Opioid-free Anaesthesia in Breast Cancer Surgery

Breast Cancer Clinical Trial

Official title:

A Comparative Evaluation of Opioid Free Anaesthesia Technique Versus the Conventional Technique in Oncological Breast Surgery

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06404983
• Other study ID #: 27
• Status: Recruiting
• Phase: N/A
• Start date: December 28, 2022
• Est. completion date: September 12, 2029

Study information

• Verified date: May 2024
• Source: University of Ioannina
• Contact: Agathi Karakosta
• Phone: +306948066243
• Email: akarakosta[@]uoi.gr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background:

Various analgesic modalities are adopted for perioperative analgesia in breast cancer surgeries. Opioid-free and opioid-sparing techniques are gaining popularity due to the lack of opioid-dependent undesirable effects, including respiratory depression, urinary retention, nausea and vomiting, constipation, itching, opioid-induced hyperalgesia, tolerance, addiction, and immune system disorders.

The goal of this prospective randomized clinical trial is to investigate the impact of opioid-free anaesthesia (OFA) versus conventional general anaesthesia (CGA) on postoperative analgesic requirements after breast cancer surgery (lumpectomy/mastectomy, with or without axillary lymph node excision).

Secondary objectives include comparative perioperative evaluation of cognitive function and postoperative adverse events during the first 48 hours atfter surgery. Comparative evaluation of intraoperative haemodynamics and hospital length of stay are also secondary objectives, as well as the incidence of neuropathic pain assessed by validated questionnaires at 3 and 6 months postoperatively.

During the preoperative screening, body measurements, age, gender, ASA (American Society of Anesthesiologists) physical status classification, educational level (using a 6-level scale: elementary, middle school, high school, higher education, higher education, and postgraduate/doctoral degree), home medication, and comorbidities (using the Charlson Comorbidity Index) are recorded.

Intraoperatively, the duration of anaesthesia, duration of surgery, associated intraoperative data (e.g., haemodynamic instability, adverse effects associated with protocol-administered pharmaceutical agents, etc.), and medications administered (type and quantity) are recorded.

The investigators expect to recruit at least 100 participants per group.

Description:

INTRODUCTION. Opioids are the mainstay for achieving analgesia in the perioperative setting. Standard anaesthetic practice in breast cancer surgery involves balanced general anaesthesia with the use of opioids intra- and postoperatively. Opioid-free anaesthesia (OFA) is a relatively recent anaesthetic proposal whereby no opioid is administered intraoperatively (systemically, in neuraxial or peripheral block or intra-cavity) and the use of opioids is avoided throughout the perioperative period.

Non-opioid anaesthesia appears to provide adequate postoperative analgesia while protecting the patient from the side effects of opioids, which include respiratory depression, opioid-induced hyperalgesia, postoperative nausea/vomiting, cognitive dysfunction, etc. Recently, concerns have arisen regarding delayed healing, immunosuppression, and worsening of oncological outcomes in cancer patients due to the systemic use of opioids.

Side effects of opioids include:

• Respiratory depression

• Muscle stiffness

• Weakness of pharyngeal muscles

• Upper airway obstruction (muscle atony)

• Negative inotropic action

• Nausea, vomiting

• Ileus, constipation

• Urinary retention

• Tolerance and addiction

• Dizziness

• Excessive drowsiness and sleep disorder

BACKGROUND. During the past decade there has been a growing interest in opioid sparing and opioid free techniques for general anaesthesia. The international literature started to be enriched with interesting cases and small prospective studies supporting the benefits of this technique, especially in patients with morbid obesity. According to its proponents, this technique is characterized by: 1) sympatholysis, analgesia, and anaesthesia (MAC reduction) using dexmedetomidine, 2) analgesia with low-dose of ketamine, 3) administration of lidocaine adjunctively for anaesthesia and sympatholysis, 4) deep neuromuscular blockade until the end of the procedure, 5) use of sevoflurane or desflurane 0.7 to 1 MAC in O2/air and titration based on entropy or BIS monitoring and 6) administration of magnesium adjunctively for analgesia. Inadequate sympatholysis is corrected by titrated doses of clonidine, whereas excessive sympatholysis is treated by the administration of vasoconstrictors, preferably ephedrine because of its chronotropic action. In addition, dexamethasone, high-dose paracetamol, NSAIDs, and gabapentin can be used adjunctively in the context of multimodal management of surgical pain.

