BJA Advance Access originally published online on January 11, 2007
British Journal of Anaesthesia 2007 98(2):255-260; doi:10.1093/bja/ael342
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Premedication with controlled-release oxycodone does not improve management of postoperative pain after day-case gynaecological laparoscopic surgery
1 Department of Anaesthesia and Intensive Care Medicine, Helsinki University Hospital, Helsinki, Finland
2 National Public Health Institute, Helsinki, Finland
* Corresponding author: Department of Anaesthesia and Intensive Care Medicine, Helsinki University Hospital, PO Box 140, FIN-00029 HUCH, Finland. E-mail: ritva.m.jokela{at}hus.fi
Accepted for publication November 23, 2006.
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Abstract |
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BACKGROUND: Controlled-release (CR) oxycodone provides an option for the prevention of postoperative pain. We designed this randomized double-blinded placebo controlled study to evaluate the control of pain after premedication with CR oxycodone 15 mg in addition to ibuprofen 800 mg orally in day-case gynaecological laparoscopic surgery.
METHODS: Sixty consenting patients were anaesthetized in a standardized fashion. Postoperative analgesia was provided by ibuprofen 800 mg twice a day in combination with fentanyl i.v. in the recovery room and normal-release (NR) oxycodone orally after the recovery room. The visual analogue scale (VAS) scores for pain and side-effects, and the amounts of postoperative analgesics were recorded for 24 h after discharge from the hospital. After a statistical analysis of the original study, we extended the study to investigate another 10 patients, who received CR oxycodone 15 mg orally in an open-labelled fashion 60 min before surgery. The plasma concentrations of oxycodone were measured from samples drawn before and 2, 4, 6 and 8 h after premedication.
RESULTS: The amounts of fentanyl [100 µg (0–330) in the CR oxycodone group; 125 µg (0–330) in the placebo group], NR oxycodone, or the VAS scores for pain during the first 24 h after the discharge from the hospital did not differ after the premedication with CR oxycodone or placebo. In the extension study group, the peak plasma concentration (Cmax) of oxycodone was 10.0 (4.6–14.7) ng ml–1, indicating possibly a sub-therapeutic level.
CONCLUSION: Oral premedication with CR oxycodone did not improve management of postoperative pain after day-case gynaecological laparoscopic surgery.
Keywords: analgesia, postoperative; oxycodone, controlled-release; oxycodone, normal-release; plasma concentration; premedication; surgery, day-case
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Introduction |
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Despite major improvements in perioperative care, the management of acute postoperative pain still remains a problem.1 2 According to a large epidemiological study, postoperative pain is one of the most common causes for re-admission after outpatient surgery.3 In a systematic review and analysis evaluating post-discharge symptoms after outpatient surgery among 7600 patients, the incidence of reported post-discharge pain ranged from 6 to 95%.4
It has been proposed that an improved outcome after surgery could be achieved by reducing the incidence of postoperative organ dysfunction by controlling the surgical stress responses.5 Proper management of pain plays a major role in modifying surgical stress responses.6 In the prevention and treatment of pain after minor surgery, acetaminophen and non-steroidal anti-inflammatory drugs (NSAID) function as a cornerstone, where local anaesthetics are combined whenever applicable. Opioids are required frequently to achieve adequate analgesia after ambulatory surgery. However, the hazardous side-effects of opioids, such as respiratory depression, limit their use for outpatients.
Oxycodone is a synthetic derivative of thebaine, which was introduced into clinical use in 1917. It has been used as the primary opioid for acute pain in Finland since the 1960s.7 A controlled-release (CR) oral preparation of oxycodone (OxyContinTM, Mundipharma, Finland) has been available for a decade. CR oxycodone has become the most commonly used CR opioid in the US.8 CR oxycodone has been investigated in the management of postoperative pain.9 10 Given as premedication, CR oxycodone 10 mg has been shown to reduce pain and even the incidence of postoperative nausea and vomiting (PONV) after ambulatory laparoscopic tubal ligation.11 Hence, we hypothesized that the postoperative pain control would be better if outpatients undergoing gynaecological laparoscopic surgery would receive CR oxycodone 15 mg in addition to ibuprofen 800 mg orally as premedication.
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Methods |
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After the Institutional Ethics Committee (IEC) and the National Agency of Medicines (NAM) approved this randomized, double-blinded placebo controlled trial, we obtained the written informed consent of 61 women scheduled for day-case gynaecological laparoscopic surgery. Finnish-speaking patients over 18 yr of age and with a body mass index (BMI) of 18–35 kg m–2 met the inclusion criteria if they were ASA physical status I–II, did not have contraindications to the use of any of the study medications, or were not medicated with opioids preoperatively.
