Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05187520 |
| Other study ID # |
EMRP05111N |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2022 |
| Est. completion date |
October 1, 2023 |
Study information
| Verified date |
April 2022 |
| Source |
E-DA Hospital |
| Contact |
Chen-Fuh Lam, MD, PhD |
| Phone |
+8867-6150011 |
| Email |
lamcf[@]mail.ncku.edu.tw |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Inadequate postoperative pain management can lead to physical and psychological distress in
patients as well as impact surgical wound healing and increase the risk of developing
postoperative delirium and cardiopulmonary and thromboembolic events. Severe postoperative
pain may also result in the development of chronic post-surgical pain (CPSP), which in turn
can lead to prolonged use of opioids and increased health-care costs. A descriptive survey
study in 60 postpartum women who received cesarean section suggested that the presence of
postoperative pain significantly reduced the willingness of breastfeeding and infant care.
The incidence of CPSP after cesarean delivery has been reported to vary from 1% to 18% up to
1 year after operation. Patient-controlled epidural analgesia (PCEA) is considered as the
standard pain management strategy for post-cesarean pain. However, correct placement of
epidural catheter for effective postoperative pain management is more technical demanding,
and accidental dural puncture is associated with increased risk of postdural puncture
headache. It also increases risk of other complications, including urinary retention,
systemic toxicity of local anesthetics and formation of epidural hematoma. Therefore, the
development of a safe, conveniently operated, and long-lasting analgesic strategy, which
serves as background pain control modality up to several days after cesarean section should
provide clinically beneficial advantages in the management of acute postoperative pain and
prevention of CPSP in postpartum women. Naldebain® is prodrug of nalbuphine, which was
approved by the Taiwan FDA in 2017. Naldebain® is rapidly hydrolyzed by tissue of plasma
esterase to release nalbuphine. The bioavailability of nalbuphine following intramuscular
injection Naldebain® was 85.4%, and it took approximately 6 days for the complete release of
Naldebain® into the blood circulation. Therefore, a single parenteral injection of Naldebain®
could provide long lasting analgesic effect in several phase II trials. However, Naldebain®
has not been tested in the pain control after cesarean section. Therefore, this PI-initiated
prospective, randomized, open-label, non-inferiority trial aims to investigate the clinical
efficacy of Naldebain® in management of acute postoperative pain in term parturient who
receive elective cesarean section to provide analgesic effect that is not inferior to the
standard PCEA and prevent the development of CPSP.
Description:
Inadequate postoperative pain management can lead to physical and psychological distress in
patients as well as impact surgical wound healing and increase the risk of developing
postoperative delirium and cardiopulmonary and thromboembolic events. Severe postoperative
pain may also result in the development of chronic pain, which in turn can lead to prolonged
use of opioids and increased health-care costs. Although clinical pathways and strategies
have been recently implemented, including the introduction of the enhanced recovery after
surgery (ERAS) program and multimodal analgesia (MMA), rates of inadequate postoperative pain
management remain as high as 40-56.4% in the general surgical population and the prevalence
rates of persistent pain after major operations can reach up to 50%. CPSP is associated with
increased analgesic use, restriction of activities of daily living, significant effects on
quality of life, and increased health-care utilization.
According to the WHO survey in 2004, cesarean section deliveries represent up to 8% of all
surgical procedures. In Taiwan, about 35.9% of the newborns were delivered by cesarean
section in 2016 to 2019, which equivalent to 68,000 cesarean sections were underwent
annually. The incidence of CPSP after cesarean delivery has been reported to vary from 1% to
18% up to 1 year after operation. More specifically, an US nationwide survey reported that
79% of mothers who received cesarean section reported experiencing pain at the incision site
in the first two months and 18% had persistent pain at least 6 months after operation.
Following surgical incision of abdominal wall and visceral organs, the efferent sensory
neurons initiate the cascade of neurochemical changes that activates and sensitizes the
peripheral nociceptors and spinal dorsal horn neurons, leading to peripheral and central
sensitization and a hyperalgesic state. With inadequate pain management after operation or
prolonged healing process, the sustained activation of the pronociceptive system results in
hyperalgesia and allodynia. Surgical insults and neuron axon damage may also activate
regional inflammatory and immune reactions to release of neurotransmitters in the spinal cord
to produce hypersensitivity and ectopic neural activity, and eventually contributing to the
development of central sensitization and CPSP.
