Pre-medication with controlled-release oxycodone in the management of postoperative pain after ambulatory laparoscopic gynaecological surgery

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1 Page 1 of 5 Anaesthetics & Critical Care Pre-medication with controlled-release oxycodone in the management of postoperative pain after ambulatory laparoscopic gynaecological surgery B Lim 1, SY Thong 2 *, HB Zhu 2, Y Lim 3 Abstract Introduction Oxycodone controlled-release is a potent opioid analgesic. We aim to assess the efficacy of pre-medication of oral oxycodone controlled-release in the reduction of postoperative pain in ambulatory laparoscopic gynaecological surgery. Materials and Methods A randomised, double blind, placebocontrolled trial was performed. This was conducted in 60 patients undergoing ambulatory laparoscopic gynaecological surgery. They were randomised into two groups to receive either oral oxycodone controlled-release 10 mg (Group C, n = 30) or placebo (Group P, n = 30 ) 1 h preoperatively. Postoperative pain score and side effects of oxycodone controlled-release were assessed in the recovery room. Rescue analgesia of intravenous fentanyl (25 μg every 15 min) was given in the recovery room until the numerical rating pain score was 5. These patients were followed up 24 h postoperatively via telephone questionnaire. Results We found no difference in pain scores at rest or on exertion at 15 min, 1 h, 2 h or 24 h after the surgery between the two groups of patients. In * Corresponding Author thongszeying@gmail.com 1 Department of Anaesthesiology, Intensive Care and Pain Medicine, Tan Tock Seng Hospital, Singapore 2 Department of Anaesthesiology, Singapore General Hospital, Singapore 3 Department of Women s Anaesthesia, KK Women s and Children s Hospital, Singapore addition, fentanyl usage, discharge time and satisfaction score were not significantly different. The side effect profiles were similar between the two groups except an increased incidence of headache at 24 h after surgery in the oxycodone controlledrelease group (p < 0.05). Conclusion There was no difference in postoperative pain scores in patients who were pre-medicated with oral oxycodone controlled-release as compared with placebo. Introduction Laparoscopic surgery can be associated with severe postoperative pain, for example laparoscopic ligation is associated with more than 20% incidence of severe postoperative pain 1. Postoperative pain remains a common reason for delayed discharge 2 and unanticipated hospital admission in ambulatory surgery 3,4. Effective management of postoperative pain in patients undergoing laparoscopic surgery is essential to the success of ambulatory surgery. Oxycodone controlled-release (CR) (OxyContin TM, Mundipharma Pharmaceutical, UK) is a potent opioid analgesic with a long duration of action and almost twice the potency of oral morphine 5. It has a biphasic absorption pattern with an initial absorption of about 40% of the drug producing analgesia 1 h after consumption in most patients. The subsequent more controlled absorption accounts for its long duration of effect, which is approximately 12 h. In addition, it is associated with a lower incidence of side effects in cancer patients compared with controlled-release morphine 6. A recent systematic review by the Cochrane Collaboration showed that singledose oxycodone at doses more than 5 mg was effective for the treatment of acute postoperative pain 7. Its efficacy was increased when combined with paracetamol. Pre-medication with oxycodone CR in reducing postoperative pain has been performed in previous studies. Of particular relevance are two of the studies, which have been performed in patients undergoing ambulatory laparoscopic gynaecological surgery. Both studies were performed in Caucasian populations and results were contradicting. One of the studies by Reuben et al. 8 showed that pre-medication with 10 mg oral oxycodone CR reduces postoperative pain, amount of postoperative analgesia required as well as reducing discharge time in day surgery. However, another study by Jokela et al. 9 involving premedication with 15 mg oral oxycodone CR did not show reduction in postoperative pain in the day-case gynaecological laparoscopic surgery patients. One possible reason for the lack of positive findings could be the multi-modal analgesia regime used in the study. All patients were pre-medicated with oral ibuprofen (800 mg 60 min) before surgery. They were given intravenous (IV) dexamethasone 5 mg at induction as well as IV fentanyl bolus mg at the end of surgery after stopping remifentanil infusion. The effects of oxycodone may have been perceptible without the various modes of analgesia.

