Background: Nalbuphine sebacate (Naldebain®), an intramuscular prodrug of nalbuphine, offers longacting relief for postoperative pain. This study evaluates the effi cacy and safety of Naldebain®
for acute pain management postelective cesarean delivery.
Methods: A retrospective review was conducted on 30 parturients who received epidural anesthesia for
elective cesarean delivery. Group C (n = 20) received patient-controlled epidural analgesia (PCEA) alone,
while Group N (n = 10) was administered a single 150 mg intramuscular dose of Naldebain®
alongside PCEA. Postoperative pain intensity was assessed using the numeric rating scale at various intervals, with
analgesic consumption, muscle tone, side effects, and patient satisfaction also recorded and analyzed.
Results: Group N exhibited a significant reduction in PCEA fentanyl consumption on the first day
compared to Group C (52.9 ± 18.7 vs. 70.8 ± 23.7 mcg, P = 0.045). Pain intensity did not signifi cantly
differ between the groups over three days postsurgery. Both groups were comparable regarding muscle
tone, side effects, and overall satisfaction although fewer patients in Group N required rescue pain control
(20% vs. 60%, P = 0.038).
Conclusion: The combination of a single-dose Naldebain®
with PCEA showed a fentanyl-sparing effect
on the first postoperative day and decreased the need for rescue analgesics during PCEA without an
increase in adverse events.

Keywords: cesarean delivery, multimodal analgesia, nalbuphine sebacate, opioid-sparing, patient-controlled
epidural analgesia (PCEA)

The increasing rates of cesarean sections, surpassing 32% of births in regions such as the United States and Taiwan, pose significant postoperative challenges [1,2]. Women undergoing cesarean delivery often experience moderate to severe pain, which can lead to prolonged pain, postpartum depression,and hindered recovery, ultimately impacting maternal-infant bonding, and breast-feeding success [3-5]. Therefore, optimizing analgesic regimens is pivotal, aiming to alleviate acute pain effectively while minimizing narcotic transfer to the newborn [6].

Sebacoyl dinalbuphine ester (Naldebain® ), created by Lumosa Therapeutic, Inc. in Taipei, Taiwan, has represented a signifi cant advancement in postoperative analgesia since its introduction in 2017. As a prodrug, it doubles the potency of nalbuphine, offering extended analgesic effects. Its efficacy, safety, and pharmacokinetic profile have been substantiated through various in vitro and in vivo research [7,8]. Sebacoyl dinalbuphine ester (Naldebain® ) and nalbuphine are related but demonstrate distinct differences in chemical structure and pharmacological properties. Nalbuphine, a synthetic opioid analgesic, acts as a kappa opioid receptor agonist and a partial μ-opioid receptor antagonist. In a previous investigation, it was documented that nalbuphine demonstrated potency ranging from 0.8 to 0.9 times when administered via intramuscular injection. [9]. Naldebain® , a prodrug of nalbuphine, is modified by esterifying nalbuphine with sebacic acid. This modification alters the drug’s pharmacokinetic properties. The onset of intravenous nalbuphine and intramuscular Naldebain® are 2–3 minutes and 18–24 hours, respectively. The analgesic duration is 3–6 hours and nearly 7 days, respectively [10,11]. With respect to analgesic onset and duration, Naldebain® shares the same analgesic mechanism with nalbuphine but provides sustained pain relief for up to 7 days as a component in multimodal analgesia regimen. As a novel analgesic agent, clinical studies examining the use of Naldebain® as a preoperative measure to mitigate postoperative pain have been scarce and inconclusive [12-15].

The advent of multimodal analgesia strategies, which aim to diminish opioid consumption and its associated adverse effects, has become increasingly prevalent. Specifically, combining Naldebain® with epidural fentanyl could potentially address opioid-related concerns, such as minimizing opioid transfer during breastfeeding [16]. This study hypothesized that the incorporation of nalbuphine sebacate with epidural fentanyl might not only alleviate postcesarean pain but also reduce the required fentanyl dosage compared to the use of epidural fentanyl alone.

Consequently, our study aimed to investigate the impact of Naldebain® within a multimodal analgesia framework for managing postcesarean pain. We compared the analgesic efficacy of ultrasound-guided Naldebain® intramuscular injections combined with patient-controlled epidural analgesia (PCEA) to PCEA monotherapy in parturients undergoing elective cesarean delivery. The primary endpoint was the pain intensity, quantified by the area under the curve of the numerical rating scale (NRS), observed from baseline to 72 hours postsurgery.

