Anaesthesia, 2007, 62, pages 1266–1280 doi:10.1111/j.1365-2044.2007.05221.

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REVIEW ARTICLE
Remifentanil for general anaesthesia: a systematic review
R. Komatsu,1,2 A. M. Turan,3 M. Orhan-Sungur,4 J. McGuire,5 O. C. Radke6 and
C. C. Apfel2,7
1 Clinical Instructor, Department of Anaesthesiology, Tokyo Women’s Medical University, 8–1 Kawada-cho,
Shinjukuku, Tokyo 162–8666, Japan
2 Outcomes Research Institute, University of Louisville, 501 E Broadway, Suite 210, Louisville, KY 40202,
USA
3 Assistant Professor, Department of Anaesthesiology & Perioperative Medicine, and the Outcomes Research Institute,
University of Louisville, USA
4 Assistant Professor, Department of Anaesthesia, Capa Medical School, Istanbul University, Istanbul, Turkey
5 Research Associate, Department of Anaesthesia and Perioperative Care, UCSF Medical Center at Mount Zion, San
Francisco, USA
6 Visiting Assistant Professor, Department of Anaesthesia and Perioperative Care, San Francisco General Hospital,
USA
7 Associate Professor, Department of Anaesthesia and Perioperative Care, Mt. Zion UCSF Medical Center,
San Francisco, USA

Summary
We performed a quantitative systematic review of randomised, controlled trials that compared
remifentanil to short-acting opioids (fentanyl, alfentanil, or sufentanil) for general anaesthesia.
Eighty-five trials were identified and these included a total of 13 057 patients. Intra-operatively,
remifentanil was associated with clinical signs of deeper analgesia and anaesthesia, such as fewer
responses to noxious stimuli (relative risk 0.65, 95% CI 0.48–0.87), more frequent episodes of
bradycardia (1.46, 1.04–2.05), more hypotension (1.68, 1.36–2.07) and less hypertension (0.60,
0.46–0.78). Postoperatively, remifentanil was associated with faster recovery (difference in
extubation time of )2.03, 9.5% CI, )2.92 to )1.14 min), more frequent postoperative
analgesic requirements (1.36, 1.21–1.53) and fewer respiratory events requiring naloxone (0.25,
0.14–0.47). Remifentanil had no overall impact on postoperative nausea (1.03, 0.97–1.09)
or vomiting (1.06, 0.96–1.17), but was associated with twice as much shivering (2.15, 1.7-
3–2.69). Remifentanil does not seem to offer any advantage for lengthy, major interventions,
but may be useful for selected patients, e.g. when postoperative respiratory depression is a
concern.
. ......................................................................................................
Correspondence to: C. C. Apfel
E-mail: apfel@ponv.org
Accepted: 20 April 2007

Remifentanil is the first ultra-short-acting opioid that can ful where rapid onset and offset of opioid effects are
be rapidly titrated for various levels of surgical stimuli desirable, as is typically the case in busy outpatient centres.
[1–5]. Relatively large doses can be administered, which As a result of the faster elimination characteristics of
assures deep intra-operative analgesia and stability of remifentanil, there should be fewer incidents of post-
intra-operative haemodynamics while permitting rapid operative nausea and vomiting and respiratory depression.
extubation and awakening at the end of the procedure. Conversely, patients treated with remifentanil might
Remifentanil differs from all other opioids in that it suffer from more postoperative pain in the immediate
possesses an ester linkage that allows predictable postoperative period. In addition, remifentanil can be
pharmacokinetics. Remifentanil may be particularly use- used at higher analgesic doses without concern for

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1266 Journal compilation  2007 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2007, 62, pages 1266–1280 R. Komatsu et al. Æ Remifentanil for general anaesthesia
. ....................................................................................................................................................................................................................

residual opioid effects. This might lead to concomitant only included if use of concomitant anaesthetic agents was
use of a lower dose of hypnotics, which could result in a either controlled for in the study design, or shown to be
higher incidence of intra-operative awareness than other equally distributed and thus similar between the study
opioids. groups.
Remifentanil has now been available for over 10 years. Our intra-operative endpoints were as follows:
Its unique pharmacokinetic characteristics have been • the number of patients who had intra-operative
demonstrated in published randomised controlled trials awareness with recall;
to be applicable for a wide range of patients. However, • the number of patients who experienced muscle
comparisons of remifentanil with conventional opioids, rigidity;
(i.e. fentanyl, alfentanil and sufentanil) have shown • the number of patients with hypertensive, hypotensive,
inconsistent results with respect to various outcomes. tachycardic, or bradycardic episodes during the entire
For example, Fortier et al. [6] reported less nausea with anaesthesia period;
remifentanil than with the comparator opioid, but Apfel • the number of patients who developed inadequate
et al. [7] did not find an overall difference between anaesthesia response (hypertension, tachycardia, soma-
remifentanil and fentanyl. Casati and colleagues [8] tic response, or autonomic response) during the entire
showed less frequent occurrence of respiratory depression anaesthesia period or at intubation, skin incision, skin
in the remifentanil group compared with another opioid, closure, or extubation;
but Joshi et al. [9] reported the opposite. Postoperative • the number of patients who required vasopressor,
rescue analgesic requirements were reported to be higher anticholinergic, or antihypertensive drugs during
in the remifentanil group by Ozkose et al. [10], but anaesthesia;
Derrode et al. [11] found no difference. • mean (SD) systolic blood pressure (SBP) and heart rate
In the face of controversial results for several outcomes, (HR) at induction, intubation, skin incision, skin
we conducted a systematic review to quantify the overall closure and extubation.
effects and to provide the best available evidence to Our postoperative outcomes were as follows:
evaluate intra- and postoperative efficacy and safety of • the number of patients who required postoperative
remifentanil in comparison with the other opioids rescue analgesics;
currently used as analgesic supplements during general • the number of patients who experienced nausea and
anaesthesia. vomiting;
• the number of patients who experienced shivering;
• the number of patients who had respiratory depression
Methods
(as defined by the authors of each article) or required
We included randomised controlled trials (RCTs) which naloxone administration;
compared remifentanil with fentanyl, alfentanil, or sufent- • the times from the end of surgery or anaesthesia to
anil. All opioids were given during general anaesthesia in extubation, to the patient being able to obey verbal
adult patients (18 years or more). Studies in which the command, to the initiation of spontaneous ventilation,
patients received general anaesthesia with tracheal intu- and to adequate ventilation.
bation or a laryngeal mask airway were included. Studies We searched systematically and without language
were excluded if remifentanil was used for sedation restrictions for relevant reports in MEDLINE, the index
during monitored anaesthesia care, or used as an adjuvant of the Institute for Scientific Indexing (ISI) and the
analgesic in conjunction with local anaesthetic technique Cochrane Library. We used the following search string,
without general anaesthesia. However, we included which looked for matches in either titles or abstracts:
studies in which rigid bronchoscopy or laryngoscopy ‘remifentanil [ti ⁄ ab] and ((fentanyl [ti ⁄ ab] OR alfentanil
was conducted under general anaesthesia without intu- [ti ⁄ ab] OR sufentanil [ti ⁄ ab]))’. A manual inspection was
bation. If remifentanil use extended into the postoperative subsequently performed through the reference lists of all
period, we only extracted the intra-operative data [11– studies in the search results until no further relevant
19]. Reports were excluded if remifentanil was used for references could be identified.
sedation and analgesia for patients in the intensive care Two authors (RK and AT) screened the retrieved
unit. Data from included trials were required to have reports and excluded irrelevant data. Each potentially
dichotomous outcomes, or mean and standard deviation relevant report was read by at least one other author
(SD) values for the investigated outcomes. If data were to assess adequacy of randomisation, blinding, and the
not presented in the text or table as numbers, we description of withdrawals, according to the validated
extracted the information from graphs if the scale allowed 3-item, 5-point Oxford scale [20]. We assigned one
a sufficiently precise estimation. Of note, studies were point to studies described as being ‘randomised’ and an

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Journal compilation  2007 The Association of Anaesthetists of Great Britain and Ireland 1267
 Table 1 Number of participants and relative risks of experiencing intra-operative outcomes

1268
Relative risk
No. of participants* or WMD§ p value for
No. of (n/N remifentanil (95% confidence statistical p value for
R. Komatsu et al.

