Comparison of oxycodone and sufentanil for patient-controlled intravenous analgesia after laparoscopic radical gastrectomy: A randomized double-blind clinical trial.

BACKGROUND: Sufentanil is widely used for patient-controlled intravenous analgesia (PCIA). Oxycodone has a powerful analgesic effect and mild side effects. We conducted this study to compare the efficacy of oxycodone and sufentanil for PCIA on postoperative pain after laparoscopic radical gastrectomy.
METHODOLOGY: A total of fifty patients scheduled for laparoscopic radical gastrectomy were equally randomized to receive postoperative pain treatment with either oxycodone (Group O) or sufentanil (Group S) for 48 h postoperatively. PCIA was set on demand mode without loading dose or background infusion. Postoperative cumulative sufentanil or oxycodone consumption, pain intensity, sedation status, and side effects were assessed.
RESULTS: No significant differences were detected in visual analog scale score at rest and during coughing in the two groups at various time points after operation. Group S was associated with more doses delivered by PCIA than Group O. The overall satisfaction degree was higher in Group O. The incidences of side effects were comparable between the two groups.
CONCLUSION: Oxycodone is a valuable alternative for PCIA in patients undergoing laparoscopic radical gastrectomy.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

In the past decade, numerous advances have been made in perioperative anesthesia techniques, which enhance the pain control. Among these great strides in pain management technology, patient-controlled intravenous analgesia (PCIA) using opioids is the most commonly used mode of postoperative analgesia.[1]

Sufentanil, a selective µ-receptor agonist, is ideal for PCIA because it is characterized by a fast onset, short duration, and strong analgesic effect with the least frequent incidence of respiratory depression than morphine, alfentanil, and fentanyl.[123] Oxycodone, which has powerful analgesic effect and mild side effects, can not only activate µ-receptor but also κ-receptor which is associated with visceral pain.[45] Therefore, oxycodone should have advantages of postoperative analgesia for laparoscopic radical gastrectomy which has relative small incision, but large visceral injury. We conducted this clinical trial to compare the effect of oxycodone and sufentanil for PCIA after laparoscopic radical gastrectomy.

METHODOLOGY

After receiving approval from the Institutional Ethics Committee and written informed consents from patients, we enrolled fifty patients who had advanced gastric adenocarcinomas and were scheduled for laparoscopic radical gastrectomy. Patients with body mass index more than 30 kg/m2, hepatic or renal insufficiency, having mental diseases and those unable to comprehend verbal instruction were removed from this clinical trial.

The instructions about this clinical trial, PCIA use, and visual analog scale (VAS) assessment method were explained to all patients 1 day before surgery. VAS (0 - no pain; 1–3 - mild pain; 4–6 - moderate pain; 7–9 - severe pain; 10 - the worst pain the patient had ever experienced) was adopted for measuring postoperative pain intensity. The patients were equally divided into two groups: Group S using sufentanil (sufentanil, Yichang Humanwell Pharmaceutical Co., Ltd., Yichang, China) and Group O using oxycodone (oxycodone, HAMOL Ltd., Nottingham, UK) for PCIA. Randomization was conducted using a sequence of numbers generated by a computer. The patients, anesthetists, and surgeons were kept blinded to the grouping situation throughout the study period.

On arrival in the operating room without preanesthetic medication, the patients were monitored with vidal signs and bispectral index (BIS), and then general anesthesia was induced with 0.05 mg/kg midazolam, 3 µg/kg fentanyl, 2 mg/kg propofol, and 0.15 mg/kg cisatracurium. Total intravenous general anesthesia was conducted in this study. The maintenance doses of propofol and remifentanil were adjusted to keep BIS between 45 and 60 during the operation. The patients received intravenous 1.5 µg/kg fentanyl, 1 mg/kg flurbiprofen axetil, and 4 mg ondansetron 20 min before the approximate completion of surgery. Extubation was performed after confirming the patient met standard extubation criteria, and then they received intravenous PCIA from a PCIA device (ZZB-I, Nantong Apon Medical Appliance Co., Ltd., Rudong, China). PCIA was set on a demand mode with a lockout interval of 10 min and without loading dose or background infusion. The dose of sufentanil was set at 0.04 µg/kg in Group S, and the dose of oxycodone was set at 0.02 mg/kg in Group O. If the patient was drowsy, having respiratory depression and not responding to oral commands appropriately, we discontinued the PCIA and reconnected later once the symptoms had subsided.

An independent researcher who did not know the grouping situation recorded postoperative cumulative analgesic doses delivered, VAS scores, sedation status, and side effects. VAS scores were assessed at 4, 8, 12, 24, 36, and 48 h after extubation of the patient. The rescue analgesia (intramuscular administration of 1 mg/kg pethidine) was given if the VAS score was more than three for 30 min. The overall satisfaction was measured as follows: poor, moderate, good, and excellent. When SpO2 was <92% and respiration rate was <10 breath/min, It was taken as respiratory depression.

There was 20–33% decrease in VAS score with respect to previous studies, so we calculated the sample size based on a mean difference of 30% in VAS score between the two groups with two-tailed α = 0.05 and β = 0.20.[678] This analysis resulted in a sample size of 22 patients per group. We enrolled 25 patients per group for possible dropout.

