Naldebain for Pain Management of Laparoscopic Cholecystectomy

E-DA Hospital

Status and phase: Completed; Phase 3; Phase 2

Conditions: Cholecystitis; Quality of Life; Pain, Postoperative; Pain, Chronic

Treatments: Drug: Placebo solution; Drug: Dinalbuphine sebacate

Study type: Interventional

Funder types: Other

Identifiers

NCT04808544

EMRP28110N

Details and patient eligibility

About

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.

Full 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.

Enrollment: 80 patients

Sex: All

Ages: 20 to 65 years old

Volunteers: No 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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80 participants in 2 patient groups, including a placebo group

Placebo group

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo solution

Naldebain group

Active Comparator group

Description:

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.

Treatment:

Drug: Dinalbuphine sebacate