Introduction

Myomas are benign smooth muscle tumors commonly present in premenopausal women, with a lifetime prevalence of about 80%1,2. The economic burden of myomas is substantial, with direct and indirect healthcare costs totaling 34 billion dollars annually in the United States of America3,4. Laparoscopic myomectomy is a surgical procedure used to treat intramural or sub-serosal myomas in symptomatic women with abnormal uterine bleeding or bulk-related symptoms, with the advantage of preserving fertility5. However, postoperative pain is often underestimated, and pain control can be inadequate after laparoscopic myomectomy. Postoperative pain is a common issue for patients after laparoscopic myomectomy. Effective postoperative pain management not only enhances patient satisfaction but also lowers the risk of complications6. The median visual analogue pain scale (VAS) scores after laparoscopic gynecologic surgery are 3 at 24 h after surgery, and 1 at 72 h after surgery7 . Inadequate pain control can delay recovery, prolong hospital stay, impair the activities of daily living, affect mood, decrease sleep, and develop into chronic pain8. The available pain control methods include systemic opioids (injected or oral)6,9,10, gabapentin11, and local analgesics12. Opioids are among the most effective pain-control drugs, but they carry a risk of dizziness, nausea, vomiting, constipation, dependence, tolerance, and respiratory depression13. Gabapentin is associated with fatigue, dizziness, and headache14. Local analgesia carries risks including failed pain relief and toxicity15. Although several analgesic strategies were described for laparoscopic surgery, few strategies were explored specifically for laparoscopic myomectomy.

Patient-controlled intravenous analgesia (PCIA) is a preferred method for postoperative analgesia because it is time-saving, rapid-acting, and has strong analgesic effects. Oral drugs, transcutaneous patches, and percutaneous pump devices have been used to alleviate postoperative pain after laparoscopic surgery, but their efficacy was often limited. In comparison, PCIA is associated with lower pain intensity and greater patient satisfaction16. Opioid-based PCIA is commonly used to manage postoperative pain after abdominal surgeries17,18.

Fentanyl, a potent opioid analgesic first synthesized in the early 1960s19, is widely used for postoperative analgesia in China due to its reliable analgesic efficacy and stable hemodynamics19,20. Nevertheless, fentanyl has significant adverse effects, including nausea, vomiting, respiratory depression, and depressive mood21. Oxycodone, a semisynthetic opioid analgesic, primarily acts as a κ-opioid receptor agonist with a relatively low affinity for μ-opioid22,23. It has been reported to be more effective in managing visceral pain, with less nausea, hallucinations, and pruritus than fentanyl24.

Although fentanyl and oxycodone have been compared in various postsurgical settings, with variable efficacy and adverse effects being reported24,25,26, the effect of intravenous oxycodone after laparoscopic hysteromyomectomy remains unclear27,28. Finding an effective analgesic strategy that minimizes the side effects is essential to optimize pain control and patient recovery without over-delaying the return to normal activities after laparoscopic myomectomy. This study aimed to explore the effect of oxycodone vs. fentanyl for PCIA after laparoscopic hysteromyomectomy.

Methods

Study design and participants

The single-blind, randomized controlled study was conducted between December 2021 and May 2022 at the Department of Anesthesiology of Qilu Hospital of Shandong University in China. Inclusion criteria: (1) 18–50 years of age, (2) scheduled for laparoscopic hysteromyomectomy, (3) American Society of Anesthesiologists (ASA) I or II, and (4) willing to participate and signed the informed consent form. Exclusion criteria: (1) body mass index (BMI) ≥ 30 kg/m2, (2) pregnant or breastfeeding, (3) history of mental illness or serious brain injury that rendered them unable to communicate correctly, (4) long history of opioid use or use of monoamine oxidase inhibitor (MAOI) antidepressant, (5) history of oxycodone or fentanyl allergy, (6) contraindication to oxycodone hydrochloride (such as respiratory depression or paralytic ileus and so on), (7) unsuitable for PCIA because of circulatory instability or hypovolemic status, (8) incomplete clinical data, (9), not willing to participate in this study. The trial was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Scientific Research of Qilu Hospital of Shandong University in China (approval number # KYLL- 202111-017-1). Full date: 9/10/2021. Written informed consent was obtained from all participants before enrollment in the study. The patients were free to withdraw their consent at any time without providing justification or reasons.

