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  1. 1. Anaesth Intensive Care 2009; 37: Remifentanil-induced abdominal pain: a randomised clinical trial S. JAHANbAKHSH*, A. bAMESHKI*, P. KHASHAyAR† Anesthesiology Department, Imam Reza Hospital, Tehran, Iran SUMMARy Remifentanil is an ultra-short-acting opioid, widely used for induction and maintenance of anaesthesia in various types of operations. We recently 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. This randomised single-blinded clinical trial was conducted on 300 patients who were undergoing elective cataract surgery under general anaesthesia. The patients were randomly divided into two groups. In the control group (n=150), anaesthesia was induced with fentanyl and propofol and maintained by propofol by infusion and 60% N2O. In the remifentanil group, anaesthesia was induced with remifentanil and propofol and maintained by remifentanil infusion and 60% N2O inhalation. Atracurium was used for muscle relaxation in both groups. Abdominal pain was observed in 79 patients (52.6%) in the remifentanil group; 10 of whom required a therapeutic intervention, but in only three patients in the control group, none of whom required an intervention (P value=0.001). Postoperative nausea and vomiting were reported in seven and 10 patients (4.7%) in the remifentanil and control group, respectively. These findings indicate that abdominal pain is very common in patients receiving remifentanil by infusion for cataract surgery. Key Words: remifentanil, side-effect, abdominal pain, cataract surgery Remifentanil is a short-acting opioid1 which, unlike allergic reactions7; abdominal pain, however, is not other traditional opioids, undergoes widespread mentioned as a frequent complaint in these patients. extrahepatic metabolism, resulting in an extremely According to our experience in this field, we noted rapid clearance in less than three to 10 minutes2-6. that a great number of patients receiving remifentanil It is a selective µ-opioid receptor agonist that in their anaesthetic regimen experienced post- provides rapid-onset but short-term analgesia with a operative abdominal pain. As a result, we performed predictable duration of action with no accumulation this study to investigate its incidence. of effect on repeated dosing or with continuous infusion1,5. The medication is widely administered METHOD AND MATERIALS for the induction and maintenance of anaesthesia After obtaining approval from the ethical board in different minor and major operations as well as in committee of Mashhad University of Medical a great variety of patients including children and Sciences, this single-blinded prospective randomised patients with renal, hepatic or cardiovascular clinical trial was conducted on all candidates for diseases1,6. cataract surgery under general anaesthesia. The Numerous studies have reported several side- patients were selected to be in ASA class I or II; effects for the drug including dizziness, drowsiness, those with positive history of abdominal discomfort nausea and vomiting, shivering, headache and or peptic ulcer disease or opium addiction were excluded from the study. The patients were all informed about the * M.D., Assistant Professor of Anesthesiology, Anesthesiology consequences of the study and informed consent was Department, Imam Reza Hospital, Medical Sciences/University of obtained from them. They were then divided into Mashhad. † M.D., General Practitioner, Research and Development Center, Sina two equal groups using a random allocation software. Hospital, Medical Sciences/University of Tehran. Upon the patients’ arrival in the operating Address for reprints: Dr P. Khashayar, Sina Hospital, Imam Khomeini St, room, standard monitoring was installed for both Tehran 11367, Iran. remifentanil and control groups. Oxygen saturation Accepted for publication on November 14, 2008. and ECG were monitored continuously and non- Anaesthesia and Intensive Care, Vol. 37, No. 3, May 2009
