Abstract
Perioperative opioids are associated with several adverse effects including nausea, vomiting, and long-term addiction. Opioid-free anesthesia may reduce postoperative morbidity, enable daycare surgery, and decrease cancer recurrence. In our study, we aimed to assess the efficacy of opioid-free anesthesia versus opioid-based anesthesia in patients undergoing breast cancer surgery in terms of postoperative opioid use, pain scores, expression of immune cells, and side effects. Hundred patients undergoing breast cancer surgery were randomized into two groups (1:1 ratio). Group O received opioid-based anesthesia and Group N did not receive any opioid intraoperatively. Our primary outcome was total postoperative morphine consumption in 24 h managed with a patient-controlled analgesia (PCA) pump containing morphine in both groups. Secondary outcomes were numerical rating scale (NRS) at rest and movement at immediate postoperative period, 30 min, 1 h, 2 h, 6 h, and 24 h postoperatively was measured. Blood samples were also taken at different time points to measure inflammatory markers. There was no statistical difference in the total 24 h postoperative morphine consumption in between the two groups (p = 0.13). The patient satisfaction scores and NRS at rest and on movement at various time points postoperatively were similar (p > 0.05). There was a significant difference in neutrophil lymphocyte ratio (NLR) between the two groups in the samples taken at 24 h postoperative period (p = 0.03). No complications were reported in any group. While our study did not show opioid-free anesthesia’s superiority in postoperative morphine consumption, it established the feasibility and safety of a non-opioid technique for breast cancer surgery. The approach may offer advantages, including potential immunosuppression relief, making it a viable option for patients prone to opioid-related side effects.
Keywords: Opioids, Breast cancer, Analgesia, Anesthesia, Regional blocks
Introduction
Breast cancer surgery is frequently associated with postoperative pain which leads to increased suffering of the patient and prolongation of hospital stay and if not controlled adequately can result in chronic post-surgical pain [1]. Opioids are the mainstay of perioperative pain management. However, they are associated with side effects like sedation, respiratory depression, nausea, vomiting, hypotension, bradycardia, pruritus, and inhibition of bowel function. Lately, use of opioids has been linked to cancer recurrence [2]. Evidence also suggests the increased association of amount of perioperative opioid use and postoperative opioid abuse in opioid naïve patients [3].
Recently, there has been a move toward opioid-free anesthesia (OFA), where no opioid is given intraoperatively whether it be via intravenous, neuraxial, or intracavitary route [4]. Regional blocks along with drugs like lignocaine, dexmedetomidine, and ketamine are used as an alternative to opioids [5]. Surgery done with OFA technique has been associated with lesser postoperative opioid need, decreased incidence of nausea, vomiting, and intraoperative complications [6, 7]. Opioids also inhibit cell-mediated immunity and have been found to enhance cancer-related inflammation. Cell-mediated immunity can be assessed by measuring natural killer cells, cytotoxic T cells, T helper cells, and neutrophil–lymphocyte ratio (NLR) [8].
Our literature search also revealed lack of randomized controlled trial on opioid-free anesthesia in breast cancer surgery patients. We hypothesized that breast cancer surgery can be performed without the need of intraoperative opioids altogether. The purpose of our study was to find out if opioid-free anesthesia technique is beneficial compared to the conventional opioid-based anesthesia technique in terms of postoperative opioid use, subjective pain, complications like nausea, vomiting, patient satisfaction, and expression of immune cells.
Materials and Methods
Ethics
This randomized control study was carried out in a tertiary cancer institute. Institute Ethics Committee approval was obtained (IECPG-387/27.06.2019). The study was registered with the Clinical Trial Registry of India (registration number: CTRI/2019/08/020865).
Study Design
This was a prospective randomized control trial with a 1:1 ratio of group allocation to either opioid-based or non-opioid-based group.
Eligibility Criteria
We included American Society of Anesthesiologists (ASA) I and II patients from 18 to 70 years of age posted for breast cancer surgery. We excluded patients with body mass index (BMI) > 35 kg/m2, infection at site of injection of erector spinae plane (ESP) block, coagulopathy, spine deformity, myopathy, neuropathy drug addicts or history of opioid dependence, allergic to opioids, local anesthetics, or magnesium.