Randomization and blinding

A random number table generated by computer was used to assign the participants to the oxycodone group and the fentanyl group randomly at a ratio of 1:1. General anesthesia and all intraoperative assessments were carried out by two anesthesiologists. The anesthesiologist knew the patient allocation. The patients, surgeons, and follow-up nurses were unaware of the patient allocation. All postoperative data were evaluated and documented by two other investigators blinded to participant grouping.

Intervention

Anesthesia induction was achieved using propofol 2 mg/kg, sufentanil 0.4 μg/kg, and cisatracurium 0.2 mg/kg. Anesthesia maintenance was performed using inhaled 2% sevoflurane combined with continuous intravenous infusion of remifentanil 0.1 μg/kg/min. Sufentanil has a long onset and duration of action, suitable for general anesthesia induction; Remifentanil has a fast onset and quick offset, suitable for anesthesia maintenance, and can be adjusted in dose to quickly match surgical stress. The bispectral index (BIS) was used during anesthesia to achieve the appropriate anesthesia depth and was controlled between 40 and 60. The respiratory parameters were set at a tidal volume (TV) of 6–8 mL/kg, respiratory rate (RR) of 14–16 breaths/min, and end-tidal carbon dioxide (ETCO2) in the normal range of 32–36 mmHg. Ondansetron 8 mg was used 30 min before the end of surgery to prevent nausea and vomiting. After that, a loading dose of oxycodone 5 mg (oxycodone group) or fentanyl 50 µg (fentanyl group) was administered 15 min before the end of the operation. A potency ratio of 100:1 was implemented because of the lack of recommendations for the direct conversion factor for the doses of intravenous oxycodone and fentanyl29. Intraoperatively, additional doses of cisatracurium were administered as needed based on the duration of surgery. After surgery, If there were no contraindications, 2 mg of neostigmine and 1 mg of atropine was routinely administered to reverse muscle relaxation, reducing the potential bradycardia and salivary or bronchial secretion. When the final suture of the skin was completed, all anesthetics were stopped, and ultrasound-guided bilateral transversus abdominis plane (TAP) blocks were performed with 20 ml of 0.375% ropivacaine on each side.

After surgery, the participants were extubated and transferred to the post-anesthesia care unit (PACU). During the PACU period, vital signs such as heart rate, blood pressure, and peripheral oxygen saturation were monitored. During surgery, hemodynamic parameters, such as heart rate and blood pressure, were recorded, typically at intervals of approximately 5 min. After returning to the hospital room and within the first 6 h post-surgery, the hemodynamic parameters were monitored at approximately 30-min intervals. The participants were admitted to the general wards after 1 h in the PACU.

The IV-PCA device was connected at the end of the surgery. For the fentanyl group (fentanyl 0.4 mg + ondansetron 8 mg + normal saline, 100 ml in total), the pump was set to deliver a bolus dose of 0.3 μg/kg and a continuous infusion at 0.1 ml/h with a lockout time of 10 min. For the oxycodone group (oxycodone 40 mg + ondansetron 8 mg + normal saline, 100 ml in total), the pump was set to deliver a bolus dose of 0.03 mg/kg, with a lockout time of 10 min. The potency of fentanyl to oxycodone is 1:100, so 1 mg of parenteral oxycodone is equivalent to 10 μg of fentanyl19,30. When the participants returned to the ward, flurbiprofen axetil could be used for rescue if needed, but at no more than 150 mg/day.

Outcomes and measurements

The primary outcome was the effect of PCIA measured using the numerical rating score (NRS)31, including NRS at rest (NRS-R) inquired at postoperative 6, 12, 24, and 48 h and the NRS of moving into the sitting position (NRS-S) at postoperative 24 and 48 h by a physician. NRS is one of the most widely used pain scales in medicine. Consensus groups have determined that NRS is the most effective measure of pain intensity in various situations32, with lower rates of incorrect responses compared to other pain scales33. The analgesic effect of the drug flurbiprofen ester administered at the end of surgery is still present within 6 h after surgery. Patients undergoing such surgeries in our hospital are usually bedridden and engage in minimal activities on the bed, resulting in generally mild pain. Therefore, we chose to record data at 6 h postoperatively. Consensus Guidelines for Enhanced Recovery after Gynecologic Surgery (2019)34 encourages patients to start early mobilization within 24 h postoperatively and gradually increase their activity levels. According to Clinical Practice Guidelines for ERAS in China (2021)35, patients can begin bedside activities as early as day 1 after surgery while setting daily activity goals and progressively increasing their physical activity. Considering the actual conditions of patients undergoing these types of surgeries at our hospital, it is common practice for patients to start bedside activities around 24 h postoperatively. Consequently, we selected to record NRS-S at 24 h after surgery. Since the participants could not move at 6 and 12 h after surgery, the NRS-S score was not evaluated at 6 and 12 h. The NRS scores range from 0 to 10: “0” indicates no pain, “5” indicates moderate pain, and “10” represents the worst imaginable pain31. The secondary outcomes included the patients’ mood and satisfaction towards PCIA 48 h after surgery. The self-rating depression scale (SDS)36 was used to assess the patients’ mood after surgery. SDS is a 20-item measure, with each item rated on a 4-point scale. The raw sum score ranges from 20 to 80, and the ranges for mild to moderate depression, moderate to severe depression, and severe depression are 50–59, 60–69, and over 70, respectively. Furthermore, the participants were asked to rate their satisfaction with PCIA at postoperative 48 h according to the following scale: 1 = very unsatisfactory, 2 = unsatisfactory, 3 = neutral, 4 = satisfactory, and 5 = very satisfactory.

