morphine). This suggests some advantage of hydromorphone over morphine for
analgesia. Additional potential clinical pharmacological advantages with regard to side-effects, such as
safety in renal failure or during acute analgesia titration, are based on limited evidence and require
substantiation by further studies.

Introduction
Potent opioids such as morphine, hydromorphone, oxycodone, piritramide, meperidine, or members
of the fentanyl group are the basic drugs specified in Step (Freedom from Cancer Pain) of WHO's
cancer pain relief ladder.
[1]
Evidence also supports the moderate use of these drugs in treating non-
cancer pain.
[23]
n short-term or chronic pain treatment, being able to choose and rotate multiple opioids is
recommended for handling major opioid-induced side-effects.
[45]

However, only morphine is on WHO's essential drugs list
(http://www.who.int/medicines/publications/essentialmedicines/en/ accessed January 27, 2010). This
raises the question as to whether this is sufficient or whether other strong opioids are needed in addition
to morphine. Hydromorphone, synthesized in Germany in 1924 and introduced in 1926, is a semi-
synthetic morphine derivative that differs (Table 1) from morphine in its chemical structure only at position
6 of the benzol ring, where it has a keto-group instead of a hydroxy group (Fig. 1). This makes it 510
times more potent than morphine
[6]
and enhances its distribution into the brain making titration of the
effects easier. n addition, due to the keto-group in position 6, hydromorphone is only glucuronidated at
position 3, and does not form an active 6-glucuronide metabolite like morphine.
[7]
Therefore,
hydromorphone may be better tolerated than morphine in patients with renal failure because the
glucuronides are eliminated via the kidney and those patients may suffer severe opioid side-effects (Table
2). However, the 3-glucuronides (morphine-3-glucuronide, M3G, hydromorphone-3-glucuronide, H3G)
have anti-analgesic and neuroexcitatory effects
811
not mediated by opioid receptors.
[12]

(Enlarge mage)
Figure 1.
Comparison of simulated time courses of plasma and effect site (CNS)
concentrations of morphine (5 i.v. injections of 2 mg morphine hydrochloride at an
interval of 10 min during titration of analgesia) vs hydromorphone (0.5 mg
hydromorphone hydrochloride every 10 min). After the titration injections are
stopped, morphine opioid concentrations at the effect site continue to increase for at
least an hour, whereas those of hydromorphone quickly decrease. For both opioids,
plasma concentrations vs time courses were described by a standard three-
compartment pharmacokinetic model. Parameter values for the simulations were
taken from previous publications.
37,4042
The k
e0
transfer half-lives between plasma
and 'CNS' effect sites were taken as 166 min for morphine
37
and 28 min for
hydromorphone as the mean of the reported range.
40
Note the different scaling of
the ordinates for optimum visibility of all curves. n addition, the chemical structures
of morphine and hydromorphone are depicted.
Hydromorphone thus may have advantages over morphine. We have conducted a meta-analysis of
the evidence supporting the additional use of hydromorphone as a standard potent opioid and compared
this with morphine.

Methods
We searched PubMed and Embase (via DMD) databases using Cochrane's search strategy,
confining the search to studies published between 1970 and June 2009. Entering the key words
'hydromorphone+morphine' yielded 1535 hits. With 'hydromorphone+morphine+pain' got 520 hits, and
with 'hydromorphone vs morphine randomized controlled trials', yielded 27 hits. Most were excluded for
the following reasons: (i) only in vitroassessment or animal data, (ii) hydromorphone was not compared
with morphine, and (iii) reviews not containing original controlled data. The references of the studies
included were hand-searched to identify any missed papers.
We selected the opioid effects for analysis to be analgesia and side-effects. Side-effects included
respiratory depression, psychotropic effects such as sedation, tolerance or addiction to opioid analgesics,
nausea, vomiting, constipation, and 'other side-effects' such as blurred vision, decreased heart rate or
arterial pressure, itching, or oedema. Meta-analyses were done for opioid effects reported in at least five
samples from at least four independent cohorts.
Two investigators, working independently, extracted data from the eligible papers, subsequently
cross-checking them, and resolving discrepancies. f data were reported in a format that did not allow
inclusion in the meta-analysis, we contacted the authors and asked them to release data. The following
data were extracted: first author, year of publication, location, diagnostic status, whether pain was acute
or chronic. When more than one study sample was reported, data were treated as subgroups of the same
study.
We used the Comprehensive Meta-Analysis software version 2.0 for Windows (Biostat nc.,
Englewood, NJ, USA) for the meta-analysis. Heterogeneity of the study sets submitted to meta-analysis
was assessed with Q-statistics
[13]
and by calculating the value of I
2

