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Remifentanil-induced abdominal pain: a randomised clinical trial.

Remifentanil is a short-acting opioid (1) which, unlike other traditional opioids, undergoes widespread extrahepatic metabolism, resulting in an extremely rapid clearance in less than three to 10 minutes (2-6).

It is a selective [mu]-opioid receptor agonist that provides rapid-onset but short-term analgesia with a predictable duration of action with no accumulation of effect on repeated dosing or with continuous infusion (1,5). The medication is widely administered for the induction and maintenance of anaesthesia in different minor and major operations as well as in a great variety of patients including children and patients with renal, hepatic or cardiovascular disease (1,6).

Numerous studies have reported several side-effects for the drug including dizziness, drowsiness, nausea and vomiting, shivering, headache and allergic reactions (7); abdominal pain, however, is not mentioned as a frequent complaint in these patients. According to our experience in this field, we noted that a great number of patients receiving remifentanil in their anaesthetic regimen experienced postoperative abdominal pain. As a result, we performed this study to investigate its incidence.


After obtaining approval from the ethical board committee of Mashhad University of Medical Sciences, this single-blinded prospective randomised clinical trial was conducted on all candidates for cataract surgery under general anaesthesia. The patients selected were of ASA classification I or II; those with positive history of abdominal discomfort or peptic ulcer disease or opium addiction were excluded from the study.

The patients were all informed about the consequences of the study and informed consent was obtained from them. They were then divided into two equal groups using a random allocation software.

Upon the patients' arrival in the operating room, standard monitoring was installed for both remifentanil and control groups. Oxygen saturation and ECG were monitored continuously and non-invasive blood pressure monitoring was performed every five minutes. After establishing venous access with a 20 to 22 gauge intravenous cannula and prior to the induction of anaesthesia, a bolus of 3 to 5 ml/kg lactated Ringer's solution followed by a constant rate of 6 ml/kg/h was infused intravenously.

In the control group, anaesthesia was induced by 1 to 2 [micro]g/kg fentanyl, 1 to 1.5 mg/kg propofol and 0.5 mg/kg atracurium after pre-oxygenation for three minutes, after which laryngoscopy and intubation was performed. A continuous infusion of 50 to 150 [micro]g/kg/min propofol and 60% [N.sub.2]O inhalation was used to maintain anaesthesia.

In the remifentanil group, pre-oxygenation was performed prior to the induction of anaesthesia with 2 [micro]g/kg remifentanil, 1 to 1.5 mg/kg propofol and 0.5 mg/kg atracurium. The patient was then intubated and anaesthesia maintained with 0.3 to 0.6 [micro]g/kg/min remifentanil infusion and 60% [N.sub.2]O inhalation.

At the end of the surgery, the administration of anaesthetic agents was terminated without tapering. Atropine (25 to 40 [micro]g/kg) and neostigmine (50 to 80 [micro]g/kg) were then infused to reverse muscle relaxation. The patients were extubated when adequate spontaneous ventilation ([V.sub.T] >4 ml/kg) was established.

The patients were directly transferred to the post-anaesthesia care unit where monitoring including pulse oximetry, ECG monitoring and NIBP measurement were continued. The minimum stay in the postoperative care unit was 30 minutes and the patients were transferred to the ward when they were haemodynamically stable.

A technician, unaware of the objectives of the study, was responsible for monitoring the patients in the postoperative care unit for the presence of symptoms such as abdominal pain, nausea and vomiting.

The severity of the abdominal pain was recorded and scored as following: 0=no abdominal pain, 1=mild abdominal pain reported by the patient when asked about it, 2=moderate abdominal pain reported by the patient her or himself, 3=severe abdominal pain requiring therapeutic intervention.

Mild to moderate abdominal pain was managed by reassuring and informing the patients of the transient nature of the pain; intramuscular hyoscine 20 mg was used to treat severe pain.

Considering the findings of the pilot study (a=0.05%, power=95%) 150 cases were needed for each group. The statistical analysis was performed using SPSS version 15; t-test and chi-square were the tests used to compare the variables. P values less than 0.05 were considered as significant.


The 300 patients enrolled in the study were randomly divided into two equal groups of 150 patients. There was no significant difference between the demographic data including age, gender, weight and haemodynamic indexes of either group (Table 1). The mean anaesthesia time in remifentanil and control groups was 34.3[+ or -]16.8 minutes and 36.7 [+ or -] 13.1 minutes, respectively (P value=0.168).

Postoperative nausea and vomiting was observed in seven cases (4.7%) in the remifentanil group and 10 cases (6.7%) in the control group; however, no statistically significant difference was reported between the two groups (P=0.454).

Abdominal pain during the postoperative period was observed in 79 patients (52.6%) of the remifentanil group and three cases (2%) of the control group. The incidence of abdominal pain in the remifentanil group was significantly higher than in the control group (P value=0.001). Severe abdominal pain requiring intervention was reported in 10 patients (6.7%) in the remifentanil group, whereas none of the control cases reported such a pain (Table 2). The pain was relieved following the administration of the above-mentioned medication in both groups.


Opioids are among routine anaesthetic agents used in almost all anaesthetic regimens. They provide excellent intra- and postoperative analgesia as well as better control of haemodynamic changes; however, several side-effects including respiratory depression, ileus and postoperative nausea and vomiting are commonly reported following the use of these agents (8,9).