Randomization and Allocation Concealment
All patients were randomized into one of the following groups:
Group N (No opioid group): Patients received ultrasound-guided ESP block along with dexmedetomidine and magnesium sulfate without any opioids with general anesthesia (GA).
Group O (Opioid group): Patients received opioids with GA.
The randomization sequence was generated using a computer-generated randomization table. Allotment concealment can be done by opaque sequentially numbered sealed envelopes. The randomized sequence was opened by an independent anesthesiologist just before surgery.
Anesthetic Care
All patients were kept fasting 6 h before surgery. Blood samples (2 ml of blood per sample) were taken 1 day before surgery to know the baseline values of neutrophil–lymphocyte ratio (NLR), number of T helper cells, natural killer cells (NKC), and cytotoxic T cells. After shifting the patient to the operation room, standard ASA monitors including pulse oximetry, non-invasive blood pressure (NIBP), 5-lead electrocardiogram (ECG), and bispectral index (BIS) were attached. Baseline readings of arterial oxygen saturation (SpO2), heart rate (HR), and blood pressure (BP) were noted. A 20-gauge peripheral venous line was secured.
General anesthesia was induced with injection propofol (1–2 mg/kg) and cisatracurium (0.1 mg/kg). After adequate muscle relaxation, supraglottic device (SAD) of appropriate size was placed. Dexamethasone 8 mg was given after induction. Anesthesia was maintained with 50% air, oxygen, and sevoflurane titrated to achieve MAC between 0.8 and 1. Ventilation was maintained using volume-controlled ventilation and ventilation was adjusted to achieve an end-tidal CO2 of 35–45 mmHg.
In group N, before administering general anesthesia, ESP block was given under ultrasound (Sonosite Edge II; Sonosite, Inc., FUJIFILM) guidance with a 10-cm (100-mm) stimuplex needle (B Braun Medical, Bethlehem, PA) in lateral position by an anesthesiologist not involved in further management. Under all aseptic precautions, the linear USG transducer (7–12 MHz) probe was placed in a longitudinal orientation, 2.5–3 cm lateral to the T5 spinous process. Trapezius, rhomboid major, and erector spinae muscles were identified superficial to the hyperechoic transverse process shadow. The puncture site was infiltrated with 1–2 ml of 2% lignocaine subcutaneously. The stimuplex needle was inserted in a cephalad-to-caudad direction until the tip lay in the interfascial plane between erector spinae muscle and the transverse process. We injected 0.5 ml/kg of 0.5% ropivacaine (Ropin 0.75%, Neon) with a maximum volume of 30 ml after aspiration to exclude intravascular needle placement.
In these patients, dexmedetomidine infusion 0.5 µg/kg/h was initiated 10 min prior to induction and continued between 0.3 and 0.7 µg/kg/h based on intraoperative hemodynamics. Magnesium sulfate 40 mg/kg was also infused slowly over 10 min after induction.
In Group O, fentanyl 2 µg/kg intravenous (IV) was given 5 min before induction and was repeated with 1 µg/kg after every hour intraoperatively.
Intraoperatively, the BIS values were kept between 50 and 60. If the patient’s heart rate increased above 20% of baseline with BIS more than 60, anesthesia was deepened by increasing sevoflurane concentration till the BIS value was less than 60. But if BIS was already within the targeted range accompanied with tachycardia, a bolus of 10 mg ketamine repeated up to a maximum of 0.5 mg/kg (group N) or a bolus of 20 µg fentanyl was given up to a maximum of three times (group O).
