Efficacy of early intravenous bolus oxycodone or fentanyl in emergence from general anaesthesia and postoperative analgesia following laparoscopic cholecystectomy: A randomized trial

Abstract

Objectives

To compare prospectively the efficacy of early intravenous bolus of oxycodone or fentanyl in providing analgesia at emergence from general anaesthesia following laparoscopic cholecystectomy.

Methods

Patients were randomly assigned to receive either 0.08 mg/kg oxycodone (Group O) or 1 µg/kg fentanyl (Group F), 20 min before the end of surgery. Postoperative pain was evaluated using a visual analogue scale (VAS). The time to first postoperative analgesic dose, requirement for analgesia and side-effects were assessed in the postanaesthesia care unit (PACU).

Results

The VAS scores at 0 min and 30 min and requirement for analgesia were significantly lower in Group O (n = 28) than in Group F (n = 26). The time to first analgesia dose was significantly longer in Group O than Group F. There were no significant between-group differences in the incidence of side-effects.

Conclusions

Oxycodone relieves immediate postoperative pain significantly better than fentanyl, and is not associated with an increase in side-effects in patients undergoing laparoscopic cholecystectomy.

Introduction

Oxycodone is a strong, pure, semisynthetic opioid that is an agonist of the central, peripheral and autonomous nervous systems. The efficacy and safety of oxycodone in treating both acute and chronic moderate-to-severe postoperative or cancer pain are well documented, and increasing doses boost analgesia without any ceiling effects.^1–6 In addition, the potency of oxycodone is around twice that of morphine.^7,8

Laparoscopic cholecystectomy is the standard treatment for cholelithiasis. Recovery is affected by several factors including shoulder-tip pain and abdominal pain caused by peritoneal stretching, diaphragm irritation due to high intra-abdominal pressure and carbon dioxide levels, nausea, vomiting and fatigue.^9,10 High intra-abdominal pressure in laparoscopic cholecystectomy can result in more severe pain than that caused by laparotomy, and this pain can induce agitation at emergence from general anaesthesia in the operating room or during transfer to or arrival at the postanaesthesia care unit (PACU).^10–14 Emergence from general anaesthesia should ideally happen quickly and smoothly, and be free from undesirable effects and altered respiration.^13,14 Patients who undergo laparoscopic cholecystectomy may therefore need prophylactic analgesia to minimize discomfort and facilitate their recovery at this time.

Intravenous fentanyl can be administered via a rapid titration protocol and is useful in ambulatory surgery,^15,16 however it provides only 30–60 min analgesia following a single intravenous dose and is associated with increases in postoperative complications (including delayed discharge and unanticipated hospital admission following day-care surgery). ¹⁷ The duration of a single intravenous dose of oxycodone is 2–5 h,^18,19 but there is a high risk of side-effects including postoperative nausea and vomiting or delayed awakening from sedation. ²⁰ Fentanyl provides almost immediate analgesic effects when given intravenously, whereas oxycodone takes effect 10–15 min after administration.^18,19

The aim of this study was to compare the effectiveness of early intravenous bolus of oxycodone or fentanyl in providing analgesia at emergence from general anaesthesia.

Patients and methods

Study population

This randomized, prospective study enrolled consecutive American Society of Anesthesiologists (ASA) physical status I and II ²¹ adult patients (aged ≥ 18 years) undergoing elective laparoscopic cholecystectomy for symptomatically uncomplicated gallstone disease in the Department of Anaesthesia and Pain Medicine, University of Ulsan College of Medicine, Asan Medical Centre, Seoul, Republic of Korea between May 2014 and July 2014. Exclusion criteria were: allergy to oxycodone or fentanyl; history of chronic morphine or fentanyl use; other comorbid conditions; use of other analgesics; pregnancy; conversion to open surgery or additional surgery; history of hepatic, renal, or cardiac disease. All patients were educated about the study protocol and the visual analogue scale (VAS; described below) for pain at the preanaesthetic check-up.