Outcome with references studies n/N other opioids) interval) significance heterogeneity
Æ

Intra-operative awareness (recall) 20 3 ⁄ 4486 0.45 (0.15–1.33) 0.150 0.880

[7, 9, 10, 14, 19, 32, 54, 59, 62, 64, 73, 81, 83, 86, 87, 89, 91, 95, 101, 106] 8 ⁄ 4384
Rigidity [8, 23, 24, 27, 32, 33, 46, 57, 70, 73, 79, 81, 86, 87, 89, 95] 16 26 ⁄ 774 1.07 (0.65–1.75) 0.80 0.87
22 ⁄ 683
Inadequate anaesthesia: responses during entire anaesthesia period 0 253 ⁄ 530 0.65 (0.48–0.87) 0.004 < 0.001
[14, 19, 25, 28, 32, 73, 81, 86, 96] 382 ⁄ 530
Inadequate anaesthesia: response at intubation [18, 19, 27, 32, 47, 57, 59, 73, 79, 89, 95, 101] 12 209 ⁄ 883 0.79 (0.52–1.19) 0.250 < 0.001
213 ⁄ 753
Inadequate anaesthesia: response at skin incision [18, 19, 27, 32, 57, 59, 73, 79, 89, 95, 101] 11 97 ⁄ 870 0.44 (0.33–0.58) < 0.001 0.160
199 ⁄ 738
Inadequate anaesthesia: response at skin closure [19, 27, 32, 59, 79, 89, 101] 7 75 ⁄ 499 0.55 (0.43–0.70) < 0.001 0.450
Remifentanil for general anaesthesia

113 ⁄ 434
Hypertension, entire anaesthesia period 20 187 ⁄ 778 0.60 (0.46–0.78) 0.0002 0.007
[19, 21, 25, 35, 37, 46, 60, 62, 67, 71, 74, 75, 77, 81–83,86, 88, 93, 95] 314 ⁄ 801
Hypotension, entire anaesthesia period 27 458 ⁄ 2177 1.68 (1.36–2.07) < 0.001 0.006
[9, 14, 19, 21, 23–25,28, 32, 37, 60, 62, 64, 67, 71, 74, 75, 77, 83, 84, 86, 92, 95, 96, 99, 100, 106] 237 ⁄ 2162
Tachycardia [19, 21, 25, 60, 62, 67, 71, 77, 81–83,86, 95] 13 119 ⁄ 594 0.88 (0.66–1.16) 0.370 0.140
145 ⁄ 592
Bradycardia 22 95 ⁄ 791 1.46 (1.04–2.05) 0.030 0.290
[14, 21, 25, 32, 37, 46, 57, 60, 62, 64, 67, 69, 71, 75, 77, 83, 84, 86, 88, 93, 95, 100] 61 ⁄ 812
Vasopressor requirement 19 728 ⁄ 3015 1.40 (1.13–1.72) 0.002 0.030
[7, 14, 16, 21, 24, 25, 37, 45, 57, 60, 67, 71, 74, 75, 77, 84, 86, 93, 100] 489 ⁄ 3063
Anticholinergic requirement [14, 16, 21, 25, 37, 46, 57, 60, 71, 75, 84, 86, 88, 91, 100] 15 78 ⁄ 530 1.33 (0.99–1.79) 0.060 0.680
9 ⁄ 542
Antihypertensive requirement [22, 46, 50, 57, 71, 74, 77, 82, 88] 9 38 ⁄ 233 0.34 (0.19–0.62) 0.0004 0.900
5 ⁄ 236
Systolic blood pressure at induction; mmHg 19 1820 ⁄ 1832§ ) 5.21§ () 8.37 to ) 2.06) 0.001 < 0.001
[9, 18, 23, 27, 29, 31, 33, 52, 56, 57, 59, 60, 63, 64, 75, 80, 86, 91, 93]
Systolic blood pressure at intubation; mmHg 18 1816 ⁄ 1830§ ) 12.62§ () 18.19 to ) 7.05) < 0.001 < 0.001
[9, 18, 23, 27, 29, 31, 33, 44, 52, 56, 57, 59, 60, 63, 64, 75, 86, 93
Systolic blood pressure at skin incision; mmHg [9, 18, 27, 36, 52, 56, 57, 59] 8 1606 ⁄ 1598§ ) 12.67§ () 15.83 to ) 9.51) < 0.001 < 0.001
Systolic blood pressure at skin closure; mmHg [9, 27, 52] 3 1320 ⁄ 1310§ ) 15.65§ () 17.02 to ) 14.28) < 0.001 0.930
Systolic blood pressure at extubation; mmHg [36, 57, 82, 86] 4 132 ⁄ 134§ ) 1.17§ () 6.13–3.80) 0.650 < 0.001
Heart rate at induction; beats.min)1 [9, 10, 18, 23, 24, 27, 29, 31, 33, 45, 52, 56, 57, 59, 60, 63, 29 2093 ⁄ 2104§ ) 2.10§ () 3.94 to ) 0.26) 0.030 < 0.001
64, 66-68, 75, 77, 86, 88, 91, 93, 94, 102, 105]
Heart rate at intubation; beats.min)1 [9, 10, 18, 23, 24, 27, 29, 31, 33, 42, 45, 52, 56, 57, 59, 60, 32 2166 ⁄ 2178§ ) 5.49§ () 9.11 to ) 1.87) 0.003 < 0.001
62, 64–68,75, 77, 85, 86, 88, 93, 94, 101, 102, 105]
Heart rate at skin incision; beats.min)1 [9, 18, 27, 36, 42, 45, 52, 56, 57, 59, 62, 65, 85, 94, 101] 15 1752 ⁄ 1745§ ) 10.19§§ () 16.33 to ) 4.04) 0.001 < 0.001
Heart rate at skin closure; beats.min)1 [9, 27, 52, 94, 101] 5 1351 ⁄ 1341§ ) 8.77§ () 12.15 to ) 5.39) < 0.00001 < 0.001
Heart rate at extubation; beats.min)1 [36, 42, 45, 57, 62, 82, 86, 94] 8 206 ⁄ 208§ ) 1.58§ () 7.54–4.38) 0.600 < 0.001

*No. of participants: n refers to number of patients who developed the outcome; N refers to the number of patients included in the analysis.
§Total number of patients and mean weighted differences (remifentanil ⁄ other opioids) are given for systolic blood pressures and heart rates.
WMD, weighted mean difference.
Anaesthesia, 2007, 62, pages 1266–1280

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Journal compilation  2007 The Association of Anaesthetists of Great Britain and Ireland
. ....................................................................................................................................................................................................................
Anaesthesia, 2007, 62, pages 1266–1280 R. Komatsu et al. Æ Remifentanil for general anaesthesia
. ....................................................................................................................................................................................................................

Figure 1 Occurrence of recall of intra-operative awareness in remifentanil-treated and control opioid-treated patients.

additional point if the method of randomisation was minimum score of included trials was zero and the
described and considered adequate (e.g. table of random maximum score was five.
numbers, computer generated). In some studies a few Relevant data were extracted by one author and checked
initial patients received remifentanil per protocol while by another. For studies comparing remifentanil with two
not being randomised in the trial but the reported data other opioids (e.g. remifentanil vs alfentanil vs fentanyl),
contained both the randomised and these non-random- we divided the number of remifentanil patients by two for
ised initial patients. These trials were not excluded, but each comparison. For studies comparing several doses of
received zero points for randomisation even if the mode remifentanil with other opioids, we only included data
of randomisation was described. One point was assigned from the remifentanil group with the lowest dose. This
when the trial was described as ‘double blind’ and an method takes into account the fairly high potency of
additional point was assigned if the method of double remifentanil and minimises the chance that differences
blinding was described and adequate (e.g. syringes contain between the drugs are due to dosing. In studies having
study opioids prepared by a person not involved in data several doses of comparator opioids, we only included the
collection and volume of syringes and speed of drug comparator opioid dose nearest to the amount used by
administration were identical). We assessed blinding other studies included in this meta-analysis.
separately for the intra-operative and postoperative peri- As fentanyl, alfentanil and sufentanil differ in their
ods because there were studies in which intra-operative pharmacokinetic profile, comparisons were divided into
and postoperative investigators were different. Finally, three corresponding subgroups. Data extracted from the
reports that described the number of withdrawals and relevant studies were entered into REVMAN 4.2 (Review
reasons for withdrawals were given one point. Thus, the Manager, Cochrane Collaboration, UK) for analysis. For

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Journal compilation  2007 The Association of Anaesthetists of Great Britain and Ireland 1269
 R. Komatsu et al. Remifentanil for general anaesthesia Æ Anaesthesia, 2007, 62, pages 1266–1280
. ....................................................................................................................................................................................................................

heterogeneity

§Total number of patients and mean weighted differences (remifentanil ⁄ other opioids) are given for times (in min) to obey command, to extubation, to spontaneous ventilation, and to adequate ventilation.
dichotomous data, the relative risks (RR) and the
p value for corresponding 95% confidence intervals (CI) were cal-