The HR, SBP (systolic blood pressure), DBP (diastolic blood pressure), MAP (mean arterial pressure), SpO2, BIS, and EtCO2 were recorded every 5 min till 30 min after induction and then every 10 min until the end of surgery in all patients. Hypotension (SBP < 20% of baseline) was treated with a 250 ml bolus of crystalloid and if required, mephentermine 3–6 mg IV was given. Bradycardia (HR < 60 beats min or < 20% of baseline) was treated with atropine IV 0.6 mg. Ondansetron 0.1 mg/kg IV was given as antiemetic prophylaxis before completion of surgery. Paracetamol 1 gm was given to both groups 30 min before completion of surgery. The residual neuromuscular block was antagonized with neostigmine (50 µg/kg) and glycopyrrolate (10 µg/kg), and the supraglottic device was removed once the patient was fully conscious and breathing spontaneously. Blood samples (2 ml of blood per sample) were taken to determine the values of NLR, and the number of T helper cells, NKC, and cytotoxic T cells immediately after the patient was shifted to the recovery room.
Sedation was assessed by the Ramsay Sedation Scale (RSS) at 0 and 1 h postoperatively and readiness to discharge to the ward was recorded at 1 h by Modified Aldrete Score (MAS). All patients received paracetamol 1g 6 hourly in the postoperative period. An anesthesiologist not involved in the administration of block or intraoperative management of the patient was responsible for the postoperative assessment of the patient. Analgesia in the postoperative period was assessed by NRS score at rest and ipsilateral arm abduction at 90 degrees at immediate postoperative (0 min), 30 min, and 1, 2, 6, and 24 h. All patients were equipped with PCA device (CADD-Legacy® PCA Ambulatory Infusion Pump, Model 6300) to manage postoperative breakthrough pain with the following settings: 1mg of morphine bolus with a lockout interval of 15 min and a maximum of 4 doses in an hour. There was no basal infusion. If the patients were still having pain with an NRS of more than 4/10, the nursing staff informed the attending anesthesiologist and a bolus of 3 mg morphine IV was given. This was continued until 24 h postoperatively and total opioid consumption in both groups was recorded.
Side effects of opioids such as nausea, vomiting, pruritus, and respiratory depression were noted at 0 min, 30 min, 1 h, 2 h, 6 h, and 24 h postoperatively. Postoperative nausea and vomiting (PONV) was assessed using a 4-point numerical scale (0 = no PONV, 1 = mild nausea, 2 = severe nausea or vomiting once, and 3 = vomiting more than once). Ondansetron 0.1 mg/kg was given IV as a rescue antiemetic if the score was 2 or more.
Patient satisfaction was evaluated and recorded 24 h after the operation on a 7-point Likert scale (1—extremely dissatisfied, 2—very dissatisfied, 3—dissatisfied, 4—neither satisfied nor dissatisfied, 5—satisfied, 6—very satisfied, 7—extremely satisfied). Twenty-four hours after surgery, another blood sample (2 ml of blood per sample) was taken to determine the values of NLR, number of T helper cells, NKC, and cytotoxic T cells from all patients.
The peripheral blood samples were processed using the standard whole blood stain-lyse-wash method. The multicolor immunophenotyping for lymphocyte subset analysis was done using the Gallios instrument (Beckman Coulter, USA). The gating and subset analysis of lymphocytes were done based on scattering properties of cells along with the expression pattern of CD45, CD3, CD4, CD8, CD19, CD16, and CD56 monoclonal antibodies. The samples were stored at 4 °C after processing and fixation, until acquisition and analysis. At least 10,000 events were recorded in each tube and analysis was done for percentage expression as well as median fluorescence intensities for each marker.
Outcome Measures
The primary outcome was the comparison of analgesic efficacy between the two groups in terms of total postoperative morphine consumption in 24 h.
The secondary outcome measures were NRS pain scores (0–10) at following time points postoperatively: 0, 30 min, 1 h, 2 h, 6 h, 24 h; patient satisfaction on a Likert scale of 1–7 at 24 h postoperatively; NLR and number of NKCs, T helper cells, cytotoxic T cells at three time points: baseline preoperatively, immediate postoperative period, and 24 h postoperatively between the two groups; and side effects if any.
