Naldebain for Pain Management of Laparoscopic Cholecystectomy

Sponsor

E-DA Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT04808544

Collaborator

(none)

Enrollment

Location

Arms

7.6

Actual Duration (Months)

10.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Laparoscopic cholecystectomy is the most common surgical procedure for removal of the inflamed gall bladder or other gall bladder pathologies. There are more than 12,000 cases of cholecystectomy performed in Taiwan annually, and more than 85% of this procedure are undertook with laparoscopic techniques. Even with minimally invasive laparoscopic operation, patients may still suffer from postoperative wound pain, deep visceral or referred pain. About 80% of patients who received laparoscopic procedures complain of moderate-to-severe pain within the first day after cholecystectomy. Most importantly, up to 20% (range from 3 to 20%) of these patients complained surgical-related pain one year after operation and they require prolonged use of opioid to control chronic postoperative pain (CPSP). However, there are currently lack of clinical practice guidelines or recommendations for prevention of CPSP after laparoscopic abdominal surgery. Although regional block techniques (i.e. truncal block or intrathecal opioid) are considered as effective supplementary analgesic approaches to improve postoperative pain control, parenteral administration of analgesics remain as the mainstay for pain management of laparoscopic abdominal surgery. Naldebain® is prodrug of nalbuphine, which was approved by the Taiwan FDA in 2017. Naldebain® is an extended-release dinalbuphine sebacate, and is rapidly hydrolyzed by tissue of plasma esterase to release nalbuphine. A number of clinical studies have shown that single-dose of pre-operative intramuscular administration of Naldebain® provides significantly higher analgesic effect up to 1 week in hemorrhoidectomy and laparotomy surgery with a well-tolerated safety profile. Therefore, this PI-initiated randomized, double-blind, placebo-control trial aims to investigate the clinical efficacy of Naldebain® in management of acute postoperative pain in patients receiving laparoscopic cholecystectomy, and prevention of the development of CPSP after surgery.

Condition or Disease	Intervention/Treatment	Phase
Pain, Postoperative Pain, Chronic Cholecystitis Quality of Life	Drug: Dinalbuphine sebacate Drug: Placebo solution	Phase 2/Phase 3

Detailed Description

Clinical studies indicate that more than 80% of patients suffer from surgical-related pain in the first few days after major laparotomy or laparoscopic abdominal surgery and about 10% of these patients may develop chronic postoperative pain (CPSP), which can last up to several years after surgery. One of the major risk factors for developing CPSP is inadequate management of the acute postoperative pain. Laparoscopic cholecystectomy is the most common surgical procedure for removal of the inflamed gall bladder or other gall bladder pathologies. There are more than 12,000 cases of cholecystectomy performed in Taiwan annually, and more than 85% of this procedure are undertook with laparoscopic techniques. Even with the minimally invasive laparoscopic operation, patients may still suffer from acute postoperative surgical-related pain. About 80% of patients who received laparoscopic procedures complain of moderate-to-severe pain within the first day after cholecystectomy. Most importantly, up to 20% (range from 3 to 20%) of these patients complained surgical-related pain one year after operation and they require prolonged use of opioid to control CPSP. The proposed mechanisms of CPSP after laparoscopic cholecystectomy include somatic component (incisional wound pain), visceral component (deep abdominal pain) and referred pain component (shoulder pain). Several important clinical observational studies suggested that inadequate management of surgical-related pain within one week after cholecystectomy is one of the major risk factors for developing CPSP. In addition to pain-related complications, CPSP may also impair patient's quality of life after surgery. However, there are currently lack of clinical practice guidelines or recommendations for prevention of CPSP after laparoscopic abdominal surgery. Although regional block techniques (i.e. truncal block or intrathecal opioid) are considered as effective supplementary analgesic approaches to improve postoperative pain control, parenteral administration of analgesics remain as the mainstay for pain management of laparoscopic abdominal surgery. Nalbuphine is a semi-synthetic opioid that acts as a mixed kappa opioid agonist and mu opioid antagonist, but its clinical applications in relieving acute postoperative pain is limited by the relatively short duration of action of 3-6h. Naldebain® is prodrug of nalbuphine, which was approved by the Taiwan FDA in 2017. Naldebain® is an extended-release dinalbuphine sebacate, and is rapidly hydrolyzed by tissue of plasma esterase to release nalbuphine. A number of clinical studies have shown that single-dose of pre-operative intramuscular administration of Naldebain® provides significantly higher analgesic effect up to 1 week in hemorrhoidectomy and laparotomy surgery with a well-tolerated safety profile. Naldebain® has not been tested in laparoscopic surgery. Therefore, this PI-initiated randomized, double-blind, placebo-control trial aims to investigate the clinical efficacy of Naldebain® in management of acute postoperative pain in patients receiving laparoscopic cholecystectomy, and prevention of the development of CPSP after surgery.