0.005

0.001
0.001
0.001
0.001
culated. For continuous data, the weighted mean differ-

0.69

0.71

0.59

0.10

0.42
ences (WMD) and 95% CI were calculated. All data were

<
<
<
<
combined by means of the random effects model and
significance
p value for

they were checked for heterogeneity with Chi-squared

statistical

< 0.001

0.340

< 0.001

< 0.001

< 0.001
< 0.001
0.030
0.27 analysis. A p value < 0.05 was considered statistically

0.08

0.03
significant. If the combined outcome was significantly
heterogeneous, studies with point estimates outside two
(95% confidence interval)

times the 95% CI of the combined outcome of the other

) 1.45)
) 1.14)
) 0.08)
) 0.10)
Relative risk or WMD§

studies (outliers) were excluded.

to
to
to
to
1.36 (1.21–1.53)

1.03 (0.97–1.09)

1.06 (0.96–1.17)

2.15 (1.73–2.69)

0.32 (0.09–1.16)

0.25 (0.14–0.47)

3.57
2.92
1.80
2.58
Results
()
()
()
()
2.51§
2.03§
0.94§
1.34§

*No. of participants: n refers to number of patients who developed postoperative outcomes; N refers to the number of patients included in the analysis.
We identified 232 potential sources of data. We were able
to retrieve 220 articles, 104 of which met the inclusion
)
)
)
)

criteria [6–19, 21–106]. We eliminated 116 of the

No. of participants*

n/N other opioids)

retrieved studies for the following reasons: two were

(n/N remifentanil

review articles, 10 did not compare remifentanil with

1384 ⁄ 4821
1329 ⁄ 4724
609 ⁄ 1085

618 ⁄ 4784
579 ⁄ 4691
232 ⁄ 2784
104 ⁄ 2800

575 ⁄ 593§
563 ⁄ 587§
509 ⁄ 528§
255 ⁄ 276§
26 ⁄ 1807
6 ⁄ 1899

other opioids, nine were not randomised trials, 37 did

364 ⁄ 992

10 ⁄ 570
79 ⁄ 484

not have relevant data or had data that could not be

extrapolated from the published graphs, five did not
mention the number of patients per group, 11 did not use
included

general anaesthesia, 10 included data from children (age

Studies

less than 18 years) and 20 used different anaesthetics in the

30

32

29

14

15

14

19
21
15
6
Table 2 Number of participants and relative risks of experiencing postooperative outcomes.

remifentanil and comparator group. Of the 12 sources

that could not be retrieved by interlibrary loan from the
extubation; min [8, 10, 22, 25, 26, 37, 41, 51, 55, 57, 62, 64, 65, 71, 74, 82, 85, 92, 100, 103, 105]
Postoperative analgesic [6, 10, 11, 25, 26, 36, 39, 40, 43, 45, 46, 51, 52 54, 57, 59, 61, 62, 64, 71, 73, 74,

University of Louisville, five were abstracts for annual

Nausea [6–9,11, 21, 25–27,30, 32, 33, 37, 40, 43, 51, 52, 59, 61, 62, 65, 73, 74, 79, 81, 86, 88, 89, 100,

obey command; min [8, 10, 21, 22, 25, 26, 37, 39, 43, 51, 55, 57, 62, 74, 81, 84, 85, 92, 103]
Vomiting [6, 7, 9, 11, 21, 25–27,30, 32, 37, 40, 43, 51, 52, 59, 61, 62, 65, 73, 74, 79, 81, 86, 88, 89,

meetings and seven were non-English papers in journals

spontaneous ventilation; min [21, 25, 26, 37, 41, 51, 55, 62, 64, 71, 81, 82, 84, 85, 103]

of low circulation [106–118]. Of the 104 articles that

could both be retrieved and that met inclusion criteria, 19
were found to contain duplicated data (i.e. the same data
were reported in more than one publication) and were
Respiratory depression [8, 9, 11, 23, 27, 32, 33, 50, 51, 62, 64, 79, 81, 89, 106]

thus not included in the analysis [12, 15–17, 33, 38, 48,
Naloxone requirement [8, 22, 25, 32, 33, 36, 52, 57, 59, 88, 89, 100, 104, 106]

49, 53, 58, 72, 76, 78, 90, 98, 119–122]. The remaining
85 trials reported data from 13 057 patients; 6621
received remifentanil and of the remaining 6436, 17%
received alfentanil, 80% received fentanyl and 3%
Shivering [7, 22, 26, 32, 40, 46, 47, 50, 55, 64, 88, 92, 97, 105]

received sufentanil (a table of detailed study characteristics

adequate ventilation; min [25, 37, 51, 62, 64, 81]

is available in Supplementary Table S1) The median

number of patients per trial was 53 (range 18–4789). The
median Oxford scale for the trials was 3 (range 1–5) for
both the intra-operative and postoperative periods.
The majority of the studies included in this meta-
WMD, weighted mean difference.

analysis were simple comparisons between patients receiv-

79, 81, 88, 89, 94, 96, 104, 106]

ing remifentanil or one other opioid. However, several

studies had three or more comparator groups. For these
Postoperative outcomes

studies, we chose which groups to include in our meta-

analysis on a case-by-case basis (see www.ponv.org).
101, 105, 106]

100, 101, 105]

Among the studies included in this analysis, the

cumulative occurrence of rigidity was approximately 3%
to
to
to
to

for both remifentanil and other opioids [8, 23, 24, 27, 32,
Time
Time
Time
Time

33, 57, 70, 73, 79, 81, 86, 87, 89, 95, 100]. When a dose

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1270 Journal compilation  2007 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2007, 62, pages 1266–1280 R. Komatsu et al. Æ Remifentanil for general anaesthesia
. ....................................................................................................................................................................................................................

Figure 2 Postoperative rescue analgesia requirement in remifentanil-treated and control opioid-treated patients.

of 1 lg.kg)1 or more of remifentanil was administered (RR ¼ 1.40), lower heart rates (WMD between 2 and 10
over 30–60 s during induction of anaesthesia [8, 23, 24, beats.min)1), more bradycardia (RR ¼ 1.46) and higher
32, 33, 57, 70, 73, 79, 87, 89, 95, 100], cumulative use of anticholinergics (R ¼ 1.33) (Table 1). Differences
occurrence of rigidity was not significantly higher (3.5%) were statistically significant for 13 of the 16 haemo-
than when it was administered at slower rates (2.9%) [27, dynamic endpoints but 10 of these 13 endpoints were
81, 86]. Accordingly, in the dose range of the included heterogeneous, i.e. there were statistically significant
studies, remifentanil did not cause a clinically significant differences between the observed differences across the
increase in rigidity compared with the other opioids, even studies. In the majority of cases, the significance of the
when a bolus dose was employed. effect and the heterogeneity across the studies persisted
Remifentanil was generally associated with lower blood when outliers were removed (data not shown).
pressures (WMD between ) 5 and 15 mmHg), more These results are consistent with significantly fewer
hypotension (RR ¼ 1.68), greater use of vasopressors signs of inadequate anaesthesia during the entire anaes-

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Journal compilation  2007 The Association of Anaesthetists of Great Britain and Ireland 1271
R. Komatsu et al. Æ Remifentanil for general anaesthesia Anaesthesia, 2007, 62, pages 1266–1280
. ....................................................................................................................................................................................................................

Figure 3 Requirement of naloxone reversal of residual opioid effect in remifentanil-treated and control opioid-treated patients.

thesia period (RR ¼ 0.65). In addition, intra-operative The number of patients who experienced nausea
awareness with recall appeared less frequently after a (Fig. 4) or vomiting (data not shown) in the remifent-
general anaesthesia with remifentanil (3 ⁄ 4486) than after anil-treated group did not differ from the number of
the use of conventional opioids (8 ⁄ 4384, Table 1 and patients in the other groups. Post-operative shivering
Fig. 1), although the relative risk of 0.45 (95% CI 0.15– occurred more frequently in the patients given remifent-
1.33) did not reach statistical significance (p ¼ 0.15). The anil (Fig. 5).
number of patients who experienced muscle rigidity did
not differ between the groups (Table 1).
Discussion
Not surprisingly, the times between the end of surgery
or anaesthesia to obeying a command, to extubation, to Remifentanil was associated with signs of deep intra-
initiation of spontaneous ventilation and to adequate operative analgesia and anaesthesia, but also with faster
spontaneous ventilation were all significantly less in the postoperative recovery and less respiratory depression. It
remifentanil-treated patients than in the other opioid- was also associated with higher postoperative analgesic
treated patients (Table 2). requirements and more shivering, but had no effect on
Patients receiving remifentanil required rescue analge- postoperative nausea and vomiting. These outcomes
sics about 1.36 times more often than did other opioid- suggest that remifentanil might be most favourably used
treated patients (Fig. 2). This difference was more for short outpatient procedures that are unlikely to
pronounced in studies where the need for rescue require more extensive postoperative pain relief.
analgesics in the comparator group was low. Despite the Egan et al. reported that high doses of remifentanil
larger doses for postoperative opioids, postoperative administered over a short period of time may be
respiratory depression appeared to occur less frequently associated with thorax ⁄ truncal rigidity, rendering face-
(RR ¼ 0.32), but did not reach statistical significance mask ventilation during induction difficult or imposs-
(p ¼ 0.08). However, naloxone requirements were sig- ible [123]. Furthermore, it is known that in rats a dose-
nificantly less in remifentanil than in other opioid-treated dependent activation of central l-receptors by opioids
patients (RR ¼ 0.25, p < 0.001; Fig. 3). can cause muscle rigidity [124]. However, recent

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1272 Journal compilation  2007 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2007, 62, pages 1266–1280 R. Komatsu et al. Æ Remifentanil for general anaesthesia
. ....................................................................................................................................................................................................................