Statistical Analysis
We have considered the study by Gurkan et al. [7] where they have reported a postoperative morphine consumption of 16.6 mg in the control group with a standard deviation of 7 mg. Assuming this as reference value, expecting no change in control group (opioid-based group), and a 30% decrease of total 24 h postoperative morphine consumption in the treatment group (opioid-free group), we estimated a sample size of 41 patients in each group. The assumed alpha error and power are 5% and 90% respectively. We included 50 patients in each group to secure patient dropouts.
Statistical analysis was done using a statistical package for social sciences (SPSS, version 16, Chicago, IL, USA). The Kolmogorov–Smirnov test was used to determine the normality of data distribution. Continuous variables are expressed as mean ± standard deviation, and median (25th–75th percentiles), and categorical variables as counts (percentages). Comparisons of normally distributed continuous variables between the groups have been performed using Student’s t-test, while non-normally distributed continuous variables between the groups are compared using the Mann–Whitney U test. For comparison of categorical data, the chi-square test/Fisher’s exact test has been performed to establish the association between the groups. A linear mixed model is applied to compare the hemodynamic changes between the two groups. A p-value < 0.05 is considered statistically significant.
Results
A total of 110 patients were assessed for eligibility, 10 were excluded. One hundred patients with 50 in each group were included for randomization (Fig. 1). The demographic characteristics (age, weight, height, body mass index (BMI), ASA grade, type of breast cancer surgery) among the two groups were comparable (Table 1) The total postoperative morphine consumption in 24 h was 2 (0–19) mg in group O and 1.5 (0–11) mg in group N (p = 0.13) in median (IQR). The number of attempts made in the patient-controlled analgesia pump in groups O and N was 2 (0–23) and 2 (0–15) in median (IQR) respectively (p = 0.18) (Table 2).
Fig. 1.
CONSORT flow diagram
Table 1.
Baseline characteristics
| Parameters | Group O (n = 50) |
Group N (n = 50) |
|---|---|---|
| Age (years) | 47 (10) | 49 (9) |
| Weight (kg) | 65 (9) | 64 (9) |
| Height (cm) | 153 (4) | 153 (4) |
| BMI (kg/m2) | 28 (3) | 27 (4) |
| ASA I/II (n) | 29/21 | 32/18 |
| Modified radical mastectomy/breast conservation surgery (n) | 46/4 | 44/6 |
| Duration of surgery (minutes) | 105 (17) | 104 (15) |
The values are given in mean (SD)
Table 2.
Postoperative morphine consumption, RSS, MAS, and patient satisfaction score; intraoperative drug details and change in laboratory parameters from baseline
| Parameters | Group O (n = 50) |
Group N (n = 50) |
p-value |
|---|---|---|---|
| Primary outcome | |||
| Total 24-h morphine consumption (mg) | 2 (0–19) | 1.5 (0–11) | 0.13 |
| Secondary outcome | |||
| Number of times PCA attempted in 24 h | 2 (0–23) | 2 (0–15) | 0.18 |
| RSS at 1 h postoperatively | 2 (2–3) | 2 (2–3) | 1.00 |
| MAS at 1 h post operatively | 9 (8–9) | 9 (8–9) | 0.11 |
| Patient satisfaction score at 24 h post operatively | 5 (4–7) | 6 (4–7) | 0.56 |
| Intraoperative drug details | |||
| Atropine use (n, %) | 0,0 | 0,0 | 1.00 |
| Mephentermine use (n, %) | 0,0 | 0,0 | 1.00 |
| Total fentanyl used (µg) [mean (SD)] | 186.3 (26.55) | - | |
| Ketamine use (n, %) | - | 6,12 | |
| Total ropivacaine used (ml) [mean (SD)] | - | 30 (0) | |
| No. of attempts for ESP block | - | 1 (1–2) | |
The values are given in median (IQR); RSS Ramsay Sedation Scale, MAS Modified Aldrete Score, NLR neutrophil lymphocyte ratio, NKC natural killer cells
RSS measured at immediate and after 1 h in postoperative period did not differ between the two groups (p = 1.0). The MAS was also similar in both groups (p = 0.11). The median (IQR) patient satisfaction score was similar in the two groups, (5 [4–7] vs 6 [4–7]) in groups O and N respectively (p = 0.56) (Table 2). The NRS at rest and on movement at immediate postoperative period, 30 min, 1 h, 2 h, 6 h, and 24 h postoperatively did not differ significantly between the two groups (p > 0.05). At the end of 24 h, NRS in both groups was less than 4 in all patients at rest and on movement (abduction of ipsilateral arm at 90°) (Fig. 2). Complications like pruritus, respiratory depression, and urinary retention were not seen in any patient. None of the patients required atropine or mephentermine administration. There was a significant difference in NLR between the two groups at 24 h (p = 0.03). The number of NKCs, T helper cells, and T cytotoxic cells measured in all the above three time points did not differ significantly between group O and group N, although group N had a greater number of lymphocytes at all time points (p > 0.05) (Table 3).