However, the OFA method is not without its disadvantages, of which the clinician should be aware. Ketamine can disrupt electrocerebral monitoring (e.g., BIS) for possible intraoperative vigilance, although according to the proponents of the method, intraoperative vigilance is only a possibility in incorrect use of the technique, and they argue that it is unlikely to occur if BIS is maintained below 60. The need for hemodynamic support with vasoconstrictor administration is an additional disadvantage, and there may be a need to infringe the OFA protocol to achieve ideal intubation conditions using small doses of short-acting opioids during induction of anesthesia. Also, a significant degree of cutaneous vasoconstriction may be observed, an expected a2 action of concern to the clinician. Finally, training of the nursing staff and familiarity with the method is required.

Despite the above disadvantages of the method, OFA is becoming increasingly popular because of its excellent management of postoperative pain, protecting the patient from surgical and opioid-induced hyperalgesia, and because of the minimization of the risk of respiratory depression in high-risk patients (COPD, sleep apnea, morbid obesity, etc.).

The prevalence of chronic postoperative pain after breast cancer surgery (mastectomy, lumpectomy, with or without lymph node excision) is high and according to recent reports is 29.8%. The OFA technique has been studied in breast cancer surgery. However, these are mostly small studies examining the efficacy of this technique in acute postoperative pain. The effect of the OFA technique on chronic pain after breast cancer surgery has not been studied so far.

GOAL OF STUDY. The primary objective of the study is to evaluate postoperative analgesia for breast cancer surgery of low and intermediate severity (mastectomy, lumpectomy, with or without lymph node excision). Specifically, this is a prospective comparative study of pain intensity and total postoperative consumption of opioids and other analgesics in patients who received general anesthesia under OFA protocol (OFA group) versus those who received general anesthesia using opioids (CGA group, conventional General Anaesthesia).

Secondary objectives are the evaluation of intraoperative haemodynamic stability by recording the total use of vasoactive substances, time of extubation, length of stay in the Post-Anesthesia Care Unit (PACU), and total length of hospitalization per study group. In addition, secondary objectives include the comparative recording of serious postoperative anaesthesia-related adverse events (postoperative hypoxaemia, postoperative ileus, nausea/vomiting, etc.) and the comparative study of cognitive function in the perioperative period.

As part of the second part of the study, all participants will be monitored for the development of postoperative chronic pain using specific tools. Chronic postsurgical pain assessment will be performed at 3 and 6 months postoperatively.

METHOD. The anaesthetic technique of the OFA group is based on the protocol of Mulier et al. The intraoperative management of the CGA group will follow standard clinical protocols. All patients will give written informed consent to be included in the study.

During the preoperative screening, somatometrics, age, gender, ASA (American Society of Anesthesiologists) physical status classification, educational level (using a 6-level scale: elementary, middle school, high school, higher education, higher education, and postgraduate/doctoral degree), home medication, and comorbidities (using the Charlson Comorbidity Index) are recorded.

Intraoperatively, the duration of anaesthesia, duration of surgery, and associated intraoperative data (e.g., haemodynamic instability, adverse effects associated with protocol-administered pharmaceutical agents, etc.) and medications administered (type and quantity) are being recorded.

The length of stay in the Post Anaesthesia Care Unit (PACU) and the length of stay in the hospital shall also be recorded. Serious adverse events related to general anaesthesia for 48 hours post-operatively shall be recorded.