SPSS 17 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Unpaired Student's t-test was used for demographic data and surgical details between the two groups. We used Mann–Whitney U-test to compare VAS scores. Fisher's exact test was used for side effects. The value of P < 0.05 was taken as significant difference.

RESULTS

No significant differences were found according to demographic data and surgical details between the two groups. No significant differences were detected in VAS score at rest and during coughing between the two groups at various time points after operation [Figures 1 and 2]. There were 51 ± 15 doses of sufentanil and 38 ± 19 doses of oxycodone delivered by PCIA for 48 h. Doses delivered by PCIA are more in Group S than in Group O [Figure 3]. The patients’ satisfaction degree was higher in Group O than in Group S [Table 1]. The incidences of side effects were comparable between the two groups during the 48 h observation period [Table 2]. No respiratory depression or other serious side effects were observed.

Figure 1

Box plots of postoperative VAS scores at rest at various time points. Results are expressed in median. The top and bottom of each box indicate 75th and 25th percentiles and the error bars maximum and minimum values. VAS = Visual analog scale, Group O = Oxycodone group, Group S = Sufentanil group

Figure 2

Box plots of postoperative VAS scores during coughing at various time points. Results are expressed in median. The top and bottom of each box indicate 75th and 25th percentiles and the error bars maximum and minimum values. VAS = Visual analog scale, Group O = Oxycodone group, Group S = Sufentanil group

Figure 3

The number of sufentanil and oxycodone doses delivered by PCIA postoperatively at various time points. PCIA = Patient-controlled intravenous analgesia, Group O = Oxycodone group, Group S = Sufentanil group. *P < 0.05, **P < 0.001 between the two groups

Table 1

The overall satisfaction degree

Table 2

Pethidine analgesia and side effects

DISCUSSION

Laparoscopic radical gastrectomy is a major surgery associated with massive tissue damage and moderate-severe postoperative pain, so opioids are the first-choice medications for the postoperative pain management.[1]

The impressing part of this study is that oxycodone-PCIA and sufentanil-PCI provide similar postoperative pain intensity, but oxycodone-PCIA is associated with higher patients’ satisfaction degree. This could be ascribed to two reasons. One is that oxycodone can effectively alleviate visceral pain. Visceral pain is defined as pain originating from the internal organs, which is distinct from somatic pain. The patients with visceral pain may not perceive pain, but abdominal discomfort which may lead to unpleasant emotions such as agitation, perspiration, and fear, along with nausea, vomiting, altered cardiovascular, and respiratory function.[9] Oxycodone is an opioid receptor agonist of mixed µ and κ type. The analgesic function of oxycodone is mainly associated with κ-receptor which is involved in visceral pain formation, so the drug has high therapeutic efficacy in visceral pain.[45] In previous studies, fentanyl, alfentanil, and morphine do not provide advantages over sufentanil for PCIA,[123] so oxycodone is promising.

The other reason is that sufentanil-PCIA is associated with more doses delivered in this study. Sufentanil is characterized by a rapid onset but short duration of action. Consequently, patients may need to redose frequently or use a higher on-demand dose, or they may require a background infusion which is not recommended because of the increased risk of respiratory depression.[3] It has reported that a great number of doses delivered resulted in low patients’ satisfaction degree and a high rate of unsuccessful patient dosing attempts.[10]

Although oxycodone has lower intrinsic activity associated with μ-receptor which is in relation with somatic pain, also called incision pain in this study, its analgesic effect on somatic pain is stronger compared with morphine. It is due to six times higher concentration of oxycodone in the brain at comparable concentrations in blood.[45] Because patients demonstrate highly variable responses to different opioids, in individual cases switching opioids can sometimes alleviate pain and side effects, when the patient has uncontrolled pain and severe side effects to an opioid drug.[11] Riley et al. have reported that 25% (47/186) of patients did not respond to morphine treatment, 20% (37/186) obtained a successful outcome when changed to oxycodone, and an extra 2% (4/186) was well controlled when switched to more than one alternative opioid. Overall successful pain control with minimal side effects was achieved in 96% (179/186) of patients after opioid switching.[12] Gastric cancer is a common cancer. Globally, gastric cancer accounts for 989,600 new cases annually, so the number of patients who have uncontrolled pain after surgery on one preferred opioid must be massively large. Oxycodone can be an alternative opioid in this situation.[1314]

No serious side effects are detected in this study. It is consistent with the previous studies that adverse reactions of oxycodone are mild and not related to the administered dose of oxycodone. It means oxycodone is safe even at high doses.[15] In addition, oxycodone has other advantages, including high bioavailability, little risk of interacting with other medicines, optimum safety profile compared to other opioids and minimal immunosuppressive activity.[1617]

Limitations

The limitation of our study was that we conducted this clinical trial on particular doses of sufentanil and oxycodone, so the result could not fully represent all the doses. Future research is needed to determine more precise dose regimens for sufentanil and oxycodone.

CONCLUSION

Oxycodone is a valuable alternative in the treatment of postoperative pain for PCIA in patients undergoing laparoscopic radical gastrectomy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.