[14]
which is interpreted as I
2
>50
showing a significant heterogeneity and I
2
<25% indicating an insignificant heterogeneity. Clinical data
were grouped for acute or chronic pain. Data were analysed within a random-effects framework, and
individual study effect sizes were calculated using Cohen's /, which quantifies the standardized difference
in parameter means between the groups receiving either hydromorphone or morphine normalized at the
joint standard deviation, /(Mean
Morphine
Mean
Hydromorphone
)/sd
Combined
. When the direction of this
difference / is a negative value, then this would indicate an advantage of one medication over another
medication. An absolute value of /0.2 indicates a small effect size, 0.5 indicates a medium one, and 0.8
indicates a large one.
[15]
Effect sizes were pooled using inverse variance methods to generate a summary
effect size and its 95% confidence interval (C). The assumption underlying a random effects framework is
that between-study variation is due to both chance or random variation and study effect. The significance
of the pooled effect size was determined using -statistics. Forest plots were generated to visualize the
standardized difference in means between genotype groups and 95% C per study. Publication bias was
assessed by testing for classic fail-safe N.
[16]
Although its utility is controversial,
[17 18]
study quality was
judged according to the criteria proposed by Jadad and colleagues,
[19]
and the appropriateness of
allocation concealment was evaluated according to the criteria of Schulz and Grimes
[20]
as appropriate or
inappropriate. n the Jadad system, 1 point for each of the following criteria will be added, so that an
overall result of 05 can be achieved: randomization, appropriate method of randomization, double-
blinding, appropriate method of double-blinding, and adequate description of excluded cases and
dropouts.

Results
The final data set consisted of 11 controlled clinical studies (Table 3). We included four studies
comparing analgesic effects of hydromorphone and morphine for acute analgesia
[2124]
and four studies
comparing analgesic effects in chronic pain treatment.
[2528]
n addition, three studies were included only
with respect to side-effects as the pain data were not suitably reported.
[2931]
Study quality was assessed
as described above and results are included inTable 3.
Analgesia
Pain data were included from 10 independent samples reported in eight studies,
[2128]
comprising
1004 patients, of whom 494 were treated with hydromorphone and 510 with morphine. Patients were
enrolled in different clinical settings with varying pain conditions such as chronic cancer pain
[2528]
and
acute pain.
[2124]
The opioids were administered orally,
[25 26 28]
s.c.,
[26 27]
and i.v.
[2124]
n three studies,
[23 26
27]
pain was measured by a 100 mm visual analogue scale (VAS), and five studies
[21 22 24 25 28]
used an 11-
point numerical rating scale (NRS). f pain intensity ratings were reported for different time points,
[24
27]
values were combined.
Hydromorphone provided significantly better analgesia than morphine in acute pain
(/0.266, !0.006, Fig. 2). The difference in pain was about 0.4 points at an NRS, calculated as the
mean difference, weighted at the study size,
[21 22 24 25 28]
between ratings after hydromorphone and
morphine administration. However, no difference was observed for chronic pain (!0.889). The apparent
advantage in acute pain treatment disappeared with the removal of any study from the analysis, showing
that the effect depended on the complete study set (Fig. 3). However, the advantage of hydromorphone
was better in higher quality studies, suggesting that it was less likely to be due to poor studies. The
advantage for acute pain treatment was reflected in a small overall advantage of hydromorphone over
morphine (/0.228, !0.012). Publication bias was not significant (classic fail-safe N: !0.14).
However, the study set was heterogeneous, as indicated by Q26.5 and I
2
73.6 (!<0.001). When
leaving out each study successively, the effects did not substantially change. This also included when
leaving out the study with the Jadad score 0,
[26]
suggesting that the hydromorphone advantage in pain
relief was not the result of including a low-quality study. Similarly, a cumulative meta-analysis of the
analgesic effects did not suggest a change in the result when including decreasingly scored studies.
(Enlarge mage)
Figure 2.
Comparative assessments in various clinical settings of the effects of
hydromorphone and morphine on pain, nausea, vomiting, and itching. Meta-analysis
indicates that hydromorphone provides significantly lower pain (negative Cohen's /)
than morphine, whereas for chronic pain both opioids provided similar analgesia.
Thus hydromorphone is slightly more advantageous than morphine at providing
analgesia in a clinical setting. n contrast, significantly less nausea (negative
Cohen's /) during chronic pain treatment with hydromorphone cannot be taken as
result due to only two studies included in that subgroup. Forest plots show the
standardized differences in means between groups with 95% Cs shown for each
study.
Figure 3.
Comparative assessments of the analgesic effects of hydromorphone and
morphine when one study was removed from the analysis (left) and cumulative
meta-analysis with successive inclusion of studies with decreasing Jadad's quality
rating. The forest plot at the left indicates, for each study, the meta-analysis result
that would have been obtained when that particular study had not been included. t
shows that the apparent advantage of hydromorphone depends on the
(Enlarge mage) completeness of the data set and disappears when either of the included studies
was removed. The plot on the right shows the changes in the meta-analysis results
when lower Jadad-scored studies were successively included. t indicates that the
advantage of hydromorphone is better justified in higher quality studies and was not
merely suggested by lower quality studies.