2 Page 2 of 5 Hence, in our study, we have excluded the use of non-steroidal antiinflammatory drugs (NSAIDs) or other modes of analgesic pre-medication except oxycontin in the intervention group. IV fentanyl will be given as rescue analgesia in the recovery room. We aim to assess the efficacy of premedication of oral oxycodone CR in the reduction of postoperative pain in patients undergoing ambulatory laparoscopic gynaecological surgery. Materials and Methods This study was approved by the Institutional Review Board of KK Women s and Children s Hospital as well as the Health Science Authority of Singapore. After the approval of the ethics committee, we recruited 60 patients with informed consent for this study. They were the American Society of Anesthesiologists physical status classification class I and II patients, between 21 and 60 years of age, presenting for elective laparoscopic gynaecological surgery in the KKH ambulatory surgical unit. Patients with allergy or intolerance to any of the drugs used in the trial, pregnant or breastfeeding mothers were excluded from the study. Patients who were morbidly obese with a body mass index (BMI) 35, history of renal, liver disease, history of opioid abuse, preoperative opioid usage as well as having a history of chronic pain were excluded. During the study, patients were excluded if surgical complications occurred, as this may confound the degree of postoperative pain. For example, if a surgical complication such as uterine perforation occurred, it is likely that greater postoperative pain is expected as the surgery is likely to be prolonged and greater surgical manipulation will be required for uterine repair. This will probably confound the degree of postoperative pain in these patients. A double blind, randomised, placebo-controlled trial was performed. Sixty patients were randomised into two groups using a computer- generated random number table to receive either oral oxycodone CR 10 mg (Group C, n = 30) or placebo, which was a vitamin C tablet, (Group P) with 20 ml water 1 h preoperatively. This is due to the pharmacokinetics of oxycodone CR with an initial analgesic effect at 1 h after consumption. Baseline demographic data, for example height, weight, age and smoking status, were collected. Preoperatively, patients were taught to use the numerical pain score 0 10 for indicating the severity of pain after surgery, with a pain score of 0 being the least severe and pain score of 10 being the most severe pain. At induction, all patients received 1 μg/kg fentanyl and mg/ kg propofol for induction followed by mg/kg of mivacurium to facilitate ventilation via a proseal laryngeal mask airway. General anaesthesia was maintained with sevoflurane in 70% N 2 O with O 2. IV Ondansetron 4 mg (anti-emesis) was given to all patients at the end of the surgery. Proseal laryngeal mask airway was removed before transferring the patients to the recovery room. At the recovery room, pain scores at rest and on movement (i.e. coughing) were assessed using the 0 10 numerical pain score. This was performed at 15 min upon waking up from anaesthesia or before the first rescue analgesia (whichever is earlier), 30 min, 1 h and 2 h postoperatively. Patients who had severe pain (pain score >5) or requests for analgesia after surgery receive rescue analgesia of IV fentanyl 25 μg every 15 min until pain score drops to <5. The time up to the first rescue analgesia as well as the total amount of fentanyl used in the recovery room were recorded. Incidence of side effects profile such as nausea and vomiting, pruritus, headache and urinary retention were recorded. Nausea was defined as the unpleasant sensation associated with awareness of the urge to vomit, and vomiting was defined as the forceful expulsion of gastric contents from the mouth. 10 Intravenous ondansetron 4 mg was administered for nausea lasting for more than 5 min, at the patient s request or when vomiting occurs. All assessments (pain score, incidence of side effects profile as well as Post Anaesthesia Discharge Scoring System (PADSS) score) were performed by an independent nurse who was blinded to the grouping of the patient. PADSS scores were recorded every 30 min and patients were fit for discharge from the ambulatory surgical unit when the PADSS score was 9 or more. They were discharged with oral paracetamol 1 g every 6 h as required. They were contacted by telephone 24 h after surgery to assess pain scores at rest and on movement. The time to first rescue analgesia at home as well as side effect profile (e.g. incidence of nausea and vomiting, pruritis, incidence of urinary retention and constipation) were assessed. Patient