At the beginning 3-6 months, the incisional wound and abdomen are the most commonly reported
location of persisted pain, and the unpleasant feeling shifts to the back or low back at 12
months postpartum and the chronic pain may significantly impact the quality of life, as
one-fifth of patients complain of moderate to very severe pain. A prospective observational
study found that the presence of CPSP after cesarean section negatively impacted the daily
activity, normal work, social relationship, psychosomatic status and postpartum depression of
the mothers at 3-6 months after delivery. A descriptive survey study in 60 postpartum women
who received cesarean section suggested that the presence of postoperative pain significantly
reduced the willingness of breastfeeding and infant care. Previous reports identified several
important risk factors for developing CPSP after cesarean section, including previous
cesarean delivery, preoperative depression or anxiety, lower society economic status, longer
duration of surgery and use of general anesthesia. Most importantly, substantial evidence
indicates that supports the general concept that higher severity of acute pain after cesarean
section is associated with significantly higher risk for transition of acute pain to CPSP.
Therefore, optimal but adequate pain management after cesarean section is important to
improve postpartum care, accelerate recovery after surgery, enhance early mobilization and
prevent the development of CPSP.
Multimodal analgesia (MMA) is the core principle for pain management after cesarean delivery,
including epidural analgesia, the use of long-acting intrathecal opioids (i.e. morphine), and
adjunct drugs (acetaminophen and nonsteroidal anti-inflammatory drugs). Intrathecal morphine
is considered as the gold standard single-shot drug for post-cesarean pain, providing
adequate analgesic effect up to 14-36h after operation. Placement of an epidural catheter can
be used for epidural anesthesia during cesarean section and continuous epidural infusions of
opioids or combined with local anesthetic after cesarean section can result in high-quality
analgesia effect for postpartum and postsurgical pain. Compared with intrathecal morphine
(ITM) alone, levels of pain scores both at rest and during mobilization were significantly
reduced in women who received patient controlled epidural analgesia (PCEA) during the second
day after cesarean section. Incidence of postoperative nausea and vomiting was also
significantly lower in the PCEA group. A more recent randomized control trial reported that
combination of PCEA with ITM provided better post-cesarean section analgesia compared to ITM
alone. Although PCEA provides with patient-controlled, better analgesic effect, particularly
the management of breakthrough pain or pain during mobilization, PCEA carries certain
clinical concerns that impede their widely use in pain management after cesarean section.
Correct placement of epidural catheter for effective postoperative pain management is more
technical demanding, and accidental dural puncture is associated with increased risk of
postdural puncture headache (PDPH). The most common complication of PCEA is urinary
retention, especially when high concentrations of local anesthetic are used. The overall
incidence of epidural hematoma and epidural abscess were 1 case per 168,000 and 1 per 145,000
women, respectively. Most seriously, unintentional intrathecal injection of large doses of
local anesthetic can result in high spinal blocks, leading to respiratory compromise, and
unintentional intravenous injection of local anesthetics can cause severe systemic toxicity,
including seizures and cardiac arrest. Therefore, the development of a safe, conveniently
operated, and long-lasting analgesic strategy, which serves as background pain control
modality up to several days after cesarean section should provide clinically beneficial
advantages in the management of acute postoperative pain and prevention of development of
CPSP in postpartum women.