Fig. 2.
a Box plot showing Numerical Rating Scale for pain at rest (NRSr) for various time points. b Box plot showing Numerical Rating Scale for pain on movement (NRSm) for various time points (0: at immediate postoperative period, 1/2: 30 min postoperatively, 1: 1 h postoperatively, 2: 2 h postoperatively, 6: 6 h postoperatively, 24: 24 h postoperatively)
Table 3.
Laboratory parameters
| Timepoints | Parameter | Group O (n = 50) | Group N (n = 50) | p-value |
|---|---|---|---|---|
| Baseline | NLR | 2.08 (1.45–2.89) | 1.54 (0.72–2.62) | 0.05 |
| NKC | 353.5 (186–589) | 375 (183–601) | 0.79 | |
| T helper cells | 738.5 (479–991) | 918.5 (534–1441) | 0.12 | |
| Cytotoxic T cells | 620 (393–1139) | 767 (343–1288) | 0.22 | |
| Immediate postoperatively | NLR | 3.365 (2.01–6.53) | 2.235 (1.23–6.3) | 0.05 |
| NKC | 311 (206–515) | 239.5 (114–423) | 0.16 | |
| T helper cells | 487.5 (321–721) | 562.5 (320–1076) | 0.22 | |
| Cytotoxic T cells | 452.5 (227–835) | 543 (232–867) | 0.58 | |
| 24 h postoperatively | NLR | 6.795 (3.87–7.67) | 3.52 (1.73–8.52) | 0.03 |
| NKC | 147 (71–240) | 180.5 (96–280) | 0.30 | |
| T helper cells | 368.5 (303–1021) | 518 (235–903) | 0.07 | |
| Cytotoxic T cells | 264 (188–501) | 375.5 (222–873) | 0.02 |
The values are given in mdian (IQR); NLR neutrophil lymphocyte ratio, NKC natural killer cells
Discussion
Our endeavor to establish the superiority of opioid-free anesthesia over conventional opioid-based anesthesia in relation to total 24-h postoperative morphine consumption among breast cancer surgery patients did not yield conclusive evidence.
The only other randomized controlled trial on similar group of patients was done by Hontoir et al. where opioid-free group had a significantly lower postoperative piritramide consumption as compared to opioid-based group [9]. However, they did not use any regional block in their patients nor was the study powered for postoperative analgesic consumption but quality of postoperative recovery which was found to be equal in both groups. Another matched cohort study in mastectomy patients found no difference in postoperative morphine consumption between the two techniques [3]. Our investigation also aligns with broader trends seen in studies involving non-cardiac surgery, thoracic surgery, gynecological laparoscopic surgeries, and invasive lumbar spine surgeries, where postoperative opioid consumption showed no significant variance between opioid-free and opioid-administered groups [10–13]. It should be noted that many of these studies were non-randomized trials [11, 13].
In our study, we opted for a 24-h observation period to encompass the entirety of the postoperative pain period, considering the standard practice of discharging mastectomy patients within this timeframe at our institute. The decision to calculate the total morphine consumption postoperatively stemmed from its role as a surrogate, objective measure of pain intensity. The use of a patient-controlled analgesia (PCA) device not only facilitated superior pain control but also mitigated potential observer bias that might arise if analgesic administration were solely dependent on the attending staff.