Side-effects
Some studies numerically listed side-effects, whereas others merely reported no statistically
significant difference without details (see below). Therefore, the numbers of patients differ from those
analysed for analgesic effects. Three studies provided data on respiratory depression,
[22 29 31]
which are
insufficient for meta-analysis. Similarly, constipation was reported in only two studies.
[25 28]
Numerical
information about pruritus,
[2125 2931]
nausea,
[2125 2831]
and vomiting
[21 22 24 25 28 30]
was available from eight,
nine, and six studies, respectively.
Nausea was comparable between hydromorphone and morphine in the acute pain group
(/0.097, !0.346). No statistical difference was seen for either the incidence of vomiting
(/0.175, !0.306, Fig. 2) or for itching (/0.361, !0.249). Too few studies compared side-effects in
the chronic pain setting. However, since separate analyses were predefined for acute and chronic pain,
the results drawn from two studies suggested an advantage of hydromorphone over morphine regarding
nausea (/0.409, !0.005) and vomiting (/0.865, !0.001) in chronic pain. When pooled with acute
pain, the overall effect was non-significant. Publication bias was significant for vomiting (classic fail-safe
N: !0.01), and the study set was heterogeneous for itching and vomiting (Q and I
2
values at !<0.05).

Discussion
Our meta-analyses suggest a slight advantage of hydromorphone for analgesia. However, both
opioids are effective analgesics, and neither is without clinically relevant side-effects. An absolute value of
Cohen's / of 0.266 for better acute analgesia produced by hydromorphone shows only a small effect size.
ndeed, the difference in pain was about 0.4 points at an 11-point NRS, in favour of hydromorphone. This
may be clinically significant when considering that the average effect of WHO Step opioids on chronic
non-cancer pain was found to be 1.1 pointsvs placebo.
[2]
The advantage of hydromorphone over
morphine is weakened as three comparative studies, which suggested the clinical equivalence of the two
opioids, were not included into the meta-analysis due to unsuitable data reporting. Moreover, the slight
advantage depended on the complete study set, as removing any of the studies eliminated the
hydromorphone advantage. However, the advantage was supported by the better quality studies rather
than the lower quality ones. The results are based on surprisingly few studies considering the >80 yr of
clinical availability of hydromorphone.
Nevertheless, in some populations, hydromorphone has been reported to be better than morphine
because it does not have an active, renally eliminated metabolite. Several case reports suggested that
morphine's 6-glucuronide metabolite is responsible for sedation and nausea in patients with impaired
renal excretory function (Table 3). Hydromorphone, pharmacokinetics, and pharmacodynamics have
been studied in a single, controlled study in patients receiving 4 h haemodialysis treatment twice
weekly.
[32]
Between haemodialysis treatments, the half-life of plasma hydromorphone was significantly
prolonged (t
1/2
33.3 h), but was normal during haemodialysis (t
1/2
3.3 h, !0.02). McGill Pain
Questionnaire and VAS pain scores decreased from 35 items and 5.9 mm between haemodialysis
sessions to 15.5 items and 4.4 mm VAS during haemodialysis, respectively. Higher H3G concentrations
were correlated with higher pain scores (r
2
0.578, !<0.001). Since no serious side-effects occurred,
hydromorphone was concluded as a safe treatment option in haemodialysis patients. However, this
finding in haemodialysis patients does not rule out neuroexcitatory symptoms triggered by H3G in renal
functional impairment without haemodialysis.
[33]
n 48 terminally ill hospice patients treated with at least 20
mg h
1
continuous parenteral hydromorphone for more than 15 days,
[34]
agitation had an incidence of 50%
and myoclonus an incidence of 60%, when treatment duration was longer.
Other perceived clinical advantages of hydromorphone, such as less sedation and other central
nervous side-effects, could not be tested against morphine because the current data are insufficient.
Moreover, the common practice of opioid-rotation does not reveal a particular advantage of
hydromorphone over morphine due to the lack of randomized controlled trials.
[35]
The only controlled
study covering opioid rotation
[26]
did not compare side-effect profiles, for which opioid rotation is especially
advised.
[5]
Moreover, in a prospective clinical trial, improvements in pain and side-effects caused by
rotation to hydromorphone could not be solely related to a better pharmacokinetic profile of the substance
hydromorphone as the technique of opioid-rotation itself and an increase in dosage may influence
effective symptom control.
[36]

