Comparison between opioid-based anaesthesia technique and opioid-free anaesthesia technique in patients undergoing laparotomy for gynaecological malignancy: A randomised controlled trial

Abstract

Background and Aims:

To investigate whether opioid-free anaesthesia (OFA) or opioid-based anaesthesia (OBA) technique with ultrasound (US)-guided rectus sheath block (RSB) provides early recovery and less opioid-related side effects in patients undergoing laparotomy for gynaecological malignancy.

Methods:

This was a double-blind randomised controlled trial. Fifty female patients of the American Society of Anesthesiologists (ASA) physical status I–II, aged 18–65 years, and scheduled to undergo elective gynaecological laparotomy under general anaesthesia were included. The patients were randomised into two groups. Both received US-guided RSB with 10 mL of local anaesthetic on each side. Group OBA (n = 25) received intravenous (IV) fentanyl 2 μg/kg at induction and 0.5 μg/kg as rescue analgesic. Group OFA (n = 25) received IV dexmedetomidine (0.5 μg/kg bolus over 10 min at induction, followed by 0.3 μg/kg/h infusion) and ketamine (0.25 mg/kg before incision, 0.15 mg/kg as rescue analgesic). The primary outcome was the time to attain post-anaesthesia care unit (PACU) discharge criteria. Time to eye-opening, time to extubation, time to shift to PACU, postoperative pain as visual analogue score (VAS), time to first rescue, total 24-h morphine consumption, and any postoperative nausea and vomiting till 24 h were also noted as secondary outcomes.

Results:

The time to attain PACU discharge criteria was comparable between the groups; however, the time to extubation and time to shift to the PACU was higher in Group OFA (P = 0.043 and P = 0.046, respectively). Other secondary outcomes were comparable (P > 0.05).

Conclusion:

OFA provides comparable postoperative analgesia and time to attain PACU discharge in adult patients undergoing open gynaecological oncological surgery under general anaesthesia.

INTRODUCTION

The use of opioids during the perioperative period can lead to side effects such as respiratory depression, sedation, postoperative nausea and vomiting (PONV), itchiness, urinary retention, and ileus,[1] which can result in delayed discharge from the day-surgery centre and may cause unexpected or extended hospital stays. ‘Opioid-free anaesthesia’ (OFA) refers to a method that eliminates the use of systemic, neuraxial, or intracavitary opioids during surgery.[2] OFA strategies utilise regional anaesthesia and/or total intravenous anaesthesia (TIVA) and may incorporate pharmacological agents, such as α2 agonists, ketamine, lidocaine, and magnesium.

Gynaecological cancer surgeries involve extensive dissections and adequate postoperative pain control is one of the most important factors needed for early mobilisation, increased patient comfort and satisfaction,[3] and thus reduced hospital stay and cost. Bilateral rectus sheath block (RSB) has been found to provide good postoperative analgesia in patients undergoing abdominal[4] and major gynaecological surgery[5] and may be considered part of the OFA technique.

OFA has been used in various scenarios, including bariatric surgery,[6,7] breast cancer surgery,[8] and gynaecological laparoscopy,[9] with better recovery profile, reduced opioid consumption, and opioid-related side effects. However, it has not been studied in gynaecological oncology surgery.

In the present study, we aimed to investigate whether an OFA technique provided early recovery along with fewer opioid-related side effects compared to the opioid-based anaesthesia (OBA) technique in adult patients undergoing laparotomy for major gynaecological malignancy. The primary objective was time to attain post-anaesthesia care unit (PACU) discharge criteria, and secondary objectives were time to eye-opening, extubation and shifting to PACU, visual analogue scale (VAS) score and time to first analgesic request at PACU, quality of recovery (QoR) as assessed by the QoR-15 at 12 and 24 h, postoperative analgesic consumption, and PONV till 24 h.

METHODS

Following the approval from the Institute Ethics Committee (vide approval number: IECPG- 565/20.12.2017, RT- 61/31.01.2018, dated 12-02-2018) and the registration of the trial with the Clinical Trials Registry-India (vide registration number: CTRI/2018/04/013335, dated 18-04-2018, accessible at www.ctri.nic.in), this double-blind randomised controlled trial was conducted in a tertiary care facility between April 2018 and October 2019. The study was carried out in accordance with the Helsinki Declaration of 2013 and adhered to Good Clinical Practice guidelines.