Patients were randomly assigned to receive oxycodone (group O) or fentanyl (group F) according to a computer-generated random-number sequence (available at http://www.randomization.com/). Equianalgesic doses^19,22 of the study drugs were administered in a double-blind manner. A computer-generated randomization list and the blinded study medication were prepared by the hospital pharmacy. Syringes were marked with the name of the study and consecutive patient numbers. The randomization list was held securely at the hospital pharmacy and released only after completion of the study.

The study protocol was approved by the institutional review board of Asan Medical Centre, Seoul, Republic of Korea (no. IIT-2014-0618), and written informed consent was obtained from each patient. This study was registered with the Clinical Research Information Service (no. KCT0001168).

Anaesthesia

Routine haemodynamic monitoring (electrocardiogram, noninvasive blood pressure and pulse oximetry) and train-of-four (TOF) monitoring were used for all patients. Anaesthesia was induced using 2 mg/kg propofol intravenous bolus followed by 0.7 mg/kg rocuronium intravenous injection, and endotracheal intubation was performed. Patients were mechanically ventilated with a tidal volume of 8–12 ml/kg at a respiratory rate of 12–18 breaths/min to maintain endtidal carbon dioxide partial pressure (ETCO₂) of 30 – 40 mmHg. Anaesthesia was maintained with 6–9 vol% desflurane with 50% oxygen and nitrous oxide, and bispectral index (BIS A-1050 Monitor, Aspect Medical Systems, Newton, MA, USA) was maintained at 40–50.

Surgery was performed using standard laparoscopic techniques with four working ports, and the duration of surgery was recorded. Study drugs were administered 20 min before the end of surgery. Patients in group O received 0.08 mg/kg OxyNorm® (oxycodone [14-hydroxy-7,8-dihydrocodeinone]; Mundipharma, Vantaa, Finland) and those in group F received 1 µg/kg fentanyl. All patients were transferred to the PACU on recovery from anaesthesia.

Outcome measures

Postoperative pain was assessed using a VAS on arrival in the PACU (0 min), and after 30 min and 1 h in the PACU and 6 h and 24 h in the ward. Associated recovery variables including sedation score (S, asleep but easily roused; 1, awake and alert; 2, occasionally drowsy, easily roused; 3, frequently drowsy, falls asleep during conversation; 4, somnolent, minimal or no response to stimulation), ²⁰ dizziness, nausea, and vomiting were noted. VAS scores ≥ 5 were treated via 0.5 µg/kg fentanyl intravenous injection (immediate onset of action).^18,19,23 Time to first and second analgesia dose were noted. Mean blood pressure (MBP) and heart rate (HR) were measured throughout the perioperative period.

Statistical analyses

A sample size calculation was performed based on an expected between-group difference in VAS change (from baseline to 0 h, 0.5 and 1 h in PACU) of 1.87 as shown in a pilot study. Assuming 5% significance level, 90% statistical power and a two-sided test, 22 participants per group were required. To allow for a 20% drop out rate, the present study required a total of 54 participants.

Data were presented as mean ± SD for continuous variables or n of patients (%) for categorical data. Demographic data and postoperative pain related parameters were analysed using χ²-test or Fisher’s exact test for categorical data, and two-sample t-test or Mann–Whitney U-test for continuous variables. Mean changes from baseline in VAS, MBP and HR were estimated and tested using two-sample t-test, or analysis of covariance when baseline values in two groups were significantly different. A generalized linear mixed model was applied to evaluate the longitudinal profile of VAS, MBP and HR. The incidence of postoperative nausea and vomiting were analysed using χ²-test. All statistical analyses were performed using SAS® version 9.3 (SAS Institute, Inc., Cary, NC, USA). P-values < 0.05 were considered to be statistically significant.

Results

The study recruited 58 patients, four of whom were excluded (three before and one after randomization). The final analysis included a total of 54 patients (31 male/23 female; mean age 54.9 ± 11.1 years; age range 23–65 years). A flow diagram of the study is shown in Figure 1. Demographic and clinical characteristics of the patients stratified according to group are shown in Table 1. There were no statistically significant between-group differences in patient age, sex, body mass index, ASA physical status, duration of surgery and anaesthesia, or the time from the end of surgery to extubation.

Figure 1.