  2. 2. 2 S. JahanbakhSh, a. bameShki , P. KhaShayar invasive blood pressure monitoring was performed The severity of the abdominal pain was recorded every five minutes. After establishing venous access and scored as following: 0=no abdominal pain, with a 20 to 22 gauge intravenous cannula and 1=mild abdominal pain reported by the patient prior to the induction of anaesthesia, a bolus of 3 when asked about it, 2=moderate abdominal pain to 5 ml/kg lactated Ringer’s solution followed by a reported by the patient her or himself, 3=severe constant rate of 6 ml/kg/h was infused intravenously. abdominal pain requiring therapeutic intervention. In the control group, anaesthesia was induced by Mild to moderate abdominal pain was managed 1 to 2 µg/kg fentanyl, 1 to 1.5 mg/kg propofol and by reassuring and informing the patients of the 0.5 mg/kg atracurium after pre-oxygenation for transient pattern of the pain; intramuscular hyoscine three minutes; thereafter, laryngoscopy and 20 mg was injected to treat severe pain. intubation were performed. The continuous infusion Considering the findings of the pilot study of 50 to 150 µg/kg/min propofol and 60% N2O (a=0.05%, power=95%) 150 cases were needed for inhalation were used to maintain anaesthesia. each group. The statistical analysis was performed In the remifentanil group, pre-oxygenation was using SPSS version 15; t-test and chi-square were performed prior to the induction of anaesthesia with the tests used to compare the variables. P values 2 µg/kg remifentanil, 1 to 1.5 mg/kg propofol and less than 0.05 were considered as significant. 0.5 mg/kg atracurium. The patient was then intubated and anaesthesia was maintained by 0.3 to RESULTS 0.6 µg/kg/min remifentanil infusion and 60% N2O The 300 patients enrolled in the study were inhalation. GlaxoSmithKline’s remifentanil was the randomly divided into two equal groups of 150 product used in the study. patients. There was no significant difference between At the end of the surgery, the administration the demographic data including age, gender, of anaesthetic agents was terminated without weight and haemodynamic indexes of either group tapering. Atropine (25 to 40 µg/kg) and neostigmine (Table 1). The mean anaesthesia time in remifentanil (50 to 80 µg/kg) were then infused to reverse the and control groups was 34.3±16.8 minutes and muscle relaxant agents’ effects. The patients were 36.7±13.1 minutes, respectively (P value=0.168). extubated when adequate spontaneous ventilation Postoperative nausea and vomiting was observed (VT >4 ml/kg) was established. in seven cases (4.7%) in the remifentanil group The patients were directly transferred to the post- and 10 cases (6.7%) in the control group; however, anaesthesia care unit where monitoring including no statistically significant difference was reported pulse oximetry, ECG monitoring and NIbP between the two groups (P=0.454). measurement was continued. The minimum stay in Abdominal pain during the postoperative the postoperative care unit was 30 minutes and the period was observed in 79 patients (52.6%) of the patients were transferred to the ward when they remifentanil group and three cases (2%) of were haemodynamically stable. the control group. The incidence of abdominal pain A technician, unaware of the objectives of the in the remifentanil group was significantly higher study, was responsible for monitoring the patients than the control group (P value=0.001). Severe in the postoperative care unit for the presence of abdominal pain requiring intervention was symptoms such as abdominal pain, nausea and reported in 10 patients (6.7%) in the remifentanil vomiting. group, whereas neither of the control cases reported Table 1 Comparison of demographic characteristics of haemodynamic indexes in remifentanil and control groups Variable Remifentanil Group (n=150) Control Group (n=150) P value Gender (M/F) 86/64 79/71 0.1550 Age (y) 68.3±12.6 (43-87) 66.3±11.1 (40-78) 0.1505 Weight (kg) 62.7±9.8 (51-95) 64.2±11.2 (50-95) 0.2157 Systolic bP (mmHg) 152±18.4 (114-180) 137±20.2 (110-176) 0.3658 Diastolic bP (mmHg) 87±12.1 (53-96) 89±11.3 (60-102) 0.1401 Mean arterial bP (mmHg) 106±15.4 (83-138) 109±17.5 (80-141) 0.1160 Heart rate (beat/min) 98±13.4 (71-121) 95±16.3 (66-110) 0.0827 Mean±SD (min-max). Anaesthesia and Intensive Care, Vol. 37, No. 3, May 2009