Adverse events such as hypotension (systolic blood pressure < 90 mmHg), hypoxemia (SpO2 < 90%), respiratory depression (respiratory rate < 10 breaths/min lasting more than 10 min), nausea, vomiting, pruritus, headache, and dizziness were recorded at 6, 12, 24, and 48 h after surgery. All adverse events from the patient’s entry into the surgical ward to discharge were recorded.

This study recorded the patients’ demographic information, such as age, height, weight, and motion sickness, as well as information regarding the surgery and anesthesia, including the use of pituitrin, oxytocin, and metronidazole, the length of the procedure, the dose, and method of anesthesia maintenance.

Sample size

Before designing this study, we referred to previous clinical research about opioids in acute pain relief after abdominal surgery, including oxycodone versus fentanyl, and oxycodone versus sufentanil37,38,39.

Referred data showed that the estimation of sample size equaled to 26, 13 cases per group (1:1)39. Take into account that the sample size is small, we planned to enlarge the sample size to a clinically significant difference depended on the referred article40. Based on its results that the NRS score at rest 24 h after surgery were 4.0 ± 2.2 in the sufentanil group and 2.5 ± 1.8 in the oxycodone group, a sample size of 28 per group was obtained with two-tailed of αequal to 0.05 and a power of 80%. (PASS 15.0.5, NCSS, LLC, Kaysville, Utah, USA). A drop-out rate of 10% was estimated, in total, 31 cases per group was obtained.

Statistical analysis

All data were analyzed using SPSS 24.0 (IBM, Armonk, NY, USA) and GraphPad Prism 7 (GraphPad Software, La Jolla, CA, USA). The primary analysis was prespecified to be performed in the per-protocol population. Continuous data with a normal distribution were expressed as mean ± SD and analyzed using Student’s t-test; otherwise, they were presented as medians (interquartile range, IQR) and analyzed using the Mann–Whitney U-test. Categorical data were presented as n (%) and analyzed using the chi-square test or Fisher’s exact test. The cumulative PCIA doses and amount of opioid consumption were compared using the Mann–Whitney U-test. Two-sided P values < 0.05 were considered statistically significant.

Ethical approval and consent to participate

The trial was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Scientific Research of Qilu Hospital of Shandong University in China (approval # KYLL- 202111-017-1). Full date: 9/10/2021. Written informed consent was obtained from all participants before enrollment in the study. The patients were free to withdraw their consent at any time without providing justification or reasons.

Results

Sixty-two participants were enrolled and randomly assigned to the oxycodone (n = 31) or fentanyl (n = 31) group. One participant from the fentanyl group was excluded due to conversion to open surgery. One participant from the oxycodone group was excluded due to incomplete data. Finally, 60 participants completed the study (n = 30 in each group) (Fig. 1). The baseline characteristics between the fentanyl and oxycodone groups were comparable, including age, weight, height, BMI, operation time, the use of pituitrin during the operation, the use of oxytocin and metronidazole in the ward, and motion sickness (all P > 0.05, Table 1). Pituitrin injection was applied during surgery to improve the contraction of uterine smooth muscle and reduce uterine bleeding. This procedure can exacerbate intraoperative and postoperative uterine contraction pain. Oxytocin was applied in the ward to promote uterine contractions and reduce postoperative uterine bleeding, which could affect postoperative pain management. Metronidazole was used in the ward, with its side effects being gastrointestinal symptoms such as nausea and vomiting. This side effect overlaps with our concerns about opioid-induced nausea and vomiting. The number of PCIA boluses and the amount of opioid consumption postoperatively were similar between the two groups (all P > 0.05) (Supplementary Table S1). The rescue dose of 50 mg flurbiprofen was used in two patients in oxycodone group, and two patients in fentanyl group.