This retrospective clinical trial in a regional teaching hospital in Kaohsiung was approved by the institutional review board at Kaohsiung Medical University Hospital [protocol No. KMUHIRBE(I)-20220335]. The medical records reviewed parturients undergoing elective cesarean delivery with PCEA from January to December 2019. All parturients were mentally oriented with gestational age between 35 and 41 weeks and American Society of Anesthesiologists physical status I–III. The exclusion criteria of the parturients were as follows: premature birth less than 35 weeks of gestation, stillbirth, and contraindications for epidural anesthesia; any substance abuse, chronic pain with analgesics, allergy or adverse reactions to local anesthetics or opioids, bleeding tendency, eclampsia, HELLP syndrome, failed epidural anesthesia, and limited comprehension to understand Chinese were excluded from the study.

When coming to the operation room, each parturient was placed with standard physiological monitoring (oximetry, electrocardiography, and non-invasive blood pressure). Parturients received epidural anesthesia as the first choice for Caesarean section in the left decubitus position by senior anesthesiologists following standard operating procedures of the healthcare system. Lumbar interspace at L4–5 levels was identified by palpation before anesthesia. An epidural catheter was indwelled at either L2–3 or L3–4 interspinous space. The epidural space was confirmed by loss of resistance to air technique with an 18-gauge Tuohy needle. Once the Tuohy needle reached epidural space, an 18-gauge multi-orifice epidural catheter (Perifix One 401 Filter Set; B. Braun Medical Inc., Bethlehem, PA, USA) was advanced 5 cm into the epidural in a cephalic direction.

A test dose of 2% lidocaine 60 mg with epinephrine (1:200,000) was routinely used. After the epidural catheter was fixed, each parturient immediately returned to the supine position. Intermittent epidural injections of 2% lidocaine were administered slowly until the target dermatome (T4–6) was achieved and the operation was allowed. If adequate anesthesia was not achieved within 20 minutes, additional intravenous anesthetics were administered and epidural anesthesia was recorded as failure.

We reviewed the medical records of 30 parturients undergoing epidural anesthesia for elective cesarean delivery. All parturients received PCEAat the end of surgery. The analgesic solution of the PCEA regimen was a mixture of 0.08% bupivacaine and fentanyl 2 μg/mL within 3 days postoperatively. The PCEA setting was a baseline infusion of 2 mL/h with a PCEA bolus of 3 mL and lockout interval of 20 minutes according to our clinical standard. Group N (n = 10) received PCEA and a single dose of Naldebain® 150 mg before PCEA loading. The same anesthesiologist (IC Lu) performed ultrasound-guided Naldebain® injection into the gluteus medius muscle [17]. Group C (n = 20) received PCEA alone for acute pain service. At the end of cesarean delivery, a one-hour observation was recorded in the postanesthesia care unit (PACU). PCEA was stopped 72 hours after cesarean delivery and the epidural catheter was removed.

The main outcome was measured by postoperative pain intensity assessed by NRS as 0–10 at the PACU, postoperative day (POD) 1, POD 2, and POD 3. Inadequate analgesia was defined as an NRS > 4 during the period and was treated with intravenous ketorolac 30 mg or parecoxib 40 mg as rescue. The secondary outcomes included PCEA consumption, rescue analgesics, motor block, opioid-related side effects (nausea, vomiting, dizziness, pruritus, numbness, or prolonged urinary catheterization > 48 hours), motor block, analgesics requirements at 4 weeks after surgery, and overall satisfaction. Motor weakness was defined as Bromage scale lower than 3. The Bromage scale was defined as 0–3, 0 = Complete motor block of the lower limbs, 1 = Inability to raise the extended leg and move the knee, able to move feet, 2 = Inability to raise the extended leg, able to move knees and feet, 3 = No motor block. In Group N, local reaction and pain at Naldebain® injection site were also recorded. The overall satisfaction of postoperative pain relief was measured by a four-point scale; 1 = poor, 2 = fair, 3 = good, and 4 = excellent.

All data were expressed as mean ± standard deviation or number of patients (%). Continuous variables between the two groups were analyzed using the Mann-Whitney-U test. Categorical data were carried out by chi-square or Fisher’s exact test as appropriate. A P < 0.05 was considered as statistically significant. Statistical analysis was performed by Microsoft Excel 2019 (Microsoft, Redmond, WA, USA).

