Efficacy of Epidural Analgesia Versus Single Dose Injection of Naldebain® in Management of Acute and Chronic Surgical Pain After Cesarean Section in Term Parturient - a PI-initiated, Randomized, Open-label, Non-inferiority Clinical Trial

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.