The intensity of acute postoperative pain shall be assessed using the NRS (Numerical Rating Scale) scale (Numerical Rating Scale, 0-10) at predefined intervals up to 48 hours postoperatively.

Participants' cognitive status, chronic postoperative pain, depression, anxiety, stress, and satisfaction will be assessed using validated questionnaires at 3 and 6 months after surgery.

STATISTICAL ANALYSIS. This is a prospective single-blind randomized clinical trial. Randomization will be carried out using sealed envelopes sorted based on computer-generated random numbers (Random Allocation Software).

Sample size calculation is based on a pilot study of 20 consecutive participants that was carried out in the University Hospital of Ioannina, with the primary outcome beeing the difference in NRS between groups at 1, 6, and 12 hours postoperatively, both at rest and at a deep breath.

Participant recruitment is expected to take up to 2 years, and the investigators expect to enroll at least 100 patients per study group.

Data analysis will be performed using Stata™ software (Version 10.1 MP, Stata Corporation, College Station, TX 77845, USA).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: September 12, 2029
• Est. primary completion date: December 20, 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

• adult patients

• breast cancer surgery (mastectomy, lumpectomy, with or without lymph node excision) under general anaesthesia

Exclusion Criteria:

• under 18 years

• patient refusal

• opioid use (systemic or not) for any reason (e.g., chronic malignant pain)

• language barrier (difficulty in communicating in Greek language)

• allergy to the administered agents

• severe arrhythmia or other serious cardiac disease

• severe liver and kidney failure

• dementia, psychiatric diseases, and/or preoperative cognitive impairment

Related Conditions & MeSH terms

• Anesthesia
• Breast Cancer
• Breast Neoplasms
• Cancer Recurrence
• Chronic Pain
• Opioid Free Anaesthesia
• Pain, Chronic
• Pain, Postoperative
• Recurrence

Intervention

Other:
• Opioid Free Anaesthesia (OFA)
Patients are allocated to receive non-opioid anaesthesia intraoperatively. Patients will receive a mixture of dexmedetomidine, ketamine and lidocaine for intraoperative analgesia.
• Conventional General Anaesthesia (CGA)
Patients are allocated to receive conventional general anaesthesia intraoperatively with the use of fentanyl and morphine for intraoperative analgesia.

Locations

Country	Name	City	State
Greece	University Hospital of Ioannina	Ioannina	Epirus

Sponsors (1)

Lead Sponsor	Collaborator
University of Ioannina

Country where clinical trial is conducted

Greece, 

References & Publications (1)