Figure 4 Overall postoperative nausea in remifentanil-treated and control opioid-treated patients.

evidence suggests the difficult facemask ventilation that clinical trials significantly influences the incidence of
can occur during induction of anaesthesia with high rigidity.
doses of opioids over a short period of time is likely to Patients treated with remifentanil had lower heart rate
be due to vocal cord closure, thus questioning the role and blood pressure, possibly due to stronger intra-
of thorax ⁄ truncal rigidity [125]. The studies included in operative analgesia causing a decreased sympathetic and
this meta-analysis considered both pre-operative and increased vagal tone. As the clinical requirements for the
intra-operative muscle rigidity, even though none of maintenance of anaesthesia with hypnotic drugs (volatile
the studies specified how rigidity was measured. Hence, anaesthetics or propofol) are generally titrated to heart
the reported occurrence of muscle rigidity for both rate and blood pressure, patients receiving remifentanil
remifentanil and the other opioids might be interpreted were more likely to be titrated to lower hypnotic doses
as the combined occurrences of vocal cord closure than those treated with other opioids [9, 10, 25, 83,
and ⁄ or chest wall rigidity. Even so, the analysis of 86, 89]. One could therefore hypothesise that patients
rigidity as an outcome fails to demonstrate that the receiving remifentanil were at a theoretically higher risk
dose and rate of remifentanil as used in the published for intra-operative awareness. However, our analysis

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Journal compilation  2007 The Association of Anaesthetists of Great Britain and Ireland 1273
R. Komatsu et al. Æ Remifentanil for general anaesthesia Anaesthesia, 2007, 62, pages 1266–1280
. ....................................................................................................................................................................................................................

Figure 5 Occurrence of postoperative shivering in remifentanil-treated and control opioid-treated patients

found about half as many patients had recall for longer acting opioids required rescue analgesics. The
intra-operative awareness in the remifentanil group properties of intra-operative opioids might therefore have
(3 ⁄ 4486) than in the other opioid groups (8 ⁄ 4384), little influence on the requirement for rescue analgesics in
although this result was not statistically significant (p ¼ the presence of severe postoperative pain.
0.15). Thus, remifentanil is not associated with an Not surprisingly, patients receiving remifentanil
increased incidence of awareness. required more postoperative opioids. However, there
Patients receiving remifentanil required additional was no statistically significant difference in the incidence
postoperative analgesics about 40% more frequently than of respiratory depression. Moreover, the need for nalox-
patients receiving one of the other opioids. This differ- one to reverse opioid-related side-effects was significantly
ence appears to be smaller in patients with a high reduced in the remifentanil group. Thus, remifentanil
postoperative analgesics requirement [11, 62, 73, 94], might be useful where opioid-induced respiratory depres-
and larger in patients with low postoperative analgesic sion is a concern.
requirement [10, 25, 39, 51, 57, 61, 88]. Most of the In 2004, Apfel et al. were the first to report that
latter studies [10, 25, 57, 61, 88] involved minor surgical remifentanil is associated with an increased incidence of
procedures that were less likely to cause severe post- postanaesthetic shivering [7]. The results from this meta-
operative pain. The reason for the larger discrepancy in analysis are consistent with this previous observation, even
postoperative rescue analgesic requirements between when the data from Apfel et al. are removed from the
remifentanil and control opioids in these less stimulating analysis. One of three possible explanations (or a combi-
procedures is unknown. However, there are several nation of the three) may account for this outcome. Firstly,
possible explanations: patients receiving remifentanil the unique kinetics of remifentanil should be considered.
develop acute opioid tolerance, the control opioids have Opioids inhibit thermoregulatory responses, including
longer acting postoperative residual effects, or remifent- shivering. Therefore, at a given level of postoperative
anil causes hyperalgesia [126]. In contrast, when post- hypothermia, the ability of patients to shiver may be less
operative pain is severe, even those patients who received blunted and occur sooner in those given remifentanil

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1274 Journal compilation  2007 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2007, 62, pages 1266–1280 R. Komatsu et al. Æ Remifentanil for general anaesthesia
. ....................................................................................................................................................................................................................

because it is eliminated faster than other opioids. The was associated with significantly more shivering, but no
second possibility is that shivering in remifentanil-treated difference in the incidence of PONV.
patients is non-thermoregulatory, and is mediated instead Taking all these findings together, remifentanil does not
by pain [127]. Remifentanil dissipates quickly after surgery seem to offer any advantage for lengthy, major interven-
and thus leaves patients in more pain relative to those tions, but might be quite useful for patients deemed to be
receiving other opioids [10, 25, 58, 88]. The third at risk for intra-operative awareness obstructive sleep
possibility is that shivering is a sign of opioid withdrawal apnoea, or for patients where early ambulation is desirable.
caused by acute tolerance. Acute opioid tolerance develops
faster in response to short-acting narcotics [128, 129].
Acknowledgements
Volunteers can show tolerance after only 60–90 min of
remifentanil infusion [130]. Remifentanil, more than other This study was supported by the Department of Anaes-
opioids, may be associated with acute tolerance, and thus thesia and the Outcomes Research Institute, University
might result in withdrawal shivering. Whatever the of Louisville, and the Department of Anaesthesia and
cause, intra-operative warming (unless contra-indicated) Perioperative Care, University of California, San
and adequate application of postoperative analgesics may Francisco, CA. The authors would like to thank
be especially important when remifentanil is used for Dorothea Rosenberger, M.D., University of Louisville,
maintenance of analgesia. for her translations of German and Italian manuscripts,
Because remifentanil has a faster elimination than other and Julia Meierhofer, Nancy Alsip, Ph.D., and Roxanne
opioids, it is reasonable to assume that its use will be Rapan, MD, MPH, for editorial assistance. Special thanks
associated with reduced opioid-related side-effects such as also to Dr Sessler for his contribution about the
postoperative nausea and vomiting (PONV). Remifent- mechanisms for shivering.
anil also reduces the requirements for intra-operative
volatile anaesthetics, which are a major cause of PONV
References
[131]. However, the occurrences of nausea and vomiting
in our analysis were similar for patients receiving 1 Egan TD. Remifentanil pharmacokinetics and pharmaco-
remifentanil and other opioids. Perhaps potential advan- dynamics. A preliminary appraisal. Clinical Pharmacokinetics
tages of remifentanil in this regard may be limited 1995; 29: 80–94.
whenever its intra-operative use results in higher require- 2 Glass PS. Remifentanil: a new opioid. Journal of Clinical
Anesthesia 1995; 7: 558–63.
ment for postoperative analgesic dosing. Nevertheless, for
3 Patel SS, Spencer CM. Remifentanil. Drugs 1996; 52: 417–
short outpatient procedures requiring no postoperative
27.
opioids, the use of remifentanil might have an advantage 4 Rosow CE. An overview of remifentanil. Anesthesia and
that has yet to be demonstrated. Analgesia 1999; 89: S1–3.
The direct measure of time to discharge could not be 5 Servin F. Remifentanil: when and how to use it. European
analysed in this meta-analysis, as it was rarely reported in Journal of Anaesthesiology 1997; 15: 41–4.
the sources. However, times to obeying a command, to 6 Fortier J, Chung F, Moote C, et al. Remifentanil vs alf-
extubation, to initiation of spontaneous ventilation and to entanil for ambulatory surgery using preoperative napr-
adequate ventilation could be analysed, and were shorter oxen-NA for pain management. Annual Meeting American
in remifentanil-treated patients than in other opioid- Society of Anesthesiologists. San Diego, California: Lippin-
treated patients. Although other factors also influence time cott-Raven, 1997.
7 Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of
to discharge, these differences, especially faster extubation
six interventions for the prevention of postoperative nausea
time, could well translate into a clinically relevant earlier
and vomiting. New England Journal of Medicine 2004; 350:
recovery time and home-readiness for remifentanil- 2441–51.
treated patients, and could reduce the subsequent work- 8 Casati A, Albertin A, Danelli G, et al. Implementing
load of postoperative care unit personnel. sevoflurane anesthesia with small doses opioid for upper
In conclusion, the administration of remifentanil was abdominal surgery. Postoperative respiratory function after
associated with signs of deep intra-operative analgesia and either remifentanil or fentanyl. Minerva Anestesiologica 2001;
anaesthesia such as lower blood pressures and heart rates, 67: 621–8.
as well as less hypertension and tachycardia in response 9 Joshi GP, Warner DS, Twersky RS, Fleisher LA.
to stimulation. Recovery is generally faster, with less A comparison of the remifentanil and fentanyl adverse
respiratory depression and need for naloxone reversal. effect profile in a multicenter phase IV study. Journal of
Clinical Anesthesia 2002; 14: 494–9.
However, remifentanil is associated with a higher need
10 Ozkose Z, Yalcin Cok O, Tuncer B, Tufekcioglu S,
for postoperative analgesic dosing. In addition, this
Yardim S. Comparison of hemodynamics, recovery
analysis confirmed our previous results that remifentanil