Flow diagram of a study to compare the analgesic effect at emergence from general anaesthesia of early intravenous bolus of oxycodone.

Table 1.

Demographic and clinical characteristics of patients undergoing laparoscopic cholecystectomy included in a study to compare the analgesic effect at emergence from general anaesthesia of early intravenous bolus of oxycodone or fentanyl.

Characteristic	Oxycodone group n = 28	Fentanyl group n = 26
Age, years	55.1 ± 11.3	54.8 ± 11.1
Sex, male/female	19/9	12/14
BMI, kg/m2	24.6 ± 3.1	23.9 ± 3.0
ASA PS I/II	16/12	13/13
Duration of surgery, min	52.3 ± 20.0	59.2 ± 20.1
Duration of anaesthesia, min	67.8 ± 17.4	73.0 ± 20.4
End of surgery to extubation, min	5.4 ± 3.0	4.9 ± 2.8

Data presented as mean ± SD or n of patients.

BMI, body mass index; ASA, American Society of Anesthesiologists physical status. ²¹

No statistically significant between-group differences (P ≥ 0.05; χ²-test or Fisher’s exact test for categorical data; two sample t-test or Mann–Whitney U-test for continuous data).

Data regarding MBP and HR are shown in Figure 2 and 3, respectively. There were no statistically significant between-group differences in either parameter at any time point.

Figure 2.

Changes in mean blood pressure in patients undergoing laparoscopic cholecystectomy, included in a study to compare the analgesic effect at emergence from general anaesthesia of early intravenous bolus of oxycodone (Group O; n = 28) or fentanyl (Group F; n = 26). A, arrival at operating room; B, start of surgery; C, 10 min after start of surgery; D, 20 min after start of surgery; E, 30 min after start of surgery; F, injection of study drug (20 min before end of surgery); G, end of surgery; H, before extubation; I, end of anaesthesia; J, arrival in postanaesthetic care unit; K, before discharge to ward. No statistically significant between-group differences (P ≥ 0.05; two sample t-test or analysis of covariance).

Figure 3.

Changes in heart rate in patients undergoing laparoscopic cholecystectomy included in a study to compare the analgesic effect at emergence from general anaesthesia of early intravenous bolus of oxycodone (Group O; n = 28) or fentanyl (Group F; n = 26). A, arrival at operating room; B, start of surgery; C, 10 min after the start of surgery; D, 20 min after the start of surgery; E, 30 min after the start of surgery; F, injection of study drug (20 min before the end of surgery); G, end of surgery; H, before extubation; I, end of anaesthesia; J, arrival in postanaesthetic care unit; K, before discharge to ward. No statistically significant between-group differences (P ≥ 0.05; two sample t-test or analysis of covariance).

Postoperative pain-related parameters and recovery variables are presented in Table 2. The time taken to administration of the first analgesic was significantly longer in Group O than Group F (P < 0.05; Table 2). There was no significant between-group difference in the timing of the second analgesic. Significantly fewer patients in Group O required a first analgesic dose in the PACU compared with those in Group F (P < 0.05; Table 2). Similar numbers of patients in each group required a second analgesic dose in the PACU, however. There were no significant between-group differences in postoperative sedation score or the incidence of dizziness and nausea/vomiting in the PACU (Table 2).

Table 2.

Postoperative parameters in patients undergoing laparoscopic cholecystectomy included in a study to compare the analgesic effect at emergence from general anaesthesia of early intravenous bolus of oxycodone or fentanyl.

Parameter	Oxycodone group n = 28	Fentanyl group n = 26	Statistical significance a
Time of first analgesic in PACU, min	21.4 ± 10.1	13.8 ± 9.7	P < 0.05
Time of second analgesic in PACU or ward, min	85.5 ± 32.3	86.3 ± 40.5	NS
Patients receiving first analgesic in PACU	11 (39.2)	24 (92.3)	P < 0.05
Patients receiving second analgesic in PACU	2 (7.1)	1 (3.8)	NS
Sedation score ≥ 2	0	0	–
Dizziness	0	0	–
Nausea in PACU	1 (3.5)	0	NS
Vomiting in PACU	0	0	–

Data presented as mean ± SD or n of patients (%).

a

χ²-test or Fisher’s exact test for categorical data; two sample t-test or Mann–Whitney U-test for continuous data.