A further possible advantage of hydromorphone over morphine may apply to short-term analgesia.
Hydromorphone has a shorter plasma:central nervous effect-site equilibration half-life than morphine
(Table 1). The physicochemical properties of morphine in a slow bloodbrain barrier transfer half-life of
~166 min.
[37]
This slow transfer can result in delayed fatal respiratory depression,
[38]
and suggests that
morphine is poorly suited by titration for immediately analgesia. Simulation shows that hydromorphone's
effects have a quicker onset time than those of morphine. mportantly, the concentrations at effect site do
not increase after titration has stopped as with morphine (Fig. 1). Therefore, hydromorphone may be
better suited than morphine for titration of acute analgesia. This theoretical pharmacokinetic
pharmacodynamic modelling-based consideration is also supported by a shorter latency [22.5 (6) min] of
the onset of postoperative analgesia after epidural administration of hydromorphone (n19) when
compared with morphine [36.6 (6) min; n37].
[39]

Our meta-analyses suggest a slight advantage of hydromorphone for analgesia but was based on
relatively few and heterogeneous studies. Further comparative studies of hydromorphone are needed,
despite its clinical use for more than 80 yr. Our comparison does not justify a preference for the current
use of morphine, but pharmacokinetic advantages and perceived clinical benefits of hydromorphone with
respect to side-effects are based on limited evidence and require substantiation by further clinical studies.

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From British Journal of Anaesthesia
Maintenance Anaesthetics during Remifentanil-based Anaesthesia
Might Affect Postoperative Pain Control after Breast Cancer
Surgery
|

S.-W. Shin; A.-R. Cho; H.-J. Lee; H.-J. Kim; G. J. Byeon; J.-W. Yoon; K.-H. Kim; J.-Y.
Kwon
Authors and Disclosures
Posted: 11/29/2010; Br J Anaesth. 2010;105(5):661-667. 2010 Oxford University
Press

Abstract and Introduction
Abstract
,.ground. Although remifentanil provides profound analgesia during operation, postoperative
occurrence of hyperalgesia and tolerance after remifentanil administration could be a challenge to the
postoperative pain control. n this investigation, we sought to determine the effect of maintenance with
propofol or sevoflurane on postoperative analgesia after remifentanil-based anaesthesia.
Methods. Two hundred and fourteen women undergoing breast cancer surgery under remifentanil-based
general anaesthesia were randomly included in this prospective and double-blind trial. The patients were
anaesthetized with sevoflurane (S) or propofol (P) under high (H) or low (L) effect-site concentration (Ce)
of remifentanil-based anaesthesia using a target-controlled infusion system; the patients were allocated
into the SH, SL, PH, and PL groups. Pain intensity (visual analogue score, VAS) and cumulative
morphine requirements were recorded 30 min, 1, 6, 12, and 24 h after operation.
ResuIts. The patient characteristics were similar. Cumulative morphine consumption at 24 h after surgery
was higher in the SH group [38.6 (SD 14.9)] compared with the SL [31.5 (3.7)], PH [31.7 (8.3)], and PL
groups [30.1 (6.1)] (!<0.001). The VAS scores during 24 h after surgery were also higher in the SH group
than the SL, PH, and PL groups (!<0.001).
on.Iusions. Remifentanil hyperalgesia was induced by high dose of remifentanil-based anaesthesia
during sevoflurane anaesthesia, whereas that was not apparent during propofol anaesthesia. Also,
remifentanil hyperalgesia did not occur during low dose of remifentanil-based anaesthesia. Maintenance
of propofol during high-dose remifentanil-based anaesthesia provided better postoperative analgesia.