 2007 The Authors

Journal compilation  2007 The Association of Anaesthetists of Great Britain and Ireland 1275
R. Komatsu et al. Æ Remifentanil for general anaesthesia
. ....................................................................................................................................................................................................................
profile, and early postoperative pain control and costs of
remifentanil versus alfentanil-based total intravenous
anesthesia (TIVA). Journal of Clinical Anesthesia 2002; 14:
161–8.
11 Derrode N, Lebrun F, Levron JC, Chauvin M, Debaene
B. Influence of perioperative opioid on postoperative pain
after major abdominal surgery: sufentanil TCI versus
remifentanil TCI. A randomized, controlled study. British
Journal of Anaesthesia 2003; 91: 842–9.
12 Cheng DC, Newman MF, Duke P, Finegan BA, Bukenya
D. A prospective randomized, double-blind controlled trial
of remifentanil and fentanyl in fast track CABG surgery:
efficacy and resource utilization. Anesthesiology 1999; 91:
A142.
13 Cheng DC, Newman MF, Duke P, et al. The efficacy and
resource utilization of remifentanil and fentanyl in fast-
track coronary artery bypass graft surgery: a prospective
randomized, double-blinded, controlled multi-center trial.
Anesthesia and Analgesia 2001; 92: 1094–102.
14 Heijmans JH, Maessen JG, Roekaerts PM. Remifentanil
provides better protection against noxious stimuli during
cardiac surgery than alfentanil. European Journal of Anaes-
thesiology 2004; 21: 612–8.
15 Hillel Z, Howie M, Hogue C, et al. A multicenter trial
comparing the safety and efficacy of remifentanil and
fentanyl in elective CABG surgery patients. Anesthesia and
Analgesia 1999; 88 (4S): p76SCA.
16 Howie MB, Cheng D, Newman MF, et al. A randomized
double-blinded multicenter comparison of remifentanil
versus fentanyl when combined with isoflurane ⁄ propofol
for early extubation in coronary artery bypass graft surgery.
Anesthesia and Analgesia 2001; 92: 1084–93.
17 Mollhoff T, Herregods L, Blake D, MacAdams C, Kirk-
ham A. Remifentanil versus fentanyl in patients undergo-
ing CABG surgery. Anesthesiology 1999; 91: A144.
18 Mollhoff T, Herregods L, Moerman A, et al. Comparative
efficacy and safety of remifentanil and fentanyl in ‘fast track’
coronary artery bypass graft surgery: a randomized, double-
blind study. British Journal of Anaesthesia 2001; 87: 718–26.
19 Sneyd JR, Camu F, Doenicke A, et al. Remifentanil and
fentanyl during anaesthesia for major abdominal and
gynaecological surgery. An open, comparative study of
safety and efficacy. European Journal of Anaesthesiology 2001;
18: 605–14.
20 Jadad AR, Moore RA, Carroll D, et al. Assessing the
quality of reports of randomized clinical trials: is blinding
necessary? Controlled Clinical Trials 1996; 17: 1–12.
21 Agnew NM, Tan NH, Scawn ND, Pennefather SH,
Russell GN. Choice of opioid supplementation for day-
case rigid bronchoscopy: a randomized placebo-controlled
comparison of a bolus of remifentanil and alfentanil. Journal
of Cardiothoracic and Vascular Anesthesia 2003; 17: 336–40.
22 Ahonen J, Olkkola KT, Verkkala K, Heikkinen L, Jarvinen
A, Salmenpera M. A comparison of remifentanil and alf-
entanil for use with propofol in patients undergoing min-
imally invasive coronary artery bypass surgery. Anesthesia
and Analgesia 2000; 90: 1269–74.
1276
Anaesthesia, 2007, 62, pages 1266–1280
23 Albertin A, Casati A, Deni F, et al. Clinical comparison of
either small doses of fentanyl or remifentanil for blunting
cardiovascular changes induced by tracheal intubation.
Minerva Anestesiologica 2000; 66: 691–6.
24 Alexander Royal, Booth J, Olufolabi AJ, El-Moalem HE,
Glass PS. Comparison of remifentanil with alfentanil or
suxamethonium following propofol anaesthesia for tracheal
intubation. Anaesthesia 1999; 54: 1032–6.
25 Alper I, Erhan E, Ugur G, Ozyar B. Remifentanil versus
alfentanil in total intravenous anaesthesia for day case
surgery. European Journal of Anaesthesiology 2003; 20:
61–4.
26 Apitzsch H, Olthoff D, Thieme V, Wiegel M, Bohne V,
Vetter B. [Remifentanil and alfentanil: Sympathetic-
adrenergic effect in the first postoperative phase in patients
at cardiovascular risk]. Anaesthesist 1999; 48: 301–9.
27 Balakrishnan G, Raudzens P, Samra SK, et al. A compar-
ison of remifentanil and fentanyl in patients undergoing
surgery for intracranial mass lesions. Anesthesia and Analgesia
2000; 91: 163–9.
28 Beers RA, Calimlim JR, Uddoh E, Esposito BF,
Camporesi EM. A comparison of the cost-effectiveness of
remifentanil versus fentanyl as an adjuvant to general an-
esthesia for outpatient gynecologic surgery. Anesthesia and
Analgesia 2000; 91: 1420–5.
29 Bekker AY, Berklayd P, Osborn I, Bloom M, Yarmush J,
Turndorf H. The recovery of cognitive function after
remifentanil-nitrous oxide anesthesia is faster than after an
isoflurane-nitrous oxide-fentanyl combination in elderly
patients. Anesthesia and Analgesia 2000; 91: 117–22.
30 Brockmann C, Raasch W, Bastian C. [Endocrine stress
parameters during TIVA with remifentanil or sufentanil].
AINS (Anästhesiologie, Intensivmedizin, Notfallmedizin,
Schmerztherapie) 2000; 35: 685–91.
31 Cafiero T, Mastronardi P, Burrelli Royal, Santoro Royal.
[The effects of remifentanil on hemodynamic response to
intubation. A comparative study with fentanyl]. Minerva
Anestesiologica 2000; 66: 793–7.
32 Cartwright DP, Kvalsvik O, Cassuto J, et al. A random-
ized, blind comparison of remifentanil and alfentanil during
anesthesia for outpatient surgery. Anesthesia and Analgesia
1997; 85: 1014–9.
33 Casati A, Albertin A, Fanelli G, et al. A comparison of
remifentanil and sufentanil as adjuvants during sevoflurane
anesthesia with epidural analgesia for upper abdominal
surgery: effects on postoperative recovery and respiratory
function. Anesthesia and Analgesia 2000; 91: 1269–73.
34 Casati A, Fanelli G, Albertin A, et al. Small doses of
remifentanil or sufentanil for blunting cardiovascular
changes induced by tracheal intubation: a double-blind
comparison. European Journal of Anaesthesiology 2001; 18:
108–12.
35 Chamizo A, Roige J, Mora A, Cortes C, Pellejero JA,
Gancedo VA. Comparative study of two total intravenous
anaesthesia techniques with propofol and remifentanil or
fentanyl for thyroidectomy. European Journal of Anaesthesi-
ology 2001; 18 (Suppl. 21): 98–9.
 2007 The Authors
Journal compilation  2007 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2007, 62, pages 1266–1280 R. Komatsu et al. Æ Remifentanil for general anaesthesia
. ....................................................................................................................................................................................................................