Nalbuphine is a synthetic agonist-antagonist opioid with analgesic properties acting on
antagonism at the μ-receptor and agonism at the κ-receptor that was introduced for medical
use in 1979. Nalbuphine has equal potency with morphine for pain relief, but it is associated
with less nausea, pruritus, and respiratory depression than morphine due to its effect on
κ-receptor. Since it is also a weak μ-receptor antagonist, nalbuphine reduces side effects
particularly respiratory depression without loss of analgesia when combined with potent
opioids. The other major clinical advantage of nalbuphine is less risk for abuse and death
due to its ceiling effect of analgesia and respiratory suppression. Nalbuphine is one of the
systemic administered opioids that can be safely used and effectively reduce the incisional
pain and uterine cramping pain in women after cesarean section. Breast-feeding is also
permissible when nalbuphine is administered to the mother to treat postpartum pain, as very
low oral bioavailability of nalbuphine and the relative infant dose is 0.59+/-0.27% of the
weight-adjusted maternal daily dose. However, the clinical use of nalbuphine for
post-cesarean section pain control is limited by the relatively short duration of action of
about 2-6h following systemic injection.
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. The bioavailability of nalbuphine following intramuscular
injection Naldebain® was 85.4% with a mean absorption time up to 145 h, and it took
approximately 6 days for the complete release of Naldebain® into the blood circulation.
Therefore, a single parenteral injection of Naldebain® could theoretically provide long
lasting analgesic effect. The first clinical trial testing the perioperative analgesic effect
of Naldebain® was reported in patients who received hemorrhoidectomy at 6 medical centers in
Taiwan. 221 patients were randomly assigned to receive Naldebain® or vehicle injection at 1
day before operation. The average pain intensity scores (AUC of VAS) over 48h and 7 days
after hemorrhoidectomy were significantly reduced in Naldebain® group (209.93 vs. 253.53 and
630.79 vs. 749.94, respectively). The Naldebain® group also had significantly lower doses of
rescue analgesics. Furthermore, most adverse events were assessed as mild and tolerable in
patients who received Naldebain® or the vehicle solution (benzyl benzoate and sesame oil).
Most recently, a prospective, open-label, randomized controlled study was performed in 110
patients scheduled for elective laparotomy. The results showed that preoperative injection
Naldebain® (150 mg) significantly reduce AUC of VAS at 4, 24, 32, 72, 120, and 144 h after
surgery with a better quality of life during the recovery phase. A retrospective study
analyzed the pain intensities in 137 patients who underwent midline laparotomy for
gynecologic cancers and reported that a single intramuscular (IM) injection of Naldebain®
significantly reduced the pain intensities than the fentanyl-based patient-controlled
analgesia and conventional analgesia groups on postoperative days 1 to 5 with less
analgesic-related side effects. The most commonly reported drug-related adverse reactions of
Naldebain® are generally well tolerable, including dizziness (6-27%), nausea/vomiting
(3-30%), injection site reactions (1.8-12%) and pyrexia.35-37 Hence, a single-dose IM
administration of Naldebain® can be served as an effective long-acting preventive analgesic
as a component of MMA that can enhance postoperative pain management and attenuate the
development of CPSP.
Naldebain® has not been tested in the pain control after cesarean section and its
pharmacokinetic profiles in the milk excretion of lactating women was also undetermined.
Therefore, this PI-initiated prospective, randomized, open-label, non-inferiority trial aims
to investigate the clinical efficacy of Naldebain® in management of acute postoperative pain
in term parturient who receive elective cesarean section, and prevention of the development
of CPSP after cesarean delivery, as Naldebain® can provide prolonged analgesic effect for up
to 7 days. This study will also analyze the milk-plasma levels of nalbuphine following a
single intramuscular injection in the parturient.
Null hypothesis: the investigators hypothesize that a single-dose IM injection of Naldebain®
(alternative treatment) is inferior to PCEA (standard treatment) for controlling pain after
cesarean section. The alternative hypothesis: a single-dose IM injection of Naldebain®
(alternative treatment) is non-inferior to PCEA (standard treatment) for controlling pain
after cesarean section. The study defines a non-inferiority margin of 10% difference in the
average pain score (0-10) at postoperative days 1-3 in Naldebain® (alternative treatment) and
PCEA (standard treatment) groups. The investigators speculated a P-value <0.05 indicates
non-inferiority of a single-dose IM injection of Naldebain® to manage pain intensity after
cesarean section in postpartum women in comparison to the standard PCEA, corresponding to the
upper limit of the one-sided 95% confidence interval (CI) of the difference not exceeding the
10% based on the type I error at 0.05 (one-sided) and a 90% statistical power.