Wang K, Yee C, Tam S, Drost L, Chan S, Zaki P, Rico V, Ariello K, Dasios M, Lam H, DeAngelis C, Chow E. Prevalence of pain in patients with breast cancer post-treatment: A systematic review. Breast. 2018 Dec;42:113-127. doi: 10.1016/j.breast.2018.08.105. Epub 2018 Sep 4. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Postoperative analgesia.	Postoperative level of analgesia assessed by the NRS (Numerical Rating Scale, ranging from 0 to 10, where 0 is no pain and 10 is the worst pain imaginable).	From PACU (Post Anaesthesia Care Unit) admission to 48 hours postoperatively.
Primary	Postoperative consumption of opioids.	Total postoperative consumption of opioids.	From PACU (Post Anaesthesia Care Unit) admission to 48 hours postoperatively.
Secondary	Perioperative blood pressure measurements.	Intermittent blood pressure measurements (every 5 minutes) - blood pressure measured in mmHg.	From the beginning of surgery to PACU (Post Anaesthesia Care Unit) discharge, assessed up to 48 hours.
Secondary	Perioparative pulse measurements.	Intermittent arterial pulse measurements (every 5 minutes) - measured in beats per minute.	From the beginning of surgery to PACU (Post Anaesthesia Care Unit) discharge, assessed up to 48 hours.
Secondary	Perioperative consumption of ephedrine.	Total intravenous consumption of ephedrine, measured in milligrams.	From the beginning of surgery to PACU (Post Anaesthesia Care Unit) discharge, assessed up to 48 hours.
Secondary	Perioperative consumption of atropine.	Total intravenous consumption of atropine, measured in milligrams.	From the beginning of surgery to PACU (Post Anaesthesia Care Unit) discharge, assessed up to 48 hours.
Secondary	Perioperative consumption of phenylephrine.	Total intravenous consumption of phenylephrine, measured in milligrams.	From the beginning of surgery to PACU (Post Anaesthesia Care Unit) discharge, assessed up to 48 hours.
Secondary	PACU (Post Anaesthesia Care Unit) length of stay.	Minutes from PACU (Post Anaesthesia Care Unit) admission to PACU discharge.	From the beginning of surgery to PACU (Post Anaesthesia Care Unit) discharge, assessed up to 48 hours.
Secondary	Duration from end of anaesthesia to extubation.	Minutes from anaesthetic drug discontinuation to removal of endotracheal tube from the patient.	From end of anaesthesia, defined by anaesthetic drug discontinuation, to removal of endotracheal tube, assessed up to 48 hours.
Secondary	Postoperative episodes of nausea and/or vomiting.	Number of participants with postoperative recording of episodes of nausea/vomiting.	From PACU (Post Anaesthesia Care Unit) admission to 48 hours postoperatively.
Secondary	Postoperative pruritus.	Number of participants with postoperative recording of pruritus.	From PACU (Post Anaesthesia Care Unit) admission to 48 hours postoperatively.
Secondary	Postoperative paralytic ileus.	Number of participants with postoperative clinical signs of paralytic ileus.	From PACU (Post Anaesthesia Care Unit) admission to 48 hours postoperatively.
Secondary	Postoperative respiratory depression.	Number of participants with postoperative recording of hypoxaemic episodes (SpO2<90% with FiO2 (fraction of inspired oxygen) 21%)	From PACU (Post Anaesthesia Care Unit) admission to 48 hours postoperatively.
Secondary	Postoperative sedation.	Number of participants with postoperative sedation measured with the Ramsay Sedation Scale (ranging from +4 (a violent dangerous patient) to -5 (an unarousable patient)).	From PACU (Post Anaesthesia Care Unit) admission to 48 hours postoperatively.
Secondary	Postoperative headache.	Number of participants with postoperative episodes of headache, as assessed in a 4 rating scale (0: no headache to 3: severe headache).	From PACU (Post Anaesthesia Care Unit) admission to 48 hours postoperatively.
Secondary	Postoperative neuropathic pain assessed by the S-LANSS pain score.	Number of participants with postoperative neuropathic pain assessed by the use of the S-LANSS pain score (ranging from 0 to 24 points, where =12 points suggest the presence of neuropathic pain symptomatology).	From hospital discharge until 6 months postoperatively.
Secondary	Postoperative neuropathic pain assessed by the McGill questionnaire.	Number of participants with postoperative neuropathic pain assessed by the use of the McGill questionnaire (The present pain intensity (PPI) is based on a scale of 0-5, with 0 meaning no pain).	From hospital discharge until 6 months postoperatively.
Secondary	Postoperative depression and anxiety.	Number of participants with postoperative depression and anxiety assessed by the use of DASS21 tool, which is a set of three self-report scales designed to measure the emotional states of depression, anxiety and stress (the greater the score the greater the risk for depression, anxiety and stress).	From hospital discharge until 6 months postoperatively.
Secondary	Postoperative cancer recurrence.	Number of participants with postoperative cancer recurrence as assessed by examination of patient records (clinical examination, imaging testing, laboratory testing and biopsies that are part of the patient's follow-up protocol).	From hospital discharge to 5 years postoperatively.

External Links

•   Opioid free anaesthesia (OFA) a Paradigm shift? (Mulier JP)