36 Chillemi S, Sinardi D, Marino A, Mantarro G, Campisi entanil- and fentanyl-based anesthesia? Journal of Clinical
Royal. The use of remifentanil for bloodless surgical field Anesthesia 2001; 13: 401–6.
during vertebral disc resection. Minerva Anestesiologica 2002; 50 Gargiulo G, Cafiero T, Frangiosa A, et al. Remifentanil for
68: 645–9. intraoperative analgesia during the endoscopic surgical
37 Chinachoti T, Werawatganon T, Suksompong S, et al. treatment of pituitary lesions. Minerva Anestesiologica 2003;
A multicenter randomized double-blind comparison of 69 (119–23): 24–6.
remifentanil and alfentanil during total intravenous 51 Gaszynski TM, Strzelczyk JM, Gaszynski WP. Post-
anaesthesia for out-patient laparoscopic gynaecological anesthesia recovery after infusion of propofol with remif-
procedures. Journal of the Medical Association of Thailand entanil or alfentanil or fentanyl in morbidly obese patients.
2000; 83: 1324–32. Obesity Surgery 2004; 14: 498–503; discussion 4.
38 Coles JP, Leary TS, Monteiro J, et al. Comparison of 52 Gelb AW, Salevsky F, Chung F, et al. Remifentanil with
remifentanil, alfentanil and fentanyl during craniotomy. morphine transitional analgesia shortens neurological
British Journal of Anaesthesia 1999; 82: 453P. recovery compared to fentanyl for supratentorial
39 Coles JP, Leary TS, Monteiro JN, et al. Propofol craniotomy. Canadian Journal of Anaesthesia 2003; 50:
anesthesia for craniotomy: a double-blind comparison of 946–52.
remifentanil, alfentanil, and fentanyl. Journal of Neurosurgical 53 Gelb AW, Salevsky FC, Chung FF, Archer DP, Ringaert
Anesthesiology 2000; 12: 15–20. KR, Manninen PH. The canadian craniotomy remifentanil
40 Crozier TA, Kietzmann D, Dobereiner B. Mood change trial - a strategy to prevent immediate postoperative pain.
after anaesthesia with remifentanil or alfentanil. European Anesthesia and Analgesia 2001; 92: S176.
Journal of Anaesthesiology 2004; 21: 20–4. 54 Gerlach K, Uhlig T, Huppe M, et al. Remifentanil-
41 Dassonville JM, Binje B, Dieu P, et al. Remifentanility propofol versus sufentanil-propofol anaesthesia for supra-
versus Fentanyl Associe au Propofological en Aivoc dans tentorial craniotomy: a randomized trial. European Journal of
la Chirurgie Carotidienne. Annales Françaises d’Anesthèsie Anaesthesiology 2003; 20: 813–20.
et de Rèanimation 2000; 19 (Suppl. 1): 75s. 55 Grottke O, Dietrich PJ, Wiegels S, Wappler F. Intrao-
42 Demirbilek S, Ganidagli S, Aksoy N, Becerik C, Baysal Z. perative wake-up test and postoperative emergence in
The effects of remifentanil and alfentanil-based total patients undergoing spinal surgery: a comparison of
intravenous anesthesia (TIVA) on the endocrine response intravenous and inhaled anesthetic techniques using
to abdominal hysterectomy. Journal of Clinical Anesthesia short-acting anesthetics. Anesthesia and Analgesia 2004;
2004; 16: 358–63. 99: 1521–7.
43 Dershwitz M, Michalowski P, Chang Y, Rosow CE, 56 Gunduz M, Gunes Y, Ozcengiz D, et al. Anesthetic
Conlay LA. Postoperative nausea and vomiting after total techniques for neurosurgery – Comparison of desflurane-
intravenous anesthesia with propofol and remifentanil or remifentanil and desflurane-fentanyl in patients undergoing
alfentanil. How important is the opioid? Journal of Clinical surgery for intracranial procedures. Neurosurgery Quarterly
Anesthesia 2002; 14: 275–8. 2004; 14: 204–8.
44 DeWinter G, Guerrero S, Mouren S, Baillard C, Bertrand 57 Guo X, Yi JYeT, Luo A, Huang Y, Ren H. Comparison
M, Coriat P. Hemodynamic stability during remifentanil of remifentanil and fentanyl in patients undergoing modi-
or sufentanil anaesthesia in patients undergoing carotid fied radical mastectomy or total hysterectomy. Chinese
endarterectomy (CE). British Journal of Anaesthesia 1999; 82 Medical Journal 2003; 116: 1386–90.
(Suppl. 1): 46–7. 58 Guo XY, Yi J, Yie TH, Luo AL, Ren HZ, Huang YG.
45 Doyle PW, Coles JP, Leary TM, Brazier P, Gupta AK. [Remifentanil for intraoperative anesthesia]. Zhongguo Yi
A comparison of remifentanil and fentanyl in patients Xue Ke Xue Yuan Xue Bao 2004; 26: 66–9.
undergoing carotid endarterectomy. European Journal of 59 Guy J, Hindman BJ, Baker KZ, et al. Comparison of
Anaesthesiology 2001; 18: 13–9. remifentanil and fentanyl in patients undergoing cranio-
46 Erhan E, Ugur G, Alper I, Gunusen I, Ozyar B. Tracheal tomy for supratentorial space-occupying lesions. Anesthes-
intubation without muscle relaxants: remifentanil or alf- iology 1997; 86: 514–24.
entanil in combination with propofol. European Journal of 60 Habib AS, Parker JL, Maguire AM, Rowbotham DJ,
Anaesthesiology 2003; 20: 37–43. Thompson JP. Effects of remifentanil and alfentanil on the
47 Facco E, Baratto F, Behr AU, et al. Remifentanil versus cardiovascular responses to induction of anaesthesia and
fentanyl in the surgery of lumbar spine: a double blind tracheal intubation in the elderly. British Journal of Anaes-
randomized study. Preliminary report. British Journal of thesia 2002; 88: 430–3.
Anaesthesia 1999; 82 (Suppl. 1): 119–20. 61 Heidvall M, Hein A, Davidson S, Jakobsson J. Cost
48 Fleisher LA, Glass PSA, Roizen MA, et al. Remifentanil comparison between three different general anaesthetic
provides superior hemodynamics and faster time to extu- techniques for elective arthroscopy of the knee. Acta
bation than a fentanyl based anesthetic in a large scale trial Anaesthesiologica Scandinavica 2000; 44: 157–62.
of effectiveness. Anesthesiology 1998; 89: A33. 62 Horrichs-Haermeyer G, Stute P, Reif H, Soukup J,
49 Fleisher LA, Hogue S, Colopy M, et al. Does functional Sabatowski Royal, Grand S. Cognitive function and
ability in the postoperative period differ between remif- reaction time after remifentanil-propofol or fentanyl-