The consenting patients were premedicated orally 60 min before surgery with the study medication: placebo or CR oxycodone 15 mg in addition to diazepam 5 mg, and ibuprofen 800 mg. The hospital pharmacy performed the randomization, using a computer-generated random number table and masked the study medication by packing both placebo and CR oxycodone (10 mg + 5 mg) into two identical capsules and further packed and sealed in opaque plastic containers labelled with the randomization numbers. Each patient received a consecutive randomization number. The randomization code was not opened until the final interview of the last study patient was performed.
In the operating theatre, an i.v. access was established and standard monitoring with ECG, pulse oximetry, non-invasive blood pressure (NIBP), and Bispectral Index (BISTM; Aspect Medical Systems Inc., Natick, MA, USA) was started. A remifentanil infusion was initiated with a dose of 0.2 µg kg–1 min–1 and induction of anaesthesia was achieved with propofol 2.0–2.5 mg kg–1. Tracheal intubation was facilitated with rocuronium 0.6 mg kg–1, and the patients were mechanically ventilated with a mixture of oxygen and nitrous oxide (0.5 l:0.5 l) to keep the E'CO2 at the level of 4.5–5.0 kPa. After intubation, a gastric tube was inserted to deflate the stomach, and the gastric tube was aspirated and removed prior to extubation. The propofol infusion was initiated with a dose of 0.1 mg kg–1 min–1 and adjusted to keep the BISTM level between 45–55, and the remifentanil infusion was adjusted to keep NIBP at – 15 to + 15% of the baseline value. To prevent PONV, all patients received dexamethasone 5 mg i.v. immediately after the induction of anaesthesia, and droperidol 0.5–0.75 mg i.v. and ondansetron 4 mg i.v. at the end of surgery. When the operation was completed, the remifentanil infusion was discontinued and a 0.075 mg i.v. bolus of fentanyl was given. During the closure of the skin, propofol infusion was stopped and neostigmine 2.5 mg with glycopyrrolate 0.5 mg i.v. was applied to reverse the neuromuscular blockade. The total amounts of remifentanil and propofol infused and the average values of BIS during the anaesthesia were recorded.
In the recovery room, postoperative pain was treated by the study nurse with 0.025 mg doses of fentanyl i.v. All patients received ibuprofen 800 mg orally on the evening of the day of surgery and on the next morning. To treat the breakthrough pain, they received normal-release (NR) oxycodone 5 mg orally. While the patients still had an i.v.-line, the rescue anti-emetic medication was droperidol 0.5 mg i.v. or ondansetron 4 mg i.v. After the i.v.-line was removed, the patients received an ondansetron disintegrating tablet to treat a possible episode of PONV. Postoperative pain was assessed using an 11-point scale (visual analogue scale, VAS), which the patients were trained to use before premedication. Besides pain scores, VAS scores for side-effects including PONV, drowsiness, lack of concentration, dizziness, and itching were recorded at 2 h after surgery and at discharge from hospital. The patients contacted by telephone 24–30 h after discharge from hospital and interviewed by the study nurse or one of the investigators who was unaware of the patients group. A structured questionnaire was used to inquire the patients' pain scores, total amounts of analgesics used, possible side-effects, and their satisfaction with the anaesthesia experience and pain treatment.
Extension of the study to determine the plasma concentrations of oxycodone
After completing the study and performing the statistical analysis on the original study patients, we applied for the approval of IEC and NAM to further study 10 patients scheduled for day-case gynaecological laparoscopic surgery, and to draw blood samples from these patients to determine their plasma concentrations of oxycodone. After obtaining the written informed consent of the patients, they received CR oxycodone 15 mg orally in addition to diazepam 5 mg and ibuprofen 800 mg as premedication 60 min before surgery in an open-labelled fashion. The anaesthesia and pain management as well as the follow-up of these patients were carried out according to the original study protocol. In addition, we drew blood samples of these patients to measure the plasma concentrations of oxycodone at the time of their premedication (0 sample) and at 2, 4, 6 and 8 h after giving the premedication. The plasma concentrations of oxycodone were analysed in the laboratory of the National Public Health Institute, Helsinki, Finland.