Introduction
During general anaesthesia, opioids are commonly administered with either i.v. or inhaled hypnotic
drugs. Remifentanil is widely used in clinical settings and as a useful supplement to general anaesthesia
for several reasons, including its minimal alveolar concentration-reducing effects,
[1]
attenuation of the
autonomic, somatic, and adrenocortical responses to noxious stimuli,
[24]
and rapid cognitive recovery.
[5]

Nevertheless, remifentanil administration during anaesthesia has been associated with the frequent
development of opioid-induced hyperalgesia due to its potent and short-acting properties.
[6 7]
Therefore,
remifentanil-based anaesthesia could be a challenge for postoperative pain control.
The mechanism underlying opioid-associated hyperalgesia is still unclear, but a critical role has been
attributed to an endogenous pain facilitatory system involving the N-methyl-D-aspartate (NMDA)
receptor.
[810]
Recently, Zhao and Joo
[11]
demonstrated that clinically relevant concentrations of
remifentanil induced rapid, persistent increases in NMDA responses that mirror the development of
remifentanil-induced hyperalgesia. Several studies have demonstrated that i.v. or inhaled anaesthetics
inhibit NMDA receptors and might modulate postoperative hyperalgesia.
[1215]

n the current study, we first examined whether high concentration of remifentanil could induce opioid-
induced hyperalgesia. We then addressed the question of whether the choice of anaesthetics might have
an influence on the postoperative pain control by modulating opioid-induced hyperalgesia. Therefore, the
aim of this study was to evaluate and compare the influence of two maintenance anaesthetics,
sevoflurane or propofol, on the intensity of postoperative pain in the clinical setting of possible occurrence
of remifentanil-induced hyperalgesia, in patients undergoing breast cancer surgery.


Methods
This study was approved by the nstitutional Review Board of the Pusan National University Hospital.
After signed informed consent was obtained from the patients, 214 adult women aged between 20 and 65
yr with an ASA physical status of or undergoing elective breast cancer surgery were enrolled. Patients
with neurological or psychiatric disorders, a history of drug abuse or chronic use of opioids or sedative
drugs, obesity (BM >30), the intake of any analgesic drug within 48 h before surgery, or poorly controlled
hypertension were excluded. Pregnant patients were also excluded from the study. All patients accepted
the use of patient-controlled analgesia (PCA) for perioperative pain control.
On the day before surgery, patients were instructed on how to use the PCA (Pain Management
Provider, Abbott, USA) device and the visual analogue scale (VAS; 0, no pain; 10, worst pain
imaginable). Patients were not allowed to have solid food or clear liquids after midnight on the day before
surgery. All patients received midazolam 3 mg and glycopyrrolate 0.2 mg, i.m., 30 min before surgery. n
the operating theatre, standard monitoring and bispectral index (BS; Bispectral index, Aspect Medical
System, Norwood, MA, USA) monitoring were performed and baseline values were recorded. According
to the method of anaesthetic induction and anaesthesia, the patients were randomly assigned, in a
double-blinded manner, to one of the four groups. Randomization was done by two independent
anaesthetists using 200 opaque-sealed envelopes, 50 for each group, indicating patient group
assignment and describing the anaesthetic protocol for this particular group. The patients and
anaesthetists involved in assessing postoperative pain, analgesic consumption, data collection, and
analysis of results were not aware of group assignment.
n the propofol groups, anaesthesia was induced with continuous propofol and remifentanil (low or
high dose) infusion by target-controlled infusion (TC) (Orchestra with Base Primea, Fresenius Kabi,
France) to reach 4 g ml
1
and 4 ng ml
1
(PH group) or 1 ng ml
1
(PL group) of target effect-site
concentration (Ce). n sevoflurane subjects, anaesthesia was induced with thiopental 5 mg kg
1
and
continuous remifentanil (low or high dose) infusion, using TC to reach 4 ng ml
1
(SH group) or 1 ng
ml
1
(SL group) of Ce. The pharmacokinetic sets used to calculate target effect-site concentrations of
propofol and remifentanil were those published by Schnider and colleagues
[16]
and Minto and
colleagues,
[17]
respectively.
Once the BS scale was stable between 40 and 50, rocuronium 0.6 mg kg
1
was used to facilitate
tracheal intubation. Anaesthesia was maintained according to the allocated group and a 1:1 mixture of
oxygen and air. Mechanical ventilation was adjusted to maintain an end-tidal carbon dioxide
concentration of 3035 mm Hg throughout surgery using an anaesthetic/respiratory gas analyzer.
Neuromuscular block was maintained via intermittent i.v. injection of rocuronium 0.2 mg kg
1
.
The BS value was used to guide administration of propofol and sevoflurane. The target range of BS
during maintenance was 4050. f the BS value was not in a given range for at least 1 min or clinical
signs of inadequate anaesthesia such as patient movement, coughing, tearing, or sweating were showed,
we treated with increasing or decreasing Ce of propofol by 0.5 g ml
1
increments or inspired
concentration of sevoflurane by 0.5%. Mean arterial pressure (MAP) and heart rate (HR) were used to
guide the administration of remifentanil. Both variables were maintained within 20% of baseline values, if
hypotension (MAP <60 mm Hg) or bradycardia (HR <45 beats min
1
) occurred more than 5 min, the
patient was treated with ephedrine 10 mg or atropine 0.5 mg. We excluded the case if the patient was
administered ephedrine or atropine more than three times.
Thirty minutes before the end of surgery, morphine sulphate 2 mg was administered i.v., and
background infusion of PCA was started. At the end of surgery, propofol, sevoflurane, and remifentanil
were discontinued and ramosetron 0.3 mg was administered i.v. for antiemetic prophylaxis.
Neuromuscular block was antagonized by combined i.v. glycopyrrolate (0.008 mg kg
1
) and
pyridostigmine (0.2 mg kg
1
) at the completion of surgery. The same surgical and anaesthesia teams
performed all the procedures. After recovery of adequate spontaneous ventilation and the obeisance to
verbal commands such as eye opening, the tracheal tube was removed. The patients were transferred to
the post-anaesthesia care unit (PACU), where standard monitoring was recorded every 15 min using the
modified Aldrete score. An Aldrete score <9 and Sp
O