Study Design

Study Type:

Interventional

Actual Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Naldebain (active drug in solvent containing benzyl benzoate and sesame oil) or placebo drug (solvent containing benzyl benzoate and sesame oil) will be prepared by the clinical pharmacists in an identical injection syringe within 30 min before injection. The participants, anesthesiologists, surgeons, investigators and outcomes assessors will be blinded to the treatment groups.

Primary Purpose:

Treatment

Official Title:

Efficacy of Preoperative Injection of Naldebain® in Management of Acute and Chronic Pain After Laparoscopic Cholecystectomy

Actual Study Start Date :

Aug 30, 2021

Actual Primary Completion Date :

Jan 21, 2022

Actual Study Completion Date :

Apr 18, 2022

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo group Patients assigned to placebo group will receive a single intramuscular injection of 2 ml solvent containing benzyl benzoate and sesame oil into the gluteus muscles under ultrasound-guidance.	Drug: Placebo solution Benzyl benzoate and sesame oil served as placebo solution (a total volume of 2ml) will be prepared in a 5-ml syringe 30 min before administration. Intramuscular injection into the gluteal muscles will be performed by an anesthesiologist under sonography-guidance. Other Names: Benzyl benzoate and sesame oil
Active Comparator: Naldebain group Patients assigned to Naldebain group will receive a single intramuscular injection of dinalbuphine sebacate (150 mg in 2 ml solvent containing benzyl benzoate and sesame oil) into the gluteus muscles under ultrasound-guidance.	Drug: Dinalbuphine sebacate Naldebain dissolved in benzyl benzoate and sesame oil (a total volume of 2ml) will be prepared in a 5-ml syringe 30 min before administration. Intramuscular injection into the gluteal muscles will be performed by an anesthesiologist under sonography-guidance. Other Names: Naldebain ER® Sebacoyl Dinalbuphine Ester Injection

Arm

Intervention/Treatment

Placebo Comparator: Placebo group

Patients assigned to placebo group will receive a single intramuscular injection of 2 ml solvent containing benzyl benzoate and sesame oil into the gluteus muscles under ultrasound-guidance.

Drug: Placebo solution

Benzyl benzoate and sesame oil served as placebo solution (a total volume of 2ml) will be prepared in a 5-ml syringe 30 min before administration. Intramuscular injection into the gluteal muscles will be performed by an anesthesiologist under sonography-guidance.

Other Names:

Benzyl benzoate and sesame oil

Active Comparator: Naldebain group

Patients assigned to Naldebain group will receive a single intramuscular injection of dinalbuphine sebacate (150 mg in 2 ml solvent containing benzyl benzoate and sesame oil) into the gluteus muscles under ultrasound-guidance.

Drug: Dinalbuphine sebacate

Naldebain dissolved in benzyl benzoate and sesame oil (a total volume of 2ml) will be prepared in a 5-ml syringe 30 min before administration. Intramuscular injection into the gluteal muscles will be performed by an anesthesiologist under sonography-guidance.

Other Names:

Naldebain ER®

Sebacoyl Dinalbuphine Ester Injection

Outcome Measures

Primary Outcome Measures

Acute postoperative pain [7 days after surgery]
Pain score measured by visual analogue scale (VAS 1-10, a continuum scale in which 0 represents "no pain" and and 10 represents "worst pain.")
Total requirement dose of rescue analgesics [7 days after surgery]
Total doses of opioids, NSAIDs, COX-2 inhibitors administered

Secondary Outcome Measures

Incidence of chronic post-surgical pain [3 months after surgery]
Pain that newly develops after operation and lasts >2 months and other causes of pain are excluded
Quality of life after surgery [3 months after surgery]
Quality of life will be assessed by the HRQoL SF -12 Questionnaire, which consists a physical component summary (PCS) and a mental component summary (MCS). The rating scales range from yes-no to likert scales, and the final score of PCS and MCS will be calculated by an algorithm (QualityMetric's SF-12v1®). Scores range from 0 to 100, in which lower scores mean lower health related quality of life.

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient scheduled to receive laparoscopic cholecystectomy

Exclusion Criteria:

Emergency operation
Open cholecystectomy
American Society of Anesthesiologists physical status > or =4
Chronic opioid user
Allergy to nalbuphine, benzyl benzoate or sesame oil
Anticipated to receive ventilator support via an endotracheal tube after operation
Unable for verbal pain assessment or not able to participate questionnaire survey