Chemicals and reagents
Oxycodone hydrochloride was obtained from Santen Oy (Tampere, Finland), and nalorphine hydrochloride (internal standard, IS) was purchased from Sigma-Aldrich Chemie Gmbh (Steinheim, Germany). All the reagents used were of the highest quality.
Determination of oxycodone concentrations in plasma samples
The frozen plasma samples were thawed overnight at 5°C. Sample preparation was carried out as follows: oxycodone was extracted from a 1 ml aliquot of the sample by mixing with 1 ml of buffer (0.5 M Na2HPO4 · 2 H2O) and 5 ml of toluene (containing 0.08 µg ml–1 of the IS). After centrifugation, the toluene layer was transferred into a clean test tube and evaporated to dryness with a vacuum evaporator. After dissolving the residue in 48 µl of butyl acetate, 12 µl of the derivatization reagent, N-methyl-N-trimethylsilyl-trifluoroacetamide were added. Two-microlitre aliquot of the sample was injected into a gas chromatograph–mass spectrometer (GC–MS).
The analysis was performed with a Hewlett-Packard (Hewlett-Packard Company, Palo Alto, CA, USA) GC–MS (EI, positive ions, 70 eV). The system was operated in the splitless injector mode. The GC column was a DB-200 of length 30 m, internal diameter 0.32 mm, and film thickness 0.25 µm (J&W Scientific Inc., Folsom, CA, USA). Helium was used as the carrier gas. The column temperature was initially 120°C with a hold time of 0.50 min, and it was increased 15°C min–1, with a final hold time of 1 min at 340°C. The inlet and MSD transfer line heater temperatures were maintained at 250 and 300°C, respectively. MS detection was performed in the selected ion monitoring mode.
The lower limit of quantitation was set at 2.0 ng ml–1 for oxycodone. At a concentration level of 50 ng ml–1, repeatability (relative standard deviation) was 11%.
Power analysis
A power analysis was performed using a power of 80% and an 
of 0.05 to detect a 30% reduction (SD 30%) in the consumption of fentanyl after premedication with CR oxycodone 15 mg compared with placebo. According to these assumptions, a sample size of 16 per group was required. When a sample size was estimated using VAS-scores, a 15 mm difference in pain scores after premedication with CR oxycodone 15 mg, compared with placebo was considered clinically significant. With an SD of 20 mm, the sample size was calculated to be 28 per study group. Using these two calculations, we decided to randomize 30 patients into each group.
Statistical analysis
Patient characteristics and clinical information including ASA physical status classification, smoking habits, and history of PONV or motion sickness, different types of surgery, and the incidences of PONV were analysed using the 
2-test. The demographic data including age and BMI, and clinical data including the duration of surgery and anaesthesia, dose of remifentanil during anaesthesia, and average BISTM-value during anaesthesia were compared by the test statistic based on the t-distribution assuming unequal variances. The times to the first rescue analgesic, the amounts of postoperative analgesics, and the VAS scores for pain and side-effects were evaluated using Kruskal–Wallis analysis. A P < 0.05 was considered significant. The statistical analysis was performed using the Statistical Package for Social Sciences (SPSSTM), Windows versions 13.0.1 and 14.0 (SPSS Inc.; Chicago, IL, USA).
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Results |
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The study was carried out in the operating theatre and on the gynaecological ward in Women's Hospital, Helsinki University Hospital, Helsinki, Finland, between October 2004 and October 2005. A total of 61 patients were enrolled in the study. In the case of one patient, the operation was cancelled after allocation into the CR oxycodone group but before premedication; in the case of two patients, one in both study groups, the laparoscopic procedure was converted to a laparotomy. These three patients were excluded from the study. Hence, in the final analysis there were 58 patients. The demographic data did not differ among the two study groups (Table 1). The distribution of laparoscopic procedures and the duration of anaesthesia and surgery were similar in the two groups. The amounts of remifentanil and propofol were equal in both groups. The average BISTM values did not differ in the two groups.
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The VAS scores for pain when the patient was at rest or in motion during the first two 2 h after surgery or during 2–24 h after surgery did not differ between the study groups (Table 2). Neither the amounts of rescue fentanyl [100 µg (0–330) in the CR oxycodone group; 125 µg (0–330) in the placebo group] in the recovery room, nor the proportions of the patients taking NR oxycodone for rescue analgesia during 2–24 h differed between the two study groups. Also the time to the first rescue analgesic dose was the same in the two study groups. The patients' satisfaction with pain medication was at the same level in both study groups (Table 2).