satisfaction to the pain management was obtained as well. Statistical analysis The study aims to detect a clinically significant reduction in pain score. A study involving similar patients undergoing laparoscopic tubal sterilisation demonstrated a postoperative mean pain score of 50 mm (standard deviation 30 mm) 10. A reduction of visual analog scale (VAS) pain score from 50 mm to 30 mm (moderate to mild pain) was considered clinically significant. Hence, power analysis was performed using a power of 80% and an α value of 0.05 to detect a 40% decrease in early postoperative pain scores taken within 15 min after surgery in patients pre-medicated with oxycodone CR 10 mg compared with placebo. A sample size of 28 per group is required. To account for possible dropouts, an additional 10% was added to the sample size and 60 patients were recruited into

3 Page 3 of 5 the study. Continuous data (e.g. age, weight, height, BMI, baseline heart rate, respiratory rate, systolic blood pressure, fentanyl usage postop, time to discharge and satisfaction score) were analysed using Student s T- tests. Ordinal data such as postoperative pain scores were analysed using the Mann Whitney U test. Categorical data such as incidence of side effects of oxycodone CR, for example nausea, vomiting and constipation were analysed using the χ 2 test. Results Baseline demographic data between the two groups were similar (Table 1). The type of laparoscopic surgery and duration of surgery were similar between the two groups. We found no difference in the pain scores at rest or on exertion at 15 min, 1 h, 2 h or 24 h after surgery between the two groups of patients. (Figures 1 and 2) The amount of fentanyl usage and the discharge time from recovery between the two groups were not significantly different (Table 2). The side effect profiles were similar between the two groups. There was, however, increased incidence of headache at 24 h after surgery in the oxycodone CR group (Table 3). We found no difference in satisfaction score between the two groups of patients (Table 2). There were no withdrawals from trials or loss of follow-up patients in this trial. Discussion Results of our study are similar to those by Jokela et al. 9 These authors also found no improvement in postoperative pain scores after pre-medication with 15 mg of oxycodone CR in day-case gynaecological laparoscopic surgery patients. This is in contrast to a similar study by Reuben et al. 8 who showed a reduction in the consumption of rescue pain analgesics, VAS scores, incidence of Table 1 Demographics and intraoperative characteristics Figure 1: Pain scores at rest over time. Group C (oxycodone CR) Figure 2: Pain scores on movement over time. Group P (placebo) Age (years) 33.4 (5.5) 34.0 (3.9) BMI (kg/m 2 ) 24.1 (4.5) 25.0 (4.6) Fentanyl usage intraop (μg) 60.4 (12.0) 59.2 (19.7) Non smoker 29 (97%) 26 (86%) History of postoperative nausea and vomiting 1 (0.03%) 0 (0%) History of motion sickness 2 (0.06%) 2 (0.06%) Type of surgery Ligation Hydrotubation 5 6 Adhesiolysis 0 1 Diagnostic laparoscopy 3 0 Values are mean (SD) or n (%). BMI, body mass index; CR, controlled release; SD, standard deviation.

4 Page 4 of 5 Table 2 Pain and analgesia Group C (oxycodone CR) Group P (placebo) p value Resting pain score postop 15 min 4.3 (2.4) 4.3 (2.5) min 3.9 (2.2) 4.4 (2.2) h 2.7 (1.6) 3.4 (2.0) h 1.8 (1.3) 2.2 (1.2) h 0.9 (1.8) 0.3 (0.6) 0.17 Pain score on movement (coughing) 15 min 4.3(2.5) 4.4(2.5) min 4.0 (2.3) 4.5 (2.2) h 2.8 ( (2.1) h 2.1 (1.5) 2.1 (1.2) h 2.4(1.8) 2.1(1.8) 0.54 Total amount of fentanyl used in recovery (μg) 39.5 (34.8) 50.5 (43.0) 0.28 Satisfaction score (%) 82.8 (14.3) 86.2 (8.7) 0.29 Time to first dose of fentanyl (min) 7.6 (4.2) 8.5 (4.7) 0.49 Time to discharge (min) (57.9) (55.2) 0.18 Values are mean (SD) or n (%). CR, controlled release; SD, standard deviation. postoperative nausea and vomiting and day surgery discharge times. There are several possible reasons for the lack of improvement in pain management. First, a single dose of oxycodone CR 10 mg may be inadequate to provide significant analgesia for postoperative pain. In the study by Jokela et al. 9, the plasma concentration of oxycodone after 15 mg of oxycodone CR amongst their patients are low compared with other studies. Hence, it might not have reached the minimum effective analgesic concentration. However, higher dose of oxycodone CR in our study may probably result in greater incidence of side effects. We found significantly higher incidence of headache and a trend to higher incidence of nausea and vomiting 24 h after surgery in the oxycodone CR group, compared with the placebo