The study included consenting American Society of Anesthesiologists (ASA) physical status I–II patients aged between 18 and 65 years, who were scheduled for elective open gynaecological oncology surgery under general anaesthesia. Those patients who declined to participate, with allergies to any medications used in the study, patients with contraindications to the regional technique (such as infection at the site of the block or any coagulation issues), individuals with a history of long-term analgesic reliance and opiate tolerance, patients with existing chronic pain requiring regular medication use, and individuals with epilepsy or mental health disorders were excluded. Participants were explained the study protocol, and written informed consent was obtained for participating and using their data for research and education.

Patients were allotted to the groups as per a computer-generated randomisation sequence (www.randomizer.org). To ensure allocation concealment, assignments were placed inside sealed, opaque envelopes that were sequentially numbered and opened when the patient arrived in the operation theatre. Both the patients and the observers were kept unaware of the group assignment. All patients were assigned to one of two groups – Group OBA (n = 25) and Group OFA (n = 25). All the study drugs and the control drugs were prepared by a single investigator (DB) in the following manner: i) infusion analgesic - dexmedetomidine (OFA) or saline (OBA) was made in identical syringes of 50 mL volume and labelled as infusion; ii) induction analgesic - fentanyl 2 μg/kg (OBA) or saline (OFA) in 5 mL syringe as 5 mL volume and labelled as induction analgesic; iii) primary analgesic - pre-incision ketamine 0.25 μg/kg (OFA) or saline (OBA) were kept in a 2-mL syringe as 2 mL volume and labelled as primary analgesic; iv) maintenance analgesic - intermittent boluses of ketamine or fentanyl were made in a 5-mL syringe (each mL containing either ketamine 0.15 mg/kg (OFA) or fentanyl 0.5 μg/kg (OBA) and labelled as maintenance analgesic; v) rescue analgesic - if more than three times maintenance analgesic was required in 1 h, then rescue analgesic intravenous (IV) fentanyl 0.5 μg/kg was given in both the groups (this was labelled as rescue analgesic).

All selected patients underwent a routine pre-anaesthetic assessment and were educated about VAS scores and the use of a patient-controlled analgesia (PCA) device. Standard fasting guidelines were followed. In the operation theatre, the pulse rate, non-invasive blood pressure (NIBP), oxygen saturation (SpO₂), and respiratory rate (RR) were recorded before the initiation of anaesthetic induction.

In the Group OBA, a normal saline bolus was administered over 10 min at the beginning of the anaesthesia induction, followed by a continuous infusion using a 50-mL syringe (infusion analgesic). General anaesthesia was induced with IV fentanyl 2 μg/kg (induction analgesic), followed by IV propofol 2–3 mg/kg, and tracheal intubation was facilitated with IV atracurium 0.5 mg/kg. A bilateral RSB was performed under all aseptic precautions under ultrasound (Sonosite, M-turbo, Bothhel, WA) guidance using a 6–13-MHz linear probe. After the induction of anaesthesia, 10 mL of local anaesthetic, consisting of 5 mL of 0.5% bupivacaine and 5 mL of 2% lignocaine with adrenaline (1:200,000), was administered on each side. Primary analgesic (normal saline) was injected, and surgery was started. Anaesthesia was maintained with oxygen, air, and isoflurane, targeting a minimum alveolar concentration (MAC) value of 0.8–1.2 and a bispectral index (BIS) of 40–60. Boluses of IV atracurium 0.2 mg/kg were administered to maintain neuromuscular blockade. Maintenance analgesic (IV fentanyl at 0.5 μg/kg) was administered if tachycardia occurred by >20% of baseline or mean arterial pressure increased by >20% of baseline. If more than three doses of maintenance analgesic were required within 1 h, rescue analgesic was administered.