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Side-effect profile was similar in the two groups (Table 3), and the incidence of PONV was equal. Also the VAS-scores for drowsiness, dizziness, concentration disturbances, itching, headache, constipation, or urinating disturbances were at the same level in both groups (Table 3).
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The extended study for analysing the plasma concentrations of oxycodone was carried out in the operating theatre and on the gynaecological ward in Women's Hospital, Helsinki University Hospital, Helsinki, Finland, during December 2005 and January 2006. Eleven women were invited to participate in the study, of whom 10 consenting were enrolled. The demographic data of this group do not differ from the two original study groups. The mean amount of fentanyl in the PACU was 75 (range 25–250) µg; the mean time to the first fentanyl dose was 26 min (range 12–107). Five (50%) of these patients required NR oxycodone for analgesia during 2–24 h after surgery. The pain VAS scores were at the same level as those in the two original study groups. The plasma concentrations of oxycodone with these 10 patients at the time of premedication and 2, 4, 6, and 8 h after premedication are given in Figure 1. The mean peak plasma concentration (Cmax) of oxycodone was 10.0 (3.8) (range 4.6–14.7) ng ml–1. The mean time to the peak plasma concentration was 4.8 (3.0) (range 2–8) h. There was no correlation between the plasma concentrations of oxycodone and the pain VAS scores.
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Discussion |
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There was no improvement in the quality of the management of postoperative pain with CR oxycodone given as premedication, compared with placebo after laparoscopic gynaecological surgery. This finding contradicts the results of Reuben et al.11 These authors showed a reduction in the consumption of rescue pain analgesics, the VAS scores, the incidence of PONV, and even in the discharge times after laparoscopic tubal ligation, by using only a single 10 mg dose of CR oxycodone as premedication. The discrepancy between the results of the two studies is even greater when we look at their similar methodology: the study subjects were women undergoing gynaecological laparoscopic surgery, and in both studies all patients received NSAIDs in addition to premedication with oral CR oxycodone. In Reuben's study, the patients were given ketorolac 15 mg after induction of anaesthesia, whereas in our study all the patients received ibuprofen 800 mg orally with the premedication. In addition, our patients received dexamethasone 5 mg for anti-emetic prophylaxis during the induction of anaesthesia. There is evidence that glucocorticoids, besides their anti-emetic activity, have analgesic potency.12 It is possible that if our patients had not received NSAIDs and dexamethasone before surgery, the analgesic effect of CR oxycodone would have been perceptible. However, we designed this study to reflect the actual clinical situation. Modern pain management after ambulatory surgery is based on NSAIDs and acetaminophen.6 Opioids are the next step in pain management, in addition to NSAIDs and acetaminophen. The analgesic medication chosen for clinical use should nevertheless have the desired effect. Although the incidence of all side-effects was equal in the two study groups, the use of opioids should be controlled because of their potential side-effects.
Oxycodone is a strong µ-receptor specific opioid. The pharmacokinetic characteristics of oxycodone are similar to those of morphine, with a parenteral analgesic potency approximately 0.75 that of parenteral morphine. The oral bioavailability of oxycodone (>60%) is approximately twice that of morphine (20–25%); this explains the fact that the relative potency of oral oxycodone is approximately twice that of oral morphine.13 Oxycodone is metabolized primarily (45%) by way of N-demethylation to noroxycodone, and only to some extent by way of O-demethylation (11%) to oxymorphone and - and ß-oxymorphol, and 6-keto-reduction (8%) to - and ß-oxycodol.14 The plasma and urine concentrations of noroxycodone have been shown to be higher after oral than after intramuscular administration, demonstrating the considerable first-pass metabolism of oxycodone.13 The liver enzyme P450 2D6 (CYP 2D6) acts as a catalyst when oxycodone is catalysed to oxymorphone, and noroxycodone to noroxymorphone.7 A weak CYP 2D6 enzyme activity was observed in 5–10% of the Caucasian population.