 2007 The Authors

Journal compilation  2007 The Association of Anaesthetists of Great Britain and Ireland 1277
R. Komatsu et al. Æ Remifentanil for general anaesthesia
. ....................................................................................................................................................................................................................
propofol anaesthesia for gynaecological laparoscopy.
Anästhesiologie and Intensivmedmedizin 2002; 43: 517–23.
63 Iannuzzi E, Iannuzzi M, Cirillo V, et al. Peri-intubation
cardiovascular response during low dose remifentanil or
sufentanil administration in association with propofol TCI.
A double blind comparison. Minerva Anestesiologica 2004;
70: 109–15.
64 Iannuzzi E, Iannuzzi M, Cirillo V, Viola G, Parisi Royal,
Chiefari M. Small doses of remifentanil and alfetanil in
continuous total intravenous anesthesia in major abdominal
surgery. A double blind comparison. Minerva Anestesiologica
2003; 69: 33–6.
65 Jellish WS, Leonetti JP, Avramov A, Fluder E, Murdoch J.
Remifentanil-based anesthesia versus a propofol technique
for otologic surgical procedures. Otolaryngology – Head and
Neck Surgery 2000; 122: 222–7.
66 Jellish WS, Sheikh T, Baker WH, Louie EK, Slogoff S.
Hemodynamic stability, myocardial ischemia, and peri-
operative outcome after carotid surgery with remifenta-
nil ⁄ propofol or isoflurane ⁄ fentanyl anesthesia. Journal of
Neurosurgical Anesthesiology 2003; 15: 176–84.
67 Joo HS, Salasidis GC, Kataoka MT, et al. Comparison of
bolus remifentanil versus bolus fentanyl for induction of
anesthesia and tracheal intubation in patients with cardiac
disease. Journal of Cardiothoracic and Vascular Anesthesia 2004;
18: 263–8.
68 Juckenhofel S, Feisel C, Schmitt HJ, Biedler A. [TIVA
with propofol-remifentanil or balanced anesthesia with
sevoflurane-fentanyl in laparoscopic operations. Hemo-
dynamics, awakening and adverse effects]. Anaesthesist
1999; 48: 807–12.
69 Karousos D, Lambadariou K, Ntoka P, et al. Pharmaco-
dynamics of remifentanil and fentanyl in carotid endar-
terectomy. European Journal of Anaesthesiology 2000; 17
(Suppl. 19): 43.
70 Klemola UM, Mennander S, Saarnivaara L. Tracheal
intubation without the use of muscle relaxants: remifent-
anil or alfentanil in combination with propofol. Acta
Anaesthesiologica Scandinavica 2000; 44: 465–9.
71 Kostopanagiotou G, Markantonis SL, Polydorou M,
Pandazi A, Kottis G. Recovery and cognitive function
after fentanyl or remifentanil administration for carotid
endarterectomy. Journal of Clinical Anesthesia 2005; 17: 16–
20.
72 Kovac A, Azad S, Batenhorst Royal, Steer P, McNeal S.
Remifentanil versus alfentanil balanced anesthesia for total
abdominal hysterectomy. Anesthesiology 1995; 83: A383.
73 Kovac AL, Azad SS, Steer P, Witkowski T, Batenhorst
Royal, McNeal S. Remifentanil versus alfentanil in a bal-
anced anesthetic technique for total abdominal hysterec-
tomy. Journal of Clinical Anesthesia 1997; 9: 532–41.
74 Lentschener C, Ghimouz A, Bonnichon P, Pepion C,
Gomola A, Ozier Y. Remifentanil-propofol vs. sufentanil-
propofol: optimal combinations in clinical anesthesia. Acta
Anaesthesiologica Scandinavica 2003; 47: 84–9.
75 Maguire AM, Kumar N, Parker JL, Rowbotham DJ,
Thompson JP. Comparison of effects of remifentanil and
1278
Anaesthesia, 2007, 62, pages 1266–1280
alfentanil on cardiovascular response to tracheal intubation
in hypertensive patients. British Journal of Anaesthesia 2001;
86: 90–3.
76 Maguire AM, Thompson JP, Kumar N, Rowbotham DJ.
Comparison of the effects of remifentanil and alfentanil on
the cardiovascular response to orotracheal intubation in
treated hypertensive patients. British Journal of Anaesthesia
2000; 84: 286p.
77 Mekis D, Kamenik M. A randomised controlled trial
comparing remifentanil and fentanyl for induction of
anaesthesia in CABG surgery. Wiener Klinische Wochenschrift
2004; 116: 484–8.
78 Michalowski P, Dershwitz M, Rosow CE, Conlay LA,
Chang Y. Total intravenous anesthesia with remifentanil or
alfentanil in ambulatory orthopedic surgery carries minimal
risk of postoperative nausea and vomiting. Anesthesiology
1998; 89: A34.
79 Minkowitz HS. Postoperative pain management in patients
undergoing major surgery after remifentanil vs. fentanyl
anesthesia. Multicentre Investigator Group Canadian Journal of
Anaesthesia 2000; 47: 522–8.
80 Monk TG, Batenhorst RL, Folger WH, et al. A compar-
ison of remifentanil and alfentanil during nitrous-narcotic
anesthesia. Anesthesia and Analgesia 1994; 78: S293.
81 Mortensen CR, Larsen B, Petersen JA, et al. Remifentanil
vs. alfentanil infusion in non-paralysed patients: a rand-
omized, double-blind study. European Journal of Anaesthes-
iology 2004; 21: 787–92.
82 Mouren S, De Winter G, Guerrero SP, Baillard C, Bert-
rand M, Coriat P. The continuous recording of blood
pressure in patients undergoing carotid surgery under
remifentanil versus sufentanil analgesia. Anesthesia and
Analgesia 2001; 93: 1402–9.
83 Myles PS, Hunt JO, Fletcher H, et al. Remifentanil,
fentanyl, and cardiac surgery: a double-blinded, random-
ized, controlled trial of costs and outcomes. Anesthesia and
Analgesia 2002; 95: 805–12.
84 Natalini G, Fassini P, Seramondi V, et al. Remifentanil vs.
fentanyl during interventional rigid bronchoscopy under
general anaesthesia and spontaneous assisted ventilation.
European Journal of Anaesthesiology 1999; 16: 605–9.
85 Neill H, Brydon C, Binning A. Comparison of fentanyl
and remifentanil based anaesthesia for carotid endarterec-
tomy. European Journal of Anaesthesiology 2001; 18 (Suppl.
21): 42–3.
86 Nilsson LB, Viby-Mogensen J, Moller J, Fonsmark L,
Ostergaard D. Remifentanil vs. alfentanil for direct lar-
yngoscopy: a randomized study comparing two total
intravenous anaesthesia techniques. TIVA for direct lar-
yngoscopy. Acta Anaesthesiologica Belgica 2002; 53: 213–9.
87 Ostapkovich ND, Baker KZ, Fogarty-Mack P, Sisti MB,
Young WL. Cerebral blood flow and CO2 reactivity is
similar during remifentanil ⁄ N2O and fentanyl ⁄ N2O
anesthesia. Anesthesiology 1998; 89: 358–63.
88 Pandazi AK, Louizos AA, Davilis DJ, Stivaktakis JM,
Georgiou LG. Inhalational anesthetic technique in micro-
laryngeal surgery: a comparison between sevoflurane-
 2007 The Authors
Journal compilation  2007 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2007, 62, pages 1266–1280
. ....................................................................................................................................................................................................................
remifentanil and sevoflurane-alfentanil anesthesia.
Annals of Otology, Rhinology, and Laryngology 2003; 112:
373–8.
89 Philip BK, Scuderi PE, Chung F, et al. Remifentanil
compared with alfentanil for ambulatory surgery using total
intravenous anesthesia. The Remifentanility ⁄ Alfentanility
Outpatient TIVA Group Anesthesia and Analgesia 1997; 84:
515–21.
90 Philip BK, Scuderi PE, Chung F, et al. Comparison of
remifentanil ⁄ propofol to alfentanil ⁄ propofol for laparo-
scopic outpatient surgery. Anesthesiology 1995; 83: A3.
91 Prakash N, McLeod T, Gao Smith F. The effects of
remifentanil on haemodynamic stability during rigid
bronchoscopy. Anaesthesia 2001; 56: 576–80.
92 Rama-Maceiras P, Ferreira TA, Molins N, Sanduende Y,
Bautista AP, Rey T. Less postoperative nausea and vom-
iting after propofol + remifentanil versus propofol +
fentanyl anaesthesia during plastic surgery. Acta Anaesthes-
iologica Scandinavica 2005; 49: 305–11.
93 Salihoglu Z, Demiroluk S, Demirkiran Kose Y. Compar-
ison of effects of remifentanil, alfentanil and fentanyl on
cardiovascular responses to tracheal intubation in morbidly
obese patients. European Journal of Anaesthesiology 2002; 19:
125–8.
94 Sator-Katzenschlager SM, Oehmke MJ, Deusch E, Dolezal
S, Heinze G, Wedrich A. Effects of remifentanil and
fentanyl on intraocular pressure during the maintenance
and recovery of anaesthesia in patients undergoing non-
ophthalmic surgery. European Journal of Anaesthesiology
2004; 21: 95–100.
95 Schuttler J, Albrecht S, Breivik H, et al. A comparison of
remifentanil and alfentanil in patients undergoing major
abdominal surgery. Anaesthesia 1997; 52: 307–17.
96 Sneyd JR, Whaley A, Dimpel HL, Andrews CJ. An open,
randomized comparison of alfentanil, remifentanil and
alfentanil followed by remifentanil in anaesthesia for cra-
niotomy. British Journal of Anaesthesia 1998; 81: 361–4.
97 Sofianou A, Batistaki C, Koutsodima C, Kanata M,
Tsakouridou M, Velmachou K. Remifentanil ⁄ sevoflurane
vs. fentanyl ⁄ sevoflurane anaesthesia: comparison of
recovery characteristics in patients undergoing laparoscopic
cholecystectomy. European Journal of Anaesthesiology 2001;
18 (Suppl. 21): 45.
98 Song D, White PF. Optimal dose of remifentanil for
maintaining hemodynamic stability during anesthetic dur-
ation and tracheal intubaiton: a comparison with fentanyl.
Anesthesia and Analgesia 1998; 86: S105.
99 Song D, Whitten CW, White PF. Use of remifentanil
during anesthetic induction: a comparison with fentanyl in
the ambulatory setting. Anesthesia and Analgesia 1999; 88:
734–6.
100 Sungun MB, Madenoglu H, Dogru K, Karamehmet Y,
Kotanoglu MS, Boyaci A. Supratentorial kraniyotomilerde
fentanil ve remifentanil karsilastirmasi. Türk Anesteziyoloji
Ve Reanimasyon Cemiyeti Mecmuasý 2003; 31: 89–94.
101 Vanacker B, Van Geldre L. A randomized study of the
efficacy and recovery of remifentanil-based and alfentanil
 2007 The Authors
Journal compilation  2007 The Association of Anaesthetists of Great Britain and Ireland
R. Komatsu et al. Æ Remifentanil for general anaesthesia
anaesthesia with desflurane or sevoflurane for gynaecolo-
gical surgery. Acta Anaesthesiologica Belgica 2002; 53: 21–6.
102 Wilhelm W, Biedler A, Huppert A, et al. Comparison of
the effects of remifentanil or fentanyl on anaesthetic
induction characteristics of propofol, thiopental or etomi-
date. European Journal of Anaesthesiology 2002; 19: 350–6.
103 Wilhelm W, Schlaich N, Harrer J, Kleinschmidt S, Muller
M, Larsen Royal. Recovery and neurological examination
after remifentanil-desflurane or fentanyl-desflurane anaes-
thesia for carotid artery surgery. British Journal of Anaesthesia
2001; 86: 44–9.
104 Witkowski T, Azad S, Lessin J, et al. Recovery following
remifentanil for prolonged operations: A comparison with
alfentanil. Annual Meeting American Society of Anesthesiolo-
gists. Atlanta, GA: Lippincott-Raven, 1995.
105 Wuesten Royal, Van Aken H, Glass PS, Buerkle H.
Assessment of depth of anesthesia and postoperative res-
piratory recovery after remifentanil- versus alfentanil-based
total intravenous anesthesia in patients undergoing ear-
nose-throat surgery. Anesthesiology 2001; 94: 211–7.
106 Yildiz K, Esmaoglu A, Dogru K, Tercan E, Boyaci A.
Total intravenoz anestezide BIS monitorizasyonu esliginde
alfentanil ve remifentanil karsilastirmasi. Türk Anesteziyoloji
Ve Reanimasyon Cemiyeti Mecmuasý 2002; 30: 309–14.
107 Alper I, Erhan E, Ozyar B, Ugur G. Remifentanil com-
pared with alfentanil using total intravenous anaesthesia for
outpatient surgery. Turk Anesteziyoloji Ve Reanimasyon
2001; 29: 262–5.
108 Asmussen H, Jorgensen L. [Remifentanil and eye surgery.
A randomized, clinical comparison of propofol ⁄ remifent-
anil anesthesia and propofol ⁄ fentanyl ⁄ alfentanil anesthe-
sia]. Ugeskrift for Laeger 2003; 165: 1774–8.
109 Camu F, Sneyd JR, Holgersen O, Helmers JH. An open,
randomised comparison of remifentanil and fentanyl in
patients during major surgery. 11th World Congress of
Anesthesiology 1996: 645.
110 Cartwright DP, Jansen JP, Kvalsvik O, Meeke Royal.
Double blind, randomised comparison of remifentanil and
alfentanil in out-patient surgery, Congress of Anesthesiology
1996: 644.
111 Guillen F, Perez-Vela JL, Renes E. Remifentanil or Fentanyl
Analgesia after Cardiac Surgery. Weimar, Germany: Euro-
pean Association of Cardiothoracic Anesthesiologists
(EACTA), 2001: abstract book, 82.
112 Gunes Y, Ozbek H, Ozalevli M, Tarhan O, Akman H.
Azot protoksitle birlikte uygulanan propofol-alfentanil ve
propofol-remifentanilin, hemodinami derlenme ve kognitif
fonksiyonlar uzerine etkilerinin karsilastirilmasi. Türk
Anesteziyoloji Ve Reanimasyon Cemiyeti Mecmuasý 2001; 29:
413–9.
113 Laberg GO, Leirvag JP, Leeuwenberg J, Bergamaschi
Royal. [Do short-term duration drugs for anaesthesia give
postoperative advantages compared to traditional drugs?]
Tidsskrift for Den Norske Laegeforening 2003; 123: 2445–7.
114 Lischke V, Westphal K, Kessler P, Behne M, Bron B,
Buck M. Untersuchung zur postoperativen Befindlichkeit
nach TIVA mit Remifentanil vs Sufentanil in der
1279
R. Komatsu et al. Æ Remifentanil for general anaesthesia Anaesthesia, 2007, 62, pages 1266–1280
. ....................................................................................................................................................................................................................