The analgesic efficacy, as assessed by Numeric Rating Scale (NRS) for pain at rest and on movement (90° abduction of the ipsilateral arm) at various postoperative time points, did not exhibit a significant difference between the two study groups. An observation study reported a significant reduction in Visual Analog Scale (VAS) scores in the OFA group supplemented by pectoral nerve block in patients undergoing mastectomy. They used dexamethasone as an adjuvant in regional block which might have resulted in prolonged analgesia and decreased VAS scores in that group [14]. The use of regional blocks is also associated with a lower incidence of PONV and promises optimal postoperative pain control with minimal use of opioids [15]. In our study, the use of ESP block in non-opioid group as part of the opioid-free technique stemmed from the same concept. Gurkan et al. found that the use of ESP block with GA significantly reduced postoperative morphine consumption than with GA alone in patients undergoing mastectomy [7].
We used intravenous dexmedetomidine infusion as part of the multimodal non-opioid technique which contributed to the opioid-sparing effect and decreased adrenergic response during SAD placement. An OFA-based multicentric trial had to be stopped prematurely because of significant bradycardia in several patients [10]. Dexmedetomidine use in our study did not yield any adverse outcomes like hypotension or bradycardia, aligning with other studies [16, 17].
There was also no difference in postoperative sedation scores between the two groups similar to previous studies [10, 17]. A meta-analysis of 26 randomized controlled trials found that OFA improved postoperative outcomes without any side effects in different types of surgeries [18].
NLR was notably lower in the OFA group, indicating less inflammation or improved cell-mediated immunity. This parallels findings by Eochagain et al., where paravertebral block and propofol anesthesia attenuated the increase in NLR during breast cancer surgery, highlighting potential immunomodulatory effects of regional anesthesia [19]. Regional anesthesia with propofol was also associated with lesser expression of µ-opioid receptors than with opioid-based technique [20]. Opioids have been linked with immunosuppressive effects whereas regional anesthesia has been found to decrease the stress response and inflammation [21]. Our study further revealed higher counts of natural killer cells (NKC), T helper cells, and cytotoxic T cells in the OFA group, suggesting a positive impact on anti-cancer immunity. A previous study has found that neither propofol nor sevoflurane-based inhalation anesthesia was associated with any significant effect on NKC or T lymphocyte counts [22]. They used opioids in both groups. Another study found that patients who received postoperative ketorolac analgesia had preserved NKC cytotoxicity as compared to patients who received postoperative fentanyl analgesia [23]. It was also found that induction and maintenance with propofol had less impact on cellular immunity and thus on T lymphocytes as compared to sevoflurane-based anesthesia [24]. There is a dearth of literature on the effect of the OFA technique on NKC and T lymphocytes. Findings from our study suggest that the OFA technique is associated with better expression of immune cells and anti-cancer immunity.
We attribute the statistically insignificant findings of our study—particularly in terms of postoperative morphine consumption, pain scores, and side effects—to the less invasive nature of the breast cancer surgeries we included, as opposed to highly invasive procedures such as abdominal oncosurgeries involving extensive resection. The oncosurgeons operating in our set of patients were highly dexterous and expert in performing such surgeries with minimal manipulation.
Our study had limitations, such as not assessing morphine consumption at specific time points and focusing on total consumption at 24 h. The inclusion of ESP block in both groups could have enhanced methodological homogeneity. Additionally, the study was confined to ASA 1 and 2 patients, limiting generalizability to those with higher comorbidities. Long-term follow-ups are crucial for investigating cancer recurrence or metastasis.
While our study did not demonstrate the superiority of opioid-free anesthesia over opioid-based anesthesia in terms of postoperative morphine consumption, it successfully established the feasibility and safety of a non-opioid technique for patients undergoing breast cancer surgery within a randomized trial setting. One notable advantage of the opioid-free approach is its potential to alleviate immunosuppression, rendering it a viable option for breast cancer surgery patients prone to opioid-related side effects such as nausea and vomiting. Nevertheless, further investigations with extended follow-up periods are warranted to draw definitive conclusions regarding inflammatory markers and oncological outcomes.