Fig. 1
figure 1

Study flowchart.

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Table 1 Baseline characteristics of patients undergone laparoscopic hysteromyomectomy with PCIA.
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The NRS scores were comparable between the oxycodone and fentanyl groups (NRS-R, postoperative 6 h, 4.97 vs. 4.70; 12 h, 4.50 vs. 3.80; 24 h, 3.20 vs. 3.10; 48 h, 1.57 vs. 0.93; NRS-S, 24 h, 5.70 vs. 4.00; 48 h: 5.93 vs. 3.80, all P > 0.05). The SDS scores at postoperative 48 h were comparable between the oxycodone and fentanyl group (45.00 vs. 49.38, P = 0.652). Patients’ satisfaction with postoperative analgesia was significantly higher in the oxycodone group than in the fentanyl group (very satisfactory: 73.3% vs. 36.7%, P = 0.004; satisfactory: 10.0% vs. 43.3%, P = 0.016) (Table 2).

Table 2 Outcomes of postoperative self-rating pain scores and reports of patient self-experience.
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Besides headaches, there were no significant differences in the side effects of hypotension, hypoxemia, respiratory depression, nausea, vomiting, pruritus, or dizziness between the oxycodone and fentanyl groups. The fentanyl group showed a significantly higher occurrence of headaches at postoperative 48 h (7 of 30[23.3%] vs. 0 of 30[0%], P = 0.016) (Table 3).

Table 3 Adverse events occurred postoperatively among patients undergone laparoscopic hysteromyomectomy with PCIA.
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Discussion

The study showed that the analgesic effects of PCIA were comparable between the oxycodone and fentanyl groups. In addition, oxycodone showed a higher satisfaction degree and lower occurrence of headaches than fentanyl in patients after laparoscopic hysteromyomectomy. Therefore, oxycodone appears to be a more favorable choice than fentanyl after laparoscopic hysteromyomectomy. The results will help physicians make informed decisions and contribute to various benefits for clinical practice, the healthcare system, and patients. They offer valuable insights that can guide clinicians in decision-making processes related to the procedure, ultimately leading to enhanced clinical outcomes, improved healthcare system efficiency, and increased patient benefits.

This study found that oxycodone and fentanyl have comparable analgesic effects after laparoscopic hysteromyomectomy. It is consistent with two previous studies by Kim et al.41,42, who studied oxycodone vs. fentanyl PCIA (but without TAP block) after laparoscopic hysterectomy that showed a similar anesthetic effect between the two drugs. Park et al.28 reported that oxycodone and fentanyl PCIA had similar analgesic effects after laparoscopic gynecologic surgery. Nevertheless, a meta-analysis by Li et al.24 showed that oxycodone had better analgesic effects than other opioids (including fentanyl, alfentanil, and morphine). Similar findings were also observed in other types of surgeries, such as cardiac surgery25, gastrointestinal laparotomy43, laparoscopic cholecystectomy37, and hip replacement44. Discrepancies among these studies could be due to the differences in patients’ characteristics, the doses used, and the type of surgery. There are also differences in pain tolerance between men and women45.

Pain is known to be associated with depressive symptoms, but we found no differences in SDS scores between the two groups, and a patient satisfaction score of 5/5 in the oxycodone group was significantly higher than in the fentanyl group, which may be related to the lower incidence of postoperative headaches in oxycodone group. Furthermore, some studies showed that oxycodone PCIA had similar satisfaction compared with fentanyl PCIA after gastrointestinal laparotomy43, laparoscopic cholecystectomy37, laparoscopic surgery (meta-analysis)24, and laparoscopic gynecological surgery28. However, it has been reported that there is lower satisfaction with oxycodone than with fentanyl after laparoscopic hysterectomy41,42. The doses of drugs and the type of surgery among studies could explain the differences.

In three previous studies regarding the effects of opioids for postoperative pain control, the incidence of headache with oxycodone ranged from 13.3 to 19.0%28,41,42, which is significantly higher than the incidence in this study. It is possible that the sample size in our study may be insufficient and skewed. The fentanyl group showed a higher occurrence of headaches at postoperative in this study. Previous studies have reported comparable incidences of headache with oxycodone and fentanyl41,42, while one study reported a higher incidence of headaches with oxycodone than fentanyl, but the difference was not statistically significant28. Both groups of patients had no special history of headache before surgery, and there are no differences between the two groups of patients with previous headaches. Although both fentanyl and oxycodone may have the side effect of headache46, for patients undergoing laparoscopic uterine fibroid resection, the postoperative headache is more likely to be caused by vasodilation due to oxytocin use in the postoperative ward. A number of studies have shown that headache is one of the main side-effects of oxytocin47. The differences in the incidence of headaches may suggest that oxycodone is more effective at relieving headaches than fentanyl, or that it has a generally better analgesic efficacy46,48.

There was no significant difference in side effects between oxycodone and fentanyl PCIA other than headaches. The differences in the incidence of headaches may be a reason for the differences in patient satisfaction. Visceral pain can also affect a person's emotions. If oxycodone group has higher satisfaction, it may also suggest that oxycodone is better than fentanyl in controlling visceral pain. In addition, patient satisfaction is a separate evaluation indicator (1 = very unsatisfactory, 2 = unsatisfactory, 3 = neutral, 4 = satisfactory, and 5 = very satisfactory), which is subjective feelings of patients; researchers do not link and compare satisfaction with NRS and side effects. Previous studies showed comparable safety profiles between oxycodone and fentanyl for PCIA after gastrointestinal laparotomy43, laparoscopic cholecystectomy37, and gynecological laparoscopy41,42. A meta-analysis suggested that oxycodone should be used cautiously24, and some studies showed that oxycodone might be associated with a higher incidence of side effects than fentanyl, such as dizziness, headache, and sedation46. Some studies reported a higher incidence of headaches with oxycodone than with fentanyl, but this difference was not statistically significant.

In the present study, ultrasound-guided bilateral TAP blocks were added to both groups to reduce the postoperative pain of the abdominal wall incision. In the laparoscopic surgery, there are 3 trocar holes in the abdominal wall, and the TAP block is essential for blocking the pain from the three trocar holes and preventing somatic pain in the abdominal wall. Studies show that it can provide relief from thoracic segments 7–11 efficiently and swiftly, effectively achieving pain relief from the trocar holes. Managing visceral pain involves comparing the effectiveness of hydrocodone, a κ-opioid receptor agonist, and fentanyl. We did not perform another block to control visceral pain as quadratus lumborum block or erector spinae block due to the lack of consensus on effectiveness of reduction of visceral pain. The type of TAP performed in our study was subcostal. Previous studies have generally compared oxycodone with other opioids without involving nerve blocking28,37,41,42,43. The effective analgesia of the TAP block lasted for about 24 h. Therefore, oxycodone or fentanyl in PCIA mainly acts on the internal pain of the abdominal cavity, that is, the uterine contraction pain. Therefore, the total analgesic drug use in this study was less than the total drug use in other studies, which is particularly significant in the actual context of the worldwide opioid crisis49. Many people who abuse opioids started opioids with a prescription or in a medically-controlled context50,51,52. Therefore, minimizing the use of perioperative opioids by optimizing their use through drug selection, route of administration, and dosage should help minimize dependence development, as was achieved in the present study with oxycodone vs. fentanyl. The multimodal analgesia proposed in the present study and the decreased dose of opioids (i.e., TAP block plus postoperative opioid analgesia pump) are also important components of rapid recovery after surgery (ERAS)53,54. ERAS pathways also aim at minimizing the use of opioids and promoting recovery55. This study suggests that compared with fentanyl, oxycodone satisfies the ERAS principle.

There were some limitations in this study. Firstly, 60 patients were included at the study center. The sample size was small, although the statistical efficacy was satisfied. Large-scale clinical trials with multiple centers are suggested in the future. Secondly, the results only represent the analgesic effects and adverse reactions of oxycodone and fentanyl among patients using PCIA with fixed dosage after laparoscopic hysteromyomectomy. Additional studies are needed to determine optimal PCIA dosing for gynecological surgeries. Finally, the design of single-blind may influence the subjective reporting of observation indicators.

In conclusion, the findings suggested that oxycodone was comparable to fentanyl for PCIA after laparoscopic hysteromyomectomy. Although the analgesic effects of oxycodone and fentanyl were similar, oxycodone was associated with higher patient satisfaction and a lower incidence of headaches. These results may facilitate the development of analgesia strategies after laparoscopic hysteromyomectomy. Indeed, oxycodone appears as effective as fentanyl for pain control but with fewer side effects. Oxycodone could satisfy the call for opioid management in the opioid crisis and the requirements of ERAS.