group. Second, the time to peak effect of oxycodone CR may be longer in our patients due to the presence of the nasogastric tube that is inserted via the proseal laryngeal mask airway for gastric decompression post-induction. This may affect the gastric motility as well as the rate of absorption of the drug. This had been shown in the study by Jokela et al. 9 as the time to peak concentration of oxycodone is about 4 h compared with 2.6 h after consumption in previous studies. Hence, oral oxycodone CR 1 h preoperatively may not have reached its peak effect to produce significant analgesia postoperatively. However, it may not be feasible to admit patients several hours preoperatively for pre-medication in a busy day surgery centre as this may significantly affect workflow as well as increase the waiting time for patients. In previous studies, it has been postulated that concurrent pre-medication with other analgesic, such as NSAIDs and even dexamethasone, may have provided analgesia such that the analgesic effect of oxycodone CR is not perceptible. In our study, no analgesic pre-medication other than oral oxycodone CR was used. IV ondansetron was used as an anti-emetic instead of dexamethasone. However, no difference in postoperative pain scores was found between the oxycodone CR group as compared with the placebo group. We suggest that future studies should investigate the different dosage regimes of oxycodone CR premedication to determine the optimal dosage for postoperative analgesia. However, careful monitoring of postoperative complications of oxycodone CR is needed. We also noted that our patients experienced moderate pain in the immediate postoperative period with a mean pain score of 4.3. This corresponded to a previous study by Wrigley et al. 10, which reported a mean postoperation pain score of 50 mm in patients undergoing laparoscopic tubal ligation. This shows that in the immediate postoperative period, pain score can be relatively high in ambulatory laparoscopic surgery. Measures can be taken to reduce the degree of postoperative pain such as giving higher doses of fetanyl intraoperatively and using multi-modal analgesia regime. Conclusion There is no difference in postoperative pain scores in patients who are pre-medicated with 10 mg of oral oxycodone CR compared with placebo in patients undergoing gynaecological laparoscopic day surgery. Abbreviations list BMI, body mass index; CR, controlled release; IV, intravenous; PADSS, Post Anaesthesia Discharge Scoring

5 Page 5 of 5 Table 3 Side effects Group C (oxycodone CR) Group P (placebo) p value Nausea Recovery room 9 (30) 8 (26) h postop 5 (16) 1 (3) 0.11 Vomiting Recovery room 4 (13) 5 (16) h postop 4 (13) 1 (3) 0.20 Headache Recovery room 0 1 (3) h postop 5 (16) Pruritus Recovery room 1 (3) h postop 0 0 Urinary retention Recovery room h postop 0 0 Constipation 24 h postop 15 (50) 11 (36) 0.49 Rescue anti-emetics given CR, controlled release. System; NSAID, non-steroidal anti-inflammatory drug; VAS, visual analog scale. References 1. White PF. Ambulatory anaesthesia into the new millennium. Anesth Analg May;90(5): (23) 6 (20) Chung F. Recovery pattern and home readiness after ambulatory surgery. Anesth Analg May;80(5): Gold BS, Kitz DS, Lecky JH, Neuhaus JM. Unanticipated admissions to the hospital following ambulatory surgery. JAMA Dec;262(21): Fortier J, Chung F, Su J. Predictive factors of unanticipated admission in ambulatory surgery: a prospective study. Can J Anaesth Jul;45(7): Levy MH. Advancement of opioid analgesia with controlled-release oxycodone. Eur J Pain. 2001;5(Suppl A): Mucci-LoRusso P, Berman BS, Sibersetin PT, Citron ML, Bressler L, Weinstein SM, et al. Controlled-release oxycodone compared with controlled-release morphine in the treatment of cancer pain: a randomised, double blind, parallel-group study. Eur J Pain. 1998;2(3): Gaskell H, Derry S, Moore RA, Mc- Quay HJ. Single dose oral oxycodone and oxycodone plus paracetamol (acetaminophen) for acute postoperative pain in adults. Cochrane Database Syst Rev Jul;(3):CD Reuben SS, Steinberg RB, Maciolek H, Wanda Joshi RN, DO. Preoperative administration of controlled-release oxycodone for the management of pain after ambulatory laparoscopic tubal ligation surgery. J Clin Anesth May;14(3): Jokela R, Ahonen J, Valjus M, Seppala T, Korttila K. Premedication with controlled-release oxycodone does not improve management of postoperative pain after day-case gynaecological laparoscopic surgery. Br J Anaesth Feb;98(2): Wrigley LC, Howard FM, Gabel D. Transcervical or intraperitoneal analgesia for laparoscopic tubal sterilization: a randomised controlled trial. Obstet Gynecol Dec;96(6):