  3. 3. CaSe reporT 3 such a pain (Table 2). The pain was relieved investigations, however, are required to determine the following the administration of the abovementioned exact aetiology of remifentanil-induced abdominal medication in both groups. pain, its prevalence and management. Table 2 CONCLUSION Comparison of incidence and severity of abdominal pain in remifentanil and control groups According to the findings of the present study, abdominal pain is a prevalent side-effect in patients Mild Moderate Severe Total receiving remifentanil; the cause, however, needs Remifentanil 43 (54.4%) 26 (32.9%) 10 (12.7%) 79 (52.6%) further studies. It is recommended to compare the Control 2 (66.7%) 1 (33.3%) 0 (0.0%) 3 (2%) effects of different analgesic agents in the future studies conducted on a larger sample size in order to reveal the underlying mechanism contributing to DISCUSSION this pain. Opioids are among routine anaesthetic agents used in almost all anaesthetic regimens. They REFERENCES provide perfect intra- and postoperative analgesia 1. Scholz J, Steinfath M. Is remifentanil an ideal opioid for as well as better control of haemodynamic changes; anesthesiologic management in the 21st century? Anasthesiol however, several side-effects including respiratory Intensivmed Notfallmed Schmerzther 1996; 31:592-607. depression, ileus and postoperative nausea and 2. Cohen J, Royston D. Remifentanil. Curr Opin Crit Care 2001; 7:227-231. vomiting are commonly reported following the use 3. Patel SS, Spencer CM. Remifentanil. Drugs 1996; 52:417-428. of these agents8,9. 4. yarmush J, D’Angelo R, Kirkhart b, O’Leary C, Pitts MC Abdominal pain was the most frequent complaint 2nd, Graf G et al. A comparison of remifentanil and morphine reported in the remifentanil group of our study. sulfate for acute postoperative analgesia after total intravenous In view of our previous experiences, this side- anesthesia with remifentanil and propofol. Anesthesiology effect commonly considered as incisional site 1997; 87:235-243. pain is frequently reported in patients undergoing 5. Vuyke J, Tonie L, Enbergre M, burm AGL, Vletter AA. The pharmacodynamic interaction of Propofol and alfentanil dur- abdominal surgery; however, it is masked by the ing lower abdominal surgery in women. Anesthesiology 1995; administration of analgesics in the postoperative 83:8-22. period. As a result, we studied patients under- 6. Albertin A, Casati A, Deni F, Danelli G, Comotti L, Grifoni going a cataract surgery which is a minor, less F. Clinical comparison of either small doses of Fentanyl or invasive surgery, so that they wouldn’t need any Remifentanil for blunting cardiovascular changes induced by tracheal intubation. Minerva Anestesiol 2000; 66:691-696. supplementary analgesics for alleviating the severe 7. Joly V, Richebe P, Guignard b, Fletcher D, Maurette P, Sessler surgical site pain. DI et al. Remifentanil-induced postoperative hyperalgesia and The mechanism of abdominal pain after its prevention with small-dose ketamine. Anesthesiology 2005; anaesthesia using remifentanil is unknown, 103:147-155. though several reports have noted postoperative 8. Hall AP, Thompson JP, Leslie NA, Fox AJ, Kumar N, remifentanil-induced hyperalgesia in animal models Rowbotham DJ. Comparison of different doses of remifentanil on the cardiovascular response to laryngoscopy and tracheal and humans which is believed to be controlled by intubation. br J Anaesth 2000; 84:100-102. adding low doses of ketamine to the anaesthetic 9. barclay K. Effects of bolus dose of Remifentanil on haemody- regimen7,10,11. namic response to tracheal intubation. Anaesth Intensive Care In opposition, the present study reports obvious 2000; 28:403-407. visceral and obscure abdominal pain, different 10. Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, from remifentanil-induced hyperalgesia. However, Schmittler J. Differential modulation of remifentanil-induced considering the fact that the pain was alleviated analgesia and post infusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology 2003; 99:152-159. with hyoscine, an antispasmodic, it is possible that 11. Luginbhl M, Gerber A, Schnider TW, Petersen-Felix S, Arendt- postoperative spasm in bowel smooth muscles has Nielsen L, Curatolo M. Modulation of remifentanil-induced contributed to the high number of abdominal analgesia hyperalgesia, and tolerance by small-dose ketamine complaints following the use of the drug. Further in humans. Anesth Analg 2003; 96:726-732. Anaesthesia and Intensive Care, Vol. 37, No. 3, May 2009