Comparative analysis of physical characteristics and anesthesia parameters revealed no significant differences between the study groups (Table 1). Successful epidural anesthesia was achieved in 90% (27/30) of cases; the remainder required supplemental intravenous anesthetics (thiamylal 75–125 mg and fentanyl 50–100 mcg) to achieve a satisfactory surgical level of anesthesia. Propofol infusion with a target concentration of 1.0 mcg/mL was kept in one parturient in the control group. The main outcome, pain intensity, was lower in Group N, but it did not reach statistical significance when compared with Group C during the first 48 hours of postcesarean delivery (P > 0.05) (Table 2). Notably, the first-day postoperative fentanyl dosage was significantly reduced in Group N (105.8 ± 37.4 mcg) compared to Group C (141.6 ± 47.4 mcg, P = 0.047). This outcome could potentially be elucidated by the additive effect observed between Naldebain® and lidocaine in Group N, as opposed to the utilization of lidocaine alone in Group C. Nevertheless, the total consumption of fentanyl demonstrated no statistically significant variance between Group N and Group C (105.6 ± 50.0 mcg, 130.2 ± 36.9, P = 0.14). However, the need for rescue analgesics was less in Group N, with only 20% (2/10) requiring additional pain management, versus 60% (12/20) in Group C, marking a statistically significant reduction (P = 0.038).

Postoperative adverse events such as postoperative nausea and vomiting, dizziness, headache, pruritus, lower limb numbness, extended urinary catheterization, and weakness were observed at similar rates across both cohorts (Table 3). No reports of injection site pain were noted in Group N. Satisfaction with postoperative pain management was unanimously high, with all participants in both groups indicating satisfaction with their pain control postcesarean.

Table 1. Physical Characteristics, Anesthesia and Surgery Profilea

Table 2. Postoperative Pain Control Profile Between Groupsa

The main finding of this study presented that multimodal analgesia in combination with Naldebain® and PCEA regimen provided adequate pain relief and fentanyl-sparing effect after cesarean delivery without increasing adverse events. Adequate postcesarean analgesia is mandatory to improve maternal early mobilization and facilitate mother’s independence for newborn care [18]. Epidural opioids in combination with local anesthetics (i.e., fentanyl 2μg/mL plus 0.08% bupivacaine) have been widely used for postcesarean pain control [19,20]. Wang et al. [20] utilized ropivacaine (0.2%) plus fentanyl (2 μg mL/1) in PCEA with continuous infusion (3 mL/hr) and reported low pain scores 3 (2–4) at rest up to 48 hours after cesarean delivery. Zheng et al. [21] compared the analgesic effect of nalbuphine patient-controlled intravenous analgesia (PCIA) and sufentanil PCIA in relieving post-cesarean uterine contraction pain and reported that nalbuphine is superior to sufentanil.

Opioid sparing is an utmost goal of multimodal analgesia. Since nalbuphine is a partial mu opioid receptor antagonist, its opioid-antagonism might have the potential of increased opioid dose or higher pain intensity. However, our results showed that Naldebain® did not attenuate the potent analgesic effects of fentanyl. Conversely, Group N required lower fentanyl consumption and fewer rescue analgesics than Group C with comparable pain intensity. In a retrospective review of patients undergoing upper extremity fracture surgery, Naldebain® reduced fentanyl dosage in the early recovery stage, breakthrough pain incidence, and pain intensity within 5 PODs. Naldebain® in combination with fentanyl demonstrated a significantly lower frequency to receive postoperative opioids compared to conventional analgesia (22% vs. 53%, P = 0.001) [22].

Yeh et al. [23] reported a possible mechanism for a better pain control profile of agonist-antagonist (nalbuphine) and opioid agonist (morphine). The analgesic effect of fentanyl and morphine is mainly through the μ-opioid receptor, while nalbuphine is primarily through the kappa-opioid receptor. When two agents are combined, the decreased analgesic effect at the μ-opioid receptor is compensated by an increased effect at the kappa-opioid receptor. The combination of nalbuphine with morphine patient-controlled analgesia provided not merely additive analgesic effects but also reduced pruritus after gynecologic surgery.

Further investigation into the opioid-sparing effect of Naldebain® warrants additional evaluation with larger sample sizes. Additionally, the preoperative administration of Naldebain® presents a potential concern due to its peak analgesic effect occurring at 24–48 hours postadministration.

There are several limitations in this study. First, this pilot study for cesarean delivery might have a bias due to a retrospective design. All anesthesia and analgesia management was performed following departmental protocols under real clinical demands. The advantage of this design reflected the application of Naldebain® more precisely in clinical relevance. Second, limited study medication resources and parturients resulted in a relatively small sample size and might affect the statistical significance of the results. Therefore, the incidence of possible adverse events was not revealed in our results.

The addition of single-dose intramuscular 150 mg Naldebain® into PCEA revealed fentanyl sparing in postcesarean pain control within POD. Naldebain® also reduced the possibility of rescue analgesics during PCEA without adverse events.

The authors are grateful to Yi-Hui Yang and I-Pin Chou Huang (Nurse anesthetist, Department of Anesthesiology, Kaohsiung Municipal Siaogang