2
>95% with oxygen 2 litre min
1
or >92% without
oxygen signified recovery of physical, mental, and physiological function to near preanaesthetic levels.
After discharge from the PACU, the patient was transferred to the general ward and the postoperative
parameters were assessed.
The pain was controlled by PCA, which was programmed to deliver demand doses of morphine
sulphate 1.0 mg with a 20 min lockout interval and continuous infusion of 1.0 mg h
1
. The 4 h limit of
morphine sulphate was set to not exceed 20 mg. Pain intensity was assessed by the patients using VAS
scale. f there was patient requirement or VAS scale was >5, the patient was administered morphine 4 mg
i.v. as rescue analgesics. This PCA regimen was maintained in the PACU and the general ward.
Measurements
Baseline HR and MAP were defined as the mean of the two lowest measurements recorded during a
35 min interval just before induction of anaesthesia. Values from all routine anaesthetic monitors were
recorded at 5 min intervals during surgery. Duration of anaesthesia and surgery, the length of stay in the
PACU, and the total doses of remifentanil given in the operating theatre were also recorded.
The cumulative consumption of morphine given by PCA and the pain intensity using the VAS were
recorded at 30 min, 1, 6, 12, and 24 h after surgery. The primary outcome was the consumption of
morphine during the first 24 h after surgery.
The degree of sedation was monitored by the Ricker sedation-agitation scale
[18]
on arrival in the
PACU and 1 h after surgery. The incidence of postoperative nausea and vomiting (PONV; including all
episodes of nausea, retching, and vomiting) and requirements for antiemetics were recorded within 24 h
after surgery. Subjects who experienced vomiting or required antiemetic therapy within 24 h after surgery
were given ondansetron 4 mg i.v. Other adverse events such as respiratory depression, muscular rigidity,
or shivering were also recorded.
Statistical Analysis
Age, weight, height, BM, duration of surgery and anaesthesia, length of stay in the PACU, and
intraoperative remifentanil consumption were analysed by one-way analysis of variance (ANOVA).
Haemodynamic variables (MAP and HR), BS scales, cumulative morphine consumption, and VAS scale
were analysed by repeated-measures ANOVA for inter-group comparison. For post hoc comparisons, we
used the Bonferroni test, as needed. The Ricker sedation-agitation scale was analysed by the Kruskal
Wallis test. The
2
test was used to compare the type of surgery, intraoperative atropine or ephedrine use,
requirement for antiemetic drugs, and incidence of postoperative complications (PONV, respiratory
depression, muscular rigidity, and shivering). The level of statistical significance was set at !<0.05. All
analyses were performed using StatView version 5.0 (SAS, Chicago, L, USA) and MedCalc version
9.3.1 (MedCalc Software, Mariakerke, Belgium). An estimated sample size indicated that 41 patients per
group would give a -risk of 80% at an d-level of 0.05 for detecting a difference in morphine consumption
of at least 5.0 mg at 24 h after the operation with a standard deviation of 8.0 for each group in the
preliminary test.