In the Group OFA, general anaesthesia was induced with an IV dexmedetomidine bolus of 0.5 μg/kg over 10 min (an infusion analgesic), IV saline (induction analgesic) and IV propofol 2–3 mg/kg. A bolus of IV atracurium 0.5 mg/kg facilitated tracheal intubation. IV dexmedetomidine infusion was continued at 0.3 μg/kg/h (an infusion analgesic). A bilateral RSB was performed, and anaesthesia was maintained as described above in the Group OBA. Primary analgesic (IV ketamine 0.25 mg/kg) was administered before the incision, and surgery was started. Maintenance analgesic (IV ketamine 0.15 mg/kg) was administered if tachycardia occurred >20% of baseline or mean arterial pressure increased by >20% of baseline. Maintenance analgesic boluses were used for a maximum of three doses in 1 h. If more than three doses of the maintenance analgesic were needed within 1 h, a rescue analgesic (IV fentanyl 0.5 μg/kg) was given. Heart rate (HR), blood pressure, SpO₂, EtCO₂, and BIS were continuously monitored and recorded every 10 min. The administration of IV fluids, temperature, blood loss, and urine output were also monitored.

Both groups received IV dexamethasone 0.1 mg/kg, paracetamol 1 g, and ketorolac 30 mg after anaesthesia induction and before the skin incision. IV ondansetron 4 mg was administered approximately 30 min before skin closure. At the beginning of skin closure, dexmedetomidine/saline infusion was stopped. The inhalational agent was stopped at the end of skin closure. After the surgery, neuromuscular blockade was reversed using IV neostigmine 50 μg/kg and IV glycopyrrolate 10 μg/kg.

The outcome assessor (RK) was unaware of group allocation and was not part of the anaesthesia team. She entered the operating room (OR) at the end of surgery and noted the outcome parameters (time to awakening, time to extubation, and time to shifting). The outcome assessor, in the PACU and the ward after that till 24 h, assessed all the outcomes (VAS scores in the PACU, time to PACU discharge criteria, QoR at 12 and 24 h, opioid-induced hyperalgesia, PONV, and postoperative analgesic consumption in 24 h).

Tracheal extubation was performed once the patient was conscious, could follow commands, and generated at least 7 mL/kg tidal volume. The duration until the patient opened their eyes, the duration until extubation, and the duration until transfer to the PACU were recorded.

Upon arrival in the PACU, the VAS was evaluated every 10 min. If the VAS score was 3 or higher, IV morphine 3 mg was administered, the time until the first request for pain relief was recorded, and the patient was connected to a PCA pump (1 mg bolus, 5-min lockout interval, and a maximum limit of 30 mg within 4 h). In the PACU, vital signs and PACU discharge criteria were recorded every 10 min, along with the VAS score at the same intervals. Patients were transferred from the PACU to the ward once they fulfilled the PACU discharge criteria (Modified Aldrete score >9). For 24 h, instances of PONV and the total amount of analgesics used were documented. PONV was assessed using a 3-point scale: (0 - No nausea or vomiting, 1 - Nausea only, 2 - Persistent nausea (>10 min) or vomiting).

Hontoir et al.[8] reported a mean postoperative PACU discharge time of 95 [standard deviation (SD): 15.2)] min in females receiving OBA for bariatric surgery. We assumed that a 15-min decrease in PACU discharge time would be clinically significant. Assuming a power of study of 90% and α of 0.05, at least 22 patients were required in each group. Considering a dropout of 15%, a total of 50 patients were recruited.

All data was entered into a Microsoft Excel spreadsheet. The analysis was done using Stata software (version 13.0; StataCorp LLC, College Station, Texas, USA). Categorical variables were analysed using Fisher’s exact test, whereas continuous variables were evaluated using the Mann-Whitney U test. A two-tailed P value below 0.05 was considered significant. As the per-group sample was less than 30, a formal normality test was not performed, and non-parametric distribution was assumed.

RESULTS

All the included patients completed the study follow-up [Figure 1]. Demographic characteristics, comorbidities, surgical data, and intraoperative haemodynamics were comparable [Table 1].

Figure 1.

CONSORT (CONsolidated Standards Of Reporting Trials) flow diagram. OBA = Opioid-Based Anaesthesia, OFA = Opioid-Free Anaesthesia

Table 1.