Abdominal pain was the most frequent complaint reported in the remifentanil group of our study. In view of our previous experiences, this side-effect commonly considered as incisional site pain is frequently reported in patients undergoing abdominal surgery: however, it is masked by the administration of analgesics in the postoperative period. As a result, we studied patients undergoing cataract surgery which is a minor, less invasive surgery, so that they would not need any supplementary analgesics.

The mechanism of abdominal pain after anaesthesia using remifentanil is unknown, though several reports have noted postoperative remifentanil-induced hyperalgesia in animal models and humans, which is controlled by adding low doses of ketamine to the anaesthetic regimen (7,10,11).

However, the present study reports obvious visceral and obscure abdominal pain, which was different from remifentanil-induced hyperalgesia. However, in view of the fact that this pain was alleviated with hyoscine, an antispasmodic, it is possible that postoperative spasm in bowel smooth muscles has contributed to the high number of abdominal complaints following the use of the drug. Further investigations, however, are required to determine the exact aetiology of remifentanil-induced abdominal pain, its prevalence and management.


According to the findings of the present study, abdominal pain is a prevalent side-effect in patients receiving remifentanil; the cause, however, needs further study. In order to determine the underlying mechanism for remifentanil-induced abdominal pain, we recommend that different analgesic agents be compared in studies conducted on a larger sample size.

Accepted for publication on November 14, 2008.


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(2.) Cohen J, Royston D. Remifentanil. Curr Opin Crit Care 2001; 7:227-231.

(3.) Patel SS, Spencer CM. Remifentanil. Drugs 1996; 52:417-428.

(4.) yarmush J, D'Angelo R, Kirkhart b, O'Leary C, Pitts MC 2nd, Graf G et al. A comparison of remifentanil and morphine sulfate for acute postoperative analgesia after total intravenous anesthesia with remifentanil and propofol. Anesthesiology 1997; 87:235-243.

(5.) Vuyke J, Tonie L, Enbergre M, Burm AGL, Vletter AA. The pharmacodynamic interaction of Propofol and alfentanil during lower abdominal surgery in women. Anesthesiology 1995; 83:8-22.

(6.) Albertin A, Casati A, Deni F, Danelli G, Comotti L, Grifoni F. Clinical comparison of either small doses of Fentanyl or Remifentanil for blunting cardiovascular changes induced by tracheal intubation. Minerva Anestesiol 2000; 66:691-696.

(7.) Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 2005; 103:147-155.

(8.) Hall AP, Thompson JP, Leslie NA, Fox AJ, Kumar N, Rowbotham DJ. Comparison of different doses of remifentanil on the cardiovascular response to laryngoscopy and tracheal intubation. br J Anaesth 2000; 84:100-102.

(9.) Barclay K. Effects of bolus dose of Remifentanil on haemodynamic response to tracheal intubation. Anaesth Intensive Care 2000; 28:403-407.

(10.) Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schmittler J. Differential modulation of remifentanil-induced analgesia and post infusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology 2003; 99:152-159.

(11.) Luginbhl M, Gerber A, Schnider TW, Petersen-Felix S, Arendt-Nielsen L, Curatolo M. Modulation of remifentanil-induced analgesia hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg 2003; 96:726-732.


Anesthesiology Department, Imam Reza Hospital, Tehran, Iran

* M.D., Assistant Professor of Anesthesiology, Anesthesiology Department, Imam Reza Hospital, Medical Sciences/University of Mashhad.

([dagger]) M.D., General Practitioner, Research and Development Center, Sina Hospital, Medical Sciences/University of Tehran.

Address for reprints: Dr P. Khashayar, Sina Hospital, Imam Khomeini St, Tehran 11367, Iran.
Comparison of demographic characteristics and haemodynamic indexes in
remifentanil and control groups

Variable Remifentanil Group

Gender (M/F) 86/64
Age (y) 68.3 [+ or -] 12.6 (43-87)
Weight (kg) 62.7 [+ or -] 9.8 (51-95)
Systolic bP (mmHg) 152 [+ or -] 18.4 (114-180)
Diastolic bP (mmHg) 87 [+ or -] 12.1 (53-96)
Mean arterial bP (mmHg) 106 [+ or -] 15.4 (83-138)
Heart rate (beat/min) 98 [+ or -] 13.4 (71-121)

Variable Control Group P value

Gender (M/F) 79/71 0.1550
Age (y) 66.3 [+ or -] 11.1 (40-78) 0.1505
Weight (kg) 64.2 [+ or -] 11.2 (50-95) 0.2157
Systolic bP (mmHg) 137 [+ or -] 20.2 (110-176) 0.3658
Diastolic bP (mmHg) 89 [+ or -] 11.3 (60-102) 0.1401
Mean arterial bP (mmHg) 109 [+ or -] 17.5 (80-141) 0.1160
Heart rate (beat/min) 95 [+ or -] 16.3 (66-110) 0.0827

Mean [+ or -] SD (min-max).

Comparison of incidence and severity of abdominal pain in
remifentanil and control groups

 Mild Moderate Severe Total

Remifentanil 43 (54.4%) 26 (32.9%) 10 (12.7%) 79 (52.6%)
Control 2 (66.7%) 1 (33.3%) 0 (0.0%) 3 (2%)
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Article Details
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Author:Jahanbakhsh, S.; Bameshki, A.; Khashayar, P.
Publication:Anaesthesia and Intensive Care
Article Type:Report
Geographic Code:1USA
Date:May 1, 2009
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