Results
Two hundred and fourteen patients were enrolled, and 14 patients were excluded because of sudden
refusal and unsuitability of the inclusion criteria. One hundred and eighty-six patients were analysed: 46 in
Group PH, 50 in Group PL, 42 in Group SH, and 48 in Group SL due to intractable PONV and excess use
of ephedrine of atropine (Fig. 1). All groups did not differ in patient characteristics among the groups
(Table 1). ntraoperative remifentanil consumption was much higher in Groups PH and SH compared with
Groups PL and SL; furthermore, intraoperative ephedrine and atropine uses were significantly higher in
Group PH (37.0%) compared with Groups PL, SH, and SL (!0.009, Table 2).
(Enlarge mage)
Figure 1.
Consort flow
diagram.
n the aspect of cumulative morphine consumption during the first 24 h after surgery, there was a
significant difference between sevoflurane and propofol under high dose of remifentanil-based
anaesthesia, whereas there was no difference between sevoflurane and propofol under low dose of
remifentanil-based anaesthesia (Fig. 2A).
(Enlarge mage)
Figure 2.
Cumulative morphine consumption (A) and VAS (B) during the first 24 h after
surgery. Group PH, propofol+4 ng ml
1
Ce of remifentanil; Group PL, propofol+1 ng
ml
1
Ce of remifentanil; Group SH, sevoflurane+4 ng ml
1
Ce of remifentanil; and
Group SL, sevoflurane+1 ng ml
1
Ce of remifentanil. *!<0.05 compared with
PH;
|
!<0.05 compared with SL;

!<0.05 compared with PL. Ce, effect-site

concentration.
There was a significant difference between sevoflurane and propofol under high dose of remifentanil-
based anaesthesia in the VAS scores, whereas there was no difference between sevoflurane and
propofol under low dose of remifentanil-based anaesthesia. The VAS scores were significantly higher in
Group SH than Groups PH and PL within 24 h after surgery, and the significant differences were
observed at 30 min and 1 h after surgery (Fig. 2B).
MAP was higher and HR was slower in Group PL than in Group SL (!0.041 and 0.001), whereas
there were no significant differences between Groups PH and SH. BS was similar among the groups.
The incidence of PONV was significantly lower in Group PL (18.0%) compared with Groups PH
(43.5%), SH (45.2%), and SL (43.8%) (!0.013). Consequently, the requirement for antiemetic drugs was
higher in Groups PH and SH than in Groups PL and SL (!0.005). The incidence of shivering was also
significantly higher in Groups PH and SH than in Groups PL and SL (!0.004). The Ricker sedation-
agitation scales were in the range of 35 for all patients, and it was possible to determine VAS. There
were no significant differences in the degree of sedation among the groups (!0.099, Table 3). Other
adverse events including respiratory depression and muscular rigidity were not shown.

Discussion
Our results showed that the maintenance of sevoflurane provided high morphine consumption and
higher VAS scores after breast cancer surgery compared with the maintenance of propofol under high
dose of remifentanil-based anaesthesia, not under low dose of remifentanil-based anaesthesia. Group SH
reported greater cumulative morphine consumption during the first 24 h than Group SL, which could be a
strong predictor of occurrence of remifentanil-induced hyperalgesia. n contrast, Group PH reports similar
cumulative morphine consumption or VAS scores compared with Group PL. These findings suggest that
maintenance of propofol in remifentanil-based anaesthesia provides better postoperative analgesia by
suppression of remifentanil-induced hyperalgesia.
Several studies suggested that acute and chronic exposure to opioids can be associated with the
development of hyperalgesia and NMDA receptor involved in the genesis of opioid-associated
hyperalgesia by pain-facilitating system.
[19]
Remifentanil supplementation during anaesthesia is known to
be associated with the occurrence of the opioid-induced hyperalgesia; this is clinically significant,
because large doses of intraoperative -opioid receptor agonists can increase postoperative pain and
morphine consumption.
[7]
More recently, Zhao and Joo
[11]
presented a cellular mechanism involving the
rapid and prolonged up-regulation of NMDA receptor function by remifentanil, which may contribute to the
clinical development of remifentanil-induced hyperalgesia. As expected, in sevoflurane groups, we
observed that the large dose of remifentanil caused hyperalgesic responses whereas those responses
were not exhibited in the small dose of remifentanil.
n the past, several investigators suggested that there was no difference in postoperative matters
between propofol and inhalation anaesthetics,
[20 21]
thus the importance of the choice of maintenance
hypnotics was overlooked. They did not conduct remifentanil-based anaesthesia, thus their study was not
sufficient to confirm the effect of hypnotics on analgesia after opioid supplementation. Several
observations suggested that propofol inhibits the NMDA subtype of the glutamate receptor.
[12 15]