Patient characteristics

Variable	Group OBA (n=25)	Group OFA (n=25)	P
Age (years)	52 (47–58)	49 (44–58)	0.676
Weight (kg)	58 (50–65)	58 (52–65)	0.892
BMI	23.4 (20–25.6)	23.1 (21–25.3)	0.778
Educational status
Primary school	10	14	0.343
High school	12	7
Graduate	3	4
ASA
1	15	14	>0.99
2	10	11
Comorbidity
DM	2	4	0.584
HTN	6	7
DM, HTN	2	0
No comorbidity	15	14
Diagnosis
Ca endometrium	9	9	>0.99
Ca cervix	7	7
Ca ovary	9	9
Preop NACT
No	20	22	0.702
Yes	5	3
Total surgery time (min)	90 (70–95)	80 (65–90)	0.343
Total anaesthesia time (min)	120 (110–120)	110 (100–120)	0.382
Type of surgery
Extra fascial hysterectomy	9	9
Type 3 radical hysterectomy	7	7	0.805
Primary debulking	4	6
Interval debulking	5	3

Data presented as number of patients or median (IQR). OBA=Opioid-Based Anaesthesia, OFA=Opioid-Free Anaesthesia, IQR=Inter-Quartile Range, n=number of patients, BMI=Body Mass Index, ASA=American Society of Anaesthesiologists, DM=Diabetes Mellitus, HTN=Hypertension, NACT=Neo Adjuvant ChemoTherapy, kg=Kilogram, min=minutes

The time to attain the PACU discharge criteria was similar for both groups, showing no statistically significant difference (P = 0.652) [Figure 2].

Figure 2.

Time to attain the PACU discharge criteria. OBA = Opioid Based Anaesthesia, OFA = Opioid Free Anaesthesia, PACU = postanaesthesia care unit

Table 2 details all the outcomes. The significant secondary outcomes were time to extubation [Figure 3] (P = 0.043) and time to shift to the PACU (P = 0.046), which were longer in the Group OFA.

Table 2.

Outcome data

Variable	Group OBA (n=25)	Group OFA (n=25)	P
Time to eye-opening (min)	13 (11–16)	15 (13–18)	0.063
Time to extubation (min)	15 (13–16)	16 (15–19)	0.043
Time to shift to PACU (min)	18 (17–19)	20 (18–22)	0.046
VAS score on arrival to PACU	0 (0–2)	0 (0–2)	0.645
Time to first analgesic request (min)	20 (20–30)	20 (20–30)	0.841
Analgesic consumption in 24 h (mg)	26 (22–29)	24 (22–29)	0.345
Time to attain the PACU discharge criteria (min)	100 (90–110)	105 (100–110)	0.652
PONV (24 h)
0	10	17	0.130
1	11	5
2	4	3

Data presented as number of patients or median (IQR). OBA=Opioid-Based Anaesthesia, OFA=Opioid-Free Anaesthesia, n=number of patients, SD=Standard deviation, IQR=Inter-Quartile Range, min=minutes, VAS=Visual Analogue scale, PACU=Post Anaesthesia Care Unit, PONV=Postoperative Nausea and Vomiting

Figure 3.

Time to extubation. OBA = Opioid-Based Anaesthesia, OFA = Opioid-Free Anaesthesia

As the composite score could not be calculated in our study because of delayed catheter removal in gynaecological oncology patients, individual parameters of QoR-15 were analysed between both groups, which were largely comparable except for two parameters at a 12-h time point. However, the clinical significance of the absolute score difference was negligible, and the statistical difference could be attributed to the small SD [Table 3].

Table 3.

