Naldebain for Pain Management of Laparoscopic Cholecystectomy
Condition: Pain, Postoperative; Pain, Chronic; Cholecystitis; Quality of Life
MeSH terms: Cholecystitis; Pain, Postoperative; Chronic Pain
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

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.
    

Intervention name(s): Dinalbuphine sebacate; Placebo solution
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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 intervention name(s): Naldebain ER®; Sebacoyl Dinalbuphine Ester Injection; Benzyl benzoate and sesame oil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Nalbupine; Dinalbuphine sebacate; Naldebain; Opioid; Laparoscopic cholecystectomy