Data Availability
The will be made availabe if required.
Declarations
Ethics Approval
This research was conducted after approval from the institutional ethics committee.
Consent to Participate
All participants provided informed consent for the study.
Competing Interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Roth RS, Qi J, Hamill JB, Kim HM, Ballard TNS, Pusic AL et al (2018) Is chronic postsurgical pain surgery-induced? A study of persistent postoperative pain following breast reconstruction. Breast 37:119–125. 10.1016/j.breast.2017.11.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Afsharimani B, Cabot P, Parat MO (2011) Morphine and tumor growth and metastasis. Cancer Metastasis Rev 30:225–238. 10.1007/s10555-011-9285-0 [DOI] [PubMed] [Google Scholar]
- 3.King CA, Perez-Alvarez IM, Bartholomew AJ, Bozzuto L, Griffith K, Sosin M et al (2020) Opioid-free anesthesia for patients undergoing mastectomy: a matched comparison. Breast J 26:1742–1747. 10.1111/tbj.13999 [DOI] [PubMed] [Google Scholar]
- 4.Mulier J (2017) Opioid free general anesthesia: a paradigm shift? Rev Esp Anestesiol Reanim 64:427–430. 10.1016/j.redar.2017.03.004 [DOI] [PubMed] [Google Scholar]
- 5.Sultana A, Torres D, Schumann R (2017) Special indications for opioid free anaesthesia and analgesia, patient and procedure related: including obesity, sleep apnoea, chronic obstructive pulmonary disease, complex regional pain syndromes, opioid addiction and cancer surgery. Best Pract Res Clin Anaesthesiol 31:547–560. 10.1016/j.bpa.2017.11.002 [DOI] [PubMed] [Google Scholar]
- 6.Ziemann-Gimmel P, Goldfarb AA, Koppman J, Marema RT (2014) Opioid free total intravenous anaesthesia reduces postoperative nausea and vomiting in bariatric surgery beyond triple prophylaxis. Br J Anaesth 112:906–911. 10.1093/bja/aet551 [DOI] [PubMed] [Google Scholar]
- 7.Gürkan Y, Aksu C, Kuş A, Yörükoğlu UH, Kılıç CT (2018) Ultrasound guided erector spinae plane block reduces postoperative opioid consumption following breast surgery: a randomized controlled study. J Clin Anesth 50:65–68. 10.1016/j.jclinane.2018.06.033 [DOI] [PubMed] [Google Scholar]
- 8.Cronin-Fenton DP, Heide-Jørgensen U, Ahern TP, Lash TL, Christiansen PM, Ejlertsen B et al (2015) Opioids and breast cancer recurrence: a Danish population-based cohort study. Cancer 121:3507–3514. 10.1002/cncr.29532 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Hontoir S, Saxena S, Gatto P, Khalife M, Ben Aziz AM, Paesmans M et al (2016) Opioid-free anesthesia: what about patient comfort? A prospective, randomized, controlled trial. Acta Anaesthesiol Belg 67:183–190 [PubMed] [Google Scholar]
- 10.Beloeil H, Garot M, Lebuffe G, Gerbaud A, Bila J, Cuvillon P, et al.; POFA Study Group; SFAR Research Network (2021) Balanced opioid-free anesthesia with dexmedetomidine versus balanced anesthesia with remifentanil for major or intermediate noncardiac surgery: the postoperative and opioid-free anesthesia (POFA) randomized clinical trial. Anesthesiology 134: 541–51. 10.1097/ALN.0000000000003725 [DOI] [PubMed]
- 11.Devine G, Cheng M, Martinez G, Patvardhan C, Aresu G, Peryt A et al (2020) Opioid-free anesthesia for lung cancer resection: a case-control study. J Cardiothorac Vasc Anesth 34:3036–3040. 10.1053/j.jvca.2020.05.022 [DOI] [PubMed] [Google Scholar]
- 12.Massoth C, Schwellenbach J, Saadat-Gilani K, Weiss R, Pöpping D, Küllmar M et al (2021) Impact of opioid-free anaesthesia on postoperative nausea, vomiting and pain after gynaecological laparoscopy - a randomised controlled trial. J Clin Anesth 75:110437. 10.1016/j.jclinane.2021.110437 [DOI] [PubMed] [Google Scholar]