The plasma concentrations of oxycodone among the 10 patients in the extension study were rather low [mean Cmax 10.0 (SD 3.8) ng ml–1]. Among 28 healthy volunteers, mean Cmax values of 23.2 (8.6) ng ml–1 were found after administration of CR oxycodone 20 mg orally.15 Benziger et al.16 observed mean Cmax values of 20.1 ng ml–1 after administration of one CR oxycodone 20 mg tablet, and 18.5 ng ml–1 after two CR oxycodone 10 mg tablets in 24 healthy male volunteers. In a recent study conducted in 16 healthy volunteers, a 15 mg dose of CR oxycodone resulted in a mean Cmax value of 38 (7.4) ng ml–1.14 It is possible that the plasma concentrations of oxycodone in the patients in our study were not at the level of analgesic efficacy. The minimum effective analgesic concentration (MEAC) of oxycodone has not been assessed, although the MEAC value for morphine is determined to range from 12 to 24 ng ml–1. However, when plasma concentrations of oxycodone were measured after plastic breast reconstruction or lumbar fusion surgery in patients during patient-controlled analgesia (PCA) with oxycodone, mean oxycodone concentrations of 37.5 ng ml–1 (range 0–100 ng ml–1) and of 38.1 ng ml–1 (range < 3–98 ng ml–1), respectively, were found.17 Apparently, the plasma concentrations of oxycodone required for analgesic potency are distinctively higher than the plasma concentrations in our patients.
We did not measure the plasma concentrations of oxycodone metabolites. According to a recent study, the parent drug appears to explain the central opioid effects of oxycodone.14 Of the metabolites of oxycodone, noroxymorphone is very active, and is found in relatively high concentrations. However, neither noroxymorphone nor any other metabolites of oxycodone appear to penetrate the blood–brain barrier.14 In addition, noroxycodone has no analgesic activity.18 Of the other metabolites, oxymorphone has analgesic potency, but the plasma concentrations of oxymorphone were shown to be insignificant after oral administration.13
The time to the maximum concentration of oxycodone is about 1.3 h after immediate-release oxycodone, and about 2.6 h after CR oxycodone.19 In the extension of the present study, the time to maximum concentration was extremely high, 4.8 (3.0) (range 2–8) h, suggesting that the absorption of CR oxycodone was clearly delayed. Our routine practice with laparoscopic surgery patients is to insert a gastric tube into the stomach immediately after intubation to deflate the stomach. The reason for this manoeuvre is to prevent the stomach from inflating with air while ventilating the patient before intubation, and the possible accidental insertion of the Verres needle into the air-expanded ventricle. It is possible that by using a gastric tube, we disturb the motility of the intestine and the intestinal absorption of the medicines taken by mouth. The absorption of the medicines in the intestine may be further reduced by the opioids that are applied throughout the entire anaesthesia and immediate recovery, as the opioids slow down the motility of intestine.
The incidence of PONV (25% of all patients) appears to be rather high in both study groups in spite of the anti-emetic management of anaesthesia: propofol anaesthesia and triple prophylaxis with dexamethasone, droperidol, and ondansetron.20 However, these patients were high-risk gynaecologic patients for PONV; 70% of them were non-smokers and 45% had a history of PONV or motion sickness. Nausea was assessed by the patients using a VAS score (0–10). For the statistical analysis, all nausea (VAS score 1–10) was included as ‘nausea’. About half of all patients experiencing PONV (12% of all patients) received rescue anti-emetic medication. The incidence of vomiting (5% of all patients) was extremely low, suggesting that the incidence of intractable nausea was negligible.
The pain after ambulatory surgery remains a problem. According to a survey conducted in Sweden, 35% of the patients, and to another in Canada, 40% of the patients in ambulatory surgery experience moderate or severe pain during the first days after surgery.21 22 In a recent survey in Finland, 57% of ambulatory surgery patients experienced moderate or severe pain during the first week after surgery.2 In the US, 70% of ambulatory surgery patients suffered from moderate, severe, or extremely severe pain after discharge from the hospital.1 The initiation of analgesic medication before surgery ensures analgesia when the postoperative pain is the most intense. Unexpectedly, pre-emptive pain medication was not found to have a beneficial effect on postoperative analgesia.23
In conclusion, premedication with 15 mg oral CR oxycodone does not improve the management of postoperative pain after day-case gynaecological laparoscopic surgery.
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We are grateful to Ms Maria Jokilehto, RN, and Ms. Eija Ruoppa, RN, and the entire staff of the operation theatre and gynaecological ward in Women's Hospital, Helsinki University Hospital for taking excellent care of our patients. The study was financially supported by the HUS-EVO Committee, Helsinki, Finland (TYH 5229) and by a grant from the Paulo Foundation, Helsinki, Finland.
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1 Apfelbaum JL, Chen C, Mehta SS, Gan TJ. (2003) Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg 97:534–40.