PACU, postanaesthetic care unit; NS, not statistically significant (P ≥ 0.05)

Sedation score (S, asleep but easily roused; 1, awake and alert; 2, occasionally drowsy, easily roused; 3, frequently drowsy, falls asleep during conversation; 4, somnolent, minimal or no response to stimulation).

Pain scores were significantly lower in Group O than Group F at 0 h (on arrival in the PACU) and 30 min (P < 0.05; Figure 4). Pain scores did not differ significantly between groups at any other time point.

Figure 4.

Pain scores assessed using visual analogue scale (VAS) in the 24 h period following laparoscopic cholecystectomy in a study to compare the analgesic effect at emergence from general anaesthesia of early intravenous bolus of oxycodone (Group O; n = 28) or fentanyl (Group F; n = 26). 0 h, arrival in postanaesthetic care unit. *P < 0.05 in compared with Group F; two sample t-test or analysis of covariance.

Discussion

Early intravenous oxycodone significantly increased the time to postoperative analgesic administration compared with intravenous fentanyl in the present study, due to its longer duration of action.

Opioid drugs are useful in relieving postoperative pain, but are associated with a high risk of side-effects.^17,20 Nonopioid alternatives include lidocaine, magnesium, ²⁴ diclofenac and celecoxib, ²⁵ all of which have been used to treat postoperative pain following laparoscopic cholecystectomy. Lidocaine can be administered during the perioperative period to control central hyperalgesia, and affects mechanoinsensitive nociceptors, provides anti-inflammatory effects to sodium channel blockade^26–28 and inhibits N-methyl-d-aspartate (NMDA) receptors. ²⁹ Magnesium noncompetitively inhibits NMDA receptors and calcium at different voltage-gated channels. ³⁰ Intraincisional infiltration with bupivacaine/phenylephrine has been shown to significantly reduce postoperative abdominal pain and narcotic analgesic consumption for up to 24 h. ³¹ Since postoperative pain after laparoscopic cholecystectomy originates from capnoperitoneum and the gallbladder bed, intraincisional infiltration is not sufficient to reduce postoperative pain. ³² Prostaglandin synthesis inhibitors, such as diclofenac and cyclo-oxygenase-2-selective nonsteroidal anti-inflammatory drugs, reduce postoperative pain following laparoscopic cholecystectomy, but do not sufficiently control pain. ²⁵

Oxycodone is an opioid agonist, and is superior to other opioids for treating visceral pain. ³³ Oxycodone has affinity for κ, μ, and Δ receptors within the central, peripheral and autonomous nervous systems, inhibits adenylylcyclase, hyperpolarizes nerve cells, and reduces excitability.^1–6 Its clinical efficacy is similar to that of fentanyl, and the doses used in the present study were equianalgesic.^19,22

It has been shown that a single bolus of oxycodone administered at the end of anaesthesia decreased the intensity of abdominal pain for up to 90 min, but there was a strong tendency towards additional side-effects (including sedation or delayed emergence) compared with fentanyl. ²⁰ Emergence agitation is a postanaesthetic phenomenon that develops in the early phase of recovery. In order to ameliorate oxycodone’s tendency toward side-effects and to provide effective analgesia at emergence, we administered study drugs at 20 min before the end of surgery. There were no between-group differences in the incidence of sedation, dizziness, nausea or vomiting in the present study. Since intraoperative remifentanil use can cause opioid induced hyperalgesia/acute opioid tolerance and may affect postoperative pain scores, the present study was performed without remifentanil. ³⁴

This study is limited by the use of a single type of surgical procedure (laparoscopic cholecystectomy). As such, the findings may not be transferrable to open surgeries or emergency procedures.

In conclusion, intravenous oxycodone bolus 20 min before the end of surgery relieves immediate postoperative pain significantly better than fentanyl, and is not associated with an increase in side-effects in patients undergoing laparoscopic cholecystectomy.