- 13.Soffin EM, Wetmore DS, Beckman JD, Sheha ED, Vaishnav AS, Albert TJ et al (2019) Opioid-free anesthesia within an enhanced recovery after surgery pathway for minimally invasive lumbar spine surgery: a retrospective matched cohort study. Neurosurg Focus 46:E8. 10.3171/2019.1.FOCUS18645 [DOI] [PubMed] [Google Scholar]
- 14.Tripathy S, Rath S, Agrawal S, Rao PB, Panda A, Mishra TS et al (2018) Opioid-free anesthesia for breast cancer surgery: an observational study. J Anaesthesiol Clin Pharmacol 34:5. 10.4103/joacp.JOACP_143_17 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Santonastaso DP, de Chiara A, Russo E, Musetti G, Lucchi L, Sibilio A et al (2019) Single shot ultrasound-guided thoracic paravertebral block for opioid-free radical mastectomy: a prospective observational study. J Pain Res 12:2701–2708. 10.2147/JPR.S211944 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Hwang W, Lee J, Park J, Joo J (2015) Dexmedetomidine versus remifentanil in postoperative pain control after spinal surgery: a randomized controlled study. BMC Anesthesiol 15:21. 10.1186/s12871-015-0004-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Feld JM, Hoffman WE, Stechert MM, Hoffman IW, Ananda RC (2006) Fentanyl or dexmedetomidine combined with desflurane for bariatric surgery. J Clin Anesth 18:24–28. 10.1016/j.jclinane.2005.05.009 [DOI] [PubMed] [Google Scholar]
- 18.Olausson A, Svensson CJ, Andréll P, Jildenstål P, Thörn SE, Wolf A (2022) Total opioid-free general anaesthesia can improve postoperative outcomes after surgery, without evidence of adverse effects on patient safety and pain management: a systematic review and meta-analysis. Acta Anaesthesiol Scand 66:170–185. 10.1111/aas.13994 [DOI] [PubMed] [Google Scholar]
- 19.Eochagáin AN, Burns D, Riedel B, Sessler DI, Buggy DJ (2018) The effect of anaesthetic technique during primary breast cancer surgery on neutrophil–lymphocyte ratio, platelet–lymphocyte ratio and return to intended oncological therapy. Anaesthesia 73:603–611. 10.1111/anae.14207 [DOI] [PubMed] [Google Scholar]
- 20.Levins KJ, Prendeville S, Conlon S, Buggy DJ (2018) The effect of anesthetic technique on µ-opioid receptor expression and immune cell infiltration in breast cancer. J Anesth 32:792–796. 10.1007/s00540-018-2554-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Gottschalk A, Sharma S, Ford J, Durieux ME, Tiouririne M (2010) The role of the perioperative period in recurrence after cancer surgery. Anesth Analg 110:1636–1643. 10.1213/ANE.0b013e3181de0ab6 [DOI] [PubMed] [Google Scholar]
- 22.Lim JA, Oh CS, Yoon TG, Lee JY, Lee SH, Yoo YB et al (2018) The effect of propofol and sevoflurane on cancer cell, natural killer cell, and cytotoxic T lymphocyte function in patients undergoing breast cancer surgery: an in vitro analysis. BMC Cancer 18:159. 10.1186/s12885-018-4064-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Cho JS, Lee MH, Kim SI, Park S, Park HS, Oh E et al (2017) The effects of perioperative anesthesia and analgesia on immune function in patients undergoing breast cancer resection: a prospective randomized study. Int J Med Sci 14:970–976. 10.7150/ijms.20064 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Zhang T, Fan Y, Liu K, Wang Y (2014) Effects of different general anaesthetic techniques on immune responses in patients undergoing surgery for tongue cancer. Anaesth Intensive Care 42:220–227. 10.1177/0310057X1404200209 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The will be made availabe if required.