Neurochirurgie. Deutscher Anaesthesiekogress 1998: (GI87084B) in healthy adult male volunteers. Anesthesiology
Anaesthesiekongress Abstraktband FP–D, 206. 1993; 79: 881–92.
115 Lopourova M, Malek J, Mizner P, Pachl J. Srovnani 124 Vankova ME, Weinger MB, Chen DY, Bronson JB, Motis
remifentanilu a sufentanilu v anestezii pacientu oper- V, Koob GF. Role of central mu, delta-1, and kappa-1
ovanych pro nitrolebni onemocneni. Anesteziologie a opioid receptors in opioid-induced muscle rigidity in the
Neodkladna Pece 2001; 12: 167–70. rat. Anesthesiology 1996; 85: 574–83.
116 Ozel M, Yosunkaya A, Tavlan A, Reisli Royal, Okesli S. 125 Bennett JA, Abrams JT, Van Riper DF, Horrow JC.
Comparison of alfentanil and remifentanil at total intra- Difficult or impossible ventilation after sufentanil-induced
venous anesthesia in short-term elective surgery. Anestezi anesthesia is caused primarily by vocal cord closure.
Dergisi 2002; 10: 177–82. Anesthesiology 1997; 87: 1070–4.
117 Paris A, Tonner PH, Bein B. Remifentanil and Changes in 126 Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M.
Practice Pattern Reduce Time to Extubation After Coronary Short-term infusion of the mu-opioid agonist remifentanil
Artery Bypass (CABG) Surgery. Weimar, Germany: Euro- in humans causes hyperalgesia during withdrawal. Pain
pean Association of Cardiothoracic Anesthesiologists 2003; 106: 49–57.
(EACTA), 2001: abstract book, 68. 127 Horn EP, Schroeder F, Wilhelm S, et al. Postoperative
118 Sener EB, Baris S, Kocamanoglu S, Karakaya D, Tur A. pain facilitates nonthermoregulatory tremor. Anesthesiology
The comparison of remifentanil and alfentanil for reflex 1999; 91: 979–84.
hemodynamic responses to direct endoscopic laryngosco- 128 Kissin I, Brown PT, Robinson CA, Bradley EL Jr.
py, awakening times, complications and costs. Anestezi Acute tolerance in morphine analgesia: continuous infu-
Dergisi 2003; 11: 23–7. sion and single injection in rats. Anesthesiology 1991; 74:
119 Chung F, Skinner EP, Jamerson BD, Reese PR. Recovery 166–71.
and reasons for discharge delay after remifentanil vs. alf- 129 Kissin I, Lee SS, Arthur GR, Bradley EL Jr. Time course
entanil in outpatient surgery. Anesthesia and Analgesia 1996; characteristics of acute tolerance development to con-
82: S65. tinuously infused alfentanil in rats. Anesthesia and Analgesia
120 Jellish WS, Brody M, Murdoch J, Fluder E, Leonetti J. 1996; 83: 600–5.
Remifentanil vs. propofol based anesthesia for otologic 130 Vinik HR, Kissin I. Rapid development of tolerance
microsurgical procedures of 1–2 hrs. duration. Anesthesia to analgesia during remifentanil infusion in humans.
and Analgesia 1999; 88 (Suppl. S): S14. Anesthesia and Analgesia 1998; 86: 1307–11.
121 Twersky RS, Jamerson B, Warner DS, Fleisher LA, Hogue 131 Apfel CC, Kranke P, Katz MH, et al. Volatile anaes-
S. Hemodynamics and emergence profile of remifentanil thetics may be the main cause of early but not delayed
versus fentanyl prospectively compared in a large popula- postoperative vomiting: a randomized controlled trial of
tion of surgical patients. Journal of Clinical Anesthesia 2001; factorial design. British Journal of Anaesthesia 2002; 88:
13: 407–16. 659–68.
122 Wilhelm W, Harrer J, Schlaich N, Aiegenfus T, Muller M,
Larsen Royal. Remifetanil or fentanyl for carotid surgery.
British Journal of Anaesthesia 1998; 80 (Suppl. 1): 36. Supplementary material
123 Egan TD, Lemmens HJ, Fiset P, et al. The pharmaco- Table S1 Study characteristics.
kinetics of the new short-acting opioid remifentanil

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