n a study of the effect of propofol on remifentanil-induced hyperalgesia, clinically relevant interactions
of propofol and remifentanil existed, and propofol could delay and weaken remifentanil-induced
hyperalgesia.
[22]
Recently, Cheng and colleagues
[23]
showed that propofol anaesthesia in fentanyl-based
anaesthesia was associated with less postoperative pain than isoflurane anaesthesia, showing a similar
conclusion to this study. The effects of sevoflurane on remifentanil-induced hyperalgesia have not yet
been fully evaluated. Some studies have demonstrated that sevoflurane antagonizes the NMDA receptor
in a dose-dependent manner.
[13 24]
A more recent study
[25]
suggested that, at clinical concentrations, the
anti-hyperalgesic properties of sevoflurane are not sufficiently potent to prevent hyperalgesia induced by
both nociceptive inputs and high doses of fentanyl.
This study was designed to assess whether the remifentanil-induced hyperalgesia or tolerance would
occur in clinical settings and whether there would be difference in suppression of the hyperalgesia or
tolerance depends on the maintenance anaesthetics. We confirmed that maintenance of propofol in
remifentanil-based anaesthesia abolished the occurrence of hyperalgesia observed after maintenance of
sevoflurane. The explanation for our results could be related to the pharmacokinetic differences between
propofol infusion and sevoflurane inhalation. n this study, we did not measure the subanaesthetic
concentrations in both groups. Previous studies demonstrated that propofol has an analgesic action at
subhypnotic doses.
[26 27]

On the other hand, the halogenous anaesthetics have been known for producing antianalgesia at
subanaesthetic concentrations, with a maximal effect at ~1/10th the concentration required for
anaesthesia.
[28]
Therefore, we could not exclude the effect of residual sevoflurane and the combined
pharmacokinetic action between sevoflurane and remifentanil on postoperative hyperalgesia expressed in
the SH group. n this study, although we demonstrated that propofol provided more benefit in the aspect
of post-anaesthetic recovery, the difference in morphine consumption and VAS scale might not be an
important matter clinically.
The PONV incidence is more than 75% without antiemetic prophylaxis in breast cancer surgical
patients.
[29]
Although all the enrolled patients were given ramosetron in this study, the beneficial effects of
propofol on PONV were attenuated during high dose of remifentanil infusion; those effects were shown
only in the PL group. The incidence of postoperative shivering was much higher in high dose of
remifentanil-based anaesthesia group. Thus, we assumed that the consumption of remifentanil might be a
strong modulating factor of PONV and postoperative shivering in our study. As the sample size
calculation was based on postoperative morphine consumption by PCA, the lack of differences in other
variables may be attributed to a lack of power.
We have demonstrated that the maintenance of propofol during high dose of remifentanil-based
anaesthesia led to better postoperative pain control compared with the maintenance of sevoflurane after
breast cancer surgery. The reduction of postoperative pain was manifested as a decrease in morphine
consumption and the VAS scale during the first 24 h after surgery. Thus, it could be assumed that
propofol might have a more potent NMDA antagonism effect on the hyperalgesia elicited by remifentanil
usage than that of sevoflurane. Although the use of propofol decreased the incidence of PONV during low
dose of remifentanil infusion, there was no benefit on PONV and shivering under high dose of
remifentanil-based anaesthesia.
There are several limitations in this study. The first limitation is that the beneficial effects of propofol
were not translated into shortening of PACU stay. We assumed that the length of PACU stay in this study
might be more dependent on the hospital facility and policy, not on the drug effect. As a second limitation,
the usage of background infusion and long lockout interval might decrease the sensitivity of morphine
consumption during the observation period.
n conclusion, our results suggest that maintenance of general anaesthesia by propofol may prevent
remifentanil-induced hyperalgesia induced by high dose of remifentanil usage. Furthermore, propofol has
the potential to reduce postoperative pain and hyperalgesia, although the combined use of propofol with
high dose of remifentanil could induce the need for inotropic treatment compared with sevoflurane. A
reduction in postoperative pain and morphine consumption might lead to earlier mobilization and earlier
hospital discharge.

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