2 Mattila K, Toivonen J, Janhunen L, Rosenberg PH, Hynynen M. (2005) Post-discharge symptoms after ambulatory surgery: first-week incidence, intensity, and risk factors. Anesth Analg 101:1643–50.
3 Gold BS, Kitz DS, Lecky JH, Neuhaus JM. (1989) Unanticipated admission to the hospital following ambulatory surgery. JAMA 262:3008–10.[Abstract]
4 Wu CL, Berenholtz SM, Pronovost PJ, Fleisher LA. (2002) Systematic review and analysis of postdischarge symptoms after outpatient surgery. Anesthesiology 96:994–1003.[CrossRef][ISI][Medline]
5 Kehlet H. (1997) Multimodal approach to control postoperative pathophysiology and rehabilitation. Br J Anaesth 78:606–17.
6 Kehlet H and Holte K. (2001) Effect of analgesia on surgical outcome. Br J Anaesth 87:62–72.
7 Kalso E. (2005) Oxycodone. J Pain Symptom Manage 29:.
8 Davis MP, Varga J, Dickerson D, Walsh D, Legrand SB, Lagman R. (2003) Normal-release and controlled-release oxycodone: pharmacokinetics, pharmacodynamics, and controversy. Support Care Cancer 11:84–92.[ISI][Medline]
9 Curtis GB, Johnson GH, Clark P, et al. (1999) Relative potency of controlled-release oxycodone and controlled-release morphine in a postoperative pain model. Eur J Clin Pharmacol 55:425–9.[CrossRef][ISI][Medline]
10 Reuben S, Connelly NR, Maciolek H. (1999) Postoperative analgesia with controlled-release oxycodone for outpatient anterior cruciate ligament surgery. Anesth Analg 88:1286–91.
11 Reuben SS, Steinberg RB, Maciolek H, Joshi W. (2002) Preoperative administration of controlled-release oxycodone for the management of pain after ambulatory laparoscopic tubal ligation surgery. J Clin Anesth 14:223–7.[CrossRef][ISI][Medline]
12 Romundstad L, Breivik H, Roald H, et al. (2006) Methylprednisolone reduces pain, emesis, and fatigue after breast augmentation surgery: a single-dose, randomized, parallel-group study with methylprednisolone 125 mg, parecoxib 40 mg, and placebo. Anesth Analg 102:418–25.
13 Pöyhiä R, Seppälä T, Olkkola KT, Kalso E. (1992) The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects. Br J Clin Pharmacol 33:617–21.[ISI][Medline]
14 Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen LY, Shen DD. (2006) Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther 79:461–79.[CrossRef][ISI][Medline]
15 Kaiko RF, Benziger DP, Fitzmartin RD, Burke BE, Reder RF, Goldenheim PD. (1996) Pharmacokinetic–pharmacodynamic relationships of controlled-release oxycodone. Clin Pharmacol Ther 59:52–61.[CrossRef][ISI][Medline]
16 Benziger DP, Miotto J, Grandy RP, Thomas GB, Swanton RE, Fitzmartin RD. (1997) A pharmacokinetic/pharmacodynamic study of controlled-release oxycodone. J Pain Symptom Manage 13:75–82.[CrossRef][ISI][Medline]
17 Silvasti M, Rosenberg PH, Seppälä T, Svartling N, Pitkänen M. (1998) Comparison of analgesic efficacy of oxycodone and morphine in postoperative intravenous patient-controlled analgesia. Acta Anaesthesiol Scand 42:576–80.[ISI][Medline]
18 Heiskanen T, Olkkola K, Kalso E. (1998) Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacol Ther 64:603–11.[CrossRef][ISI][Medline]
19 Mandema JW, Kaiko RF, Oshlack B, Reder RF, Stanski DR. (1996) Characterization and validation of a pharmacokinetic model for controlled-release oxycodone. Br J Clin Pharmacol 42:747–56.[CrossRef][ISI][Medline]
20 Apfel CC, Korttila K, Abdalla M, et al. (2004) A factorial trial to study six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 350:2441–51.
21 Rawal N, Hylander J, Nydahl PA, Olofsson I, Gupta A. (1997) Survey of postoperative analgesia following ambulatory surgery. Acta Anaesth Scand 41:1017–22.[ISI][Medline]
22 Beauregard L, Pomp A, Chonière M. (1998) Severity and impact of pain after day-surgery. Can J Anaesth 45:304–11.
23 Møiniche S, Kehlet H, Dahl JB. (2002) A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief. Anesthesiology 96:725–41.[CrossRef][ISI][Medline]
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