QoR-15 data

Quality of recovery score	Group OBA n=25	Group OFA n=25	P
QoR-15-12 h - 1	8 (8–8)	8 (8–9)	0.065
QoR-15-12 h - 3	7 (7–7)	7 (7–7)	0.887
QoR-15-12 h - 6	6 (8–9)	8 (8–8)	0.011
QoR-15-12 h - 7	8 (8–8)	8 (8–9)	0.799
QoR-15-12 h - 9	7 (7–8)	7 (7–8)	0.778
QoR-15-12 h - 10	7 (7–8)	7 (7–7)	0.415
QoR-15-12 h - 11	7 (7–8)	7 (6–7)	0.013
QoR-15-12 h - 12	10 (10–10)	10 (9–10)	0.533
QoR-15-12 h - 13	9 (8–10)	10 (8–10)	0.263
QoR-15-12 h - 14	8 (8–8)	8 (7–9)	0.833
QoR-15-12 h - 15	9 (9–10)	10 (9–10)	0.399
QoR-15-24 h - 1	8 (8–9)	8 (8–9)	0.097
QoR-15-24 h - 3	9 (8–9)	8 (8–9)	0.489
QoR-15-24 h - 4	9 (8–9)	8 (8–9)	0.489
QoR-15-24 h - 6	9 (9–9)	9 (8–9)	0.276
QoR-15-24 h - 7	9 (9–9)	9 (8–9)	0.941
QoR-15-24 h - 9	8 (8–8)	8 (8–8)	0.267
QoR-15-24 h - 10	8 (8–8)	8 (8–8)	>0.99
QoR-15-24 h - 11	8 (7–8)	8 (7–8)	0.113
QoR-15-24 h - 12	10 (10–10)	10 (10–10)	0.274
QoR-15-24 h - 13	8 (8–10)	9 (8–10)	0.244
QoR-15-24 h - 14	8 (8–8)	8 (7–9)	0.833
QoR-15-24 h - 15	10 (9–10)	9 (9–10)	0.681

Data presented median (IQR). OBA=Opioid-Based Anaesthesia, OFA=Opioid-Free Anaesthesia, n=number of patients, QoR=Quality of Recovery, IQR=Inter-Quartile Range

DISCUSSION

In this randomised, double-blind study, we observed that the time to meet the PACU discharge criteria was comparable between the two groups. This result was consistent with earlier research,[7,8] indicating no significant difference in PACU length of stay (LOS) between the OFA and OBA groups despite employing different anaesthetic approaches. Nevertheless, a recent meta-analysis[10] noted an extended length of stay in the PACU for the Group OFA, which involved varied anaesthetic regimens.

In Group OFA, time to extubation and transfer to the PACU was notably extended. This aligns with a recent meta-analysis by Yu et al.,[10] which indicated that dexmedetomidine delayed extubation in the Group OFA.

The time taken to make the first request for analgesics and the total morphine usage over 24 h were similar in both groups. Previous meta-analyses[10,11] found a reduction in postoperative pain and opioid use in OFA groups. However, this could depend on the type of surgery and anaesthesia technique used. In our study, the inclusion of RSB may explain the lack of significant differences in opioid consumption, as both groups received opioid-sparing blocks.

We observed no difference in PONV between the two groups, which contrasts with findings from Ziemann-Gimmel et al.[7] and a recent meta-analysis by Zhang et al.,[12] where OFA (TIVA) reduced PONV risk. The use of volatile anaesthetics in both groups in our study may have contributed to the similar PONV rates.

The study’s strengths include a robust, double-blind, randomised design that minimises bias. It also uses PACU discharge criteria as the primary outcome, which is a comprehensive, clinically relevant, and financially relevant measure of early recovery and anaesthesia efficacy. The study was adequately powered for the primary outcome. Moreover, both groups received RSB, ensuring effective pain management and eliminating differences in pain control as a confounding factor.

While OFA has been shown to reduce opioid consumption and improve the QoR in superficial and laparoscopic surgeries, our study suggests that OFA can also be effective even in more complex open abdominal surgeries, which are typically more painful and require more intensive postoperative care. RSB in both groups also highlights the importance of multimodal analgesia in improving postoperative outcomes. However, future research could explore various minute aspects of OFA such as the feasibility of multimodal analgesia by adding other regional blocks to OFA regimen in gynaecological oncological surgeries, the possibility of delayed recovery due to the cumulative effect of dexmedetomidine with inhalational agents, and long-term benefits of OFA in major and complex surgeries.

However, surgical heterogeneity could be a limitation. Variability in surgical procedures, ranging from staging laparotomies to extensive pelvic dissections, may have introduced variability in recovery times and pain levels, potentially affecting the results. In addition, urinary catheter removal, which is part of the QoR-15 assessment, was delayed in many patients beyond 24 h, affecting the interpretation of the QoR-15 scores.

CONCLUSION

The technique of OFA using IV dexmedetomidine, ketamine, and ultrasound-guided RSB achieves a comparable time to meet PACU discharge criteria when compared with the OBA technique in adult patients receiving general anaesthesia for open gynaecological oncological surgery.

Study data availability

De-identified data may be requested from the authors with reasonable justification (email to the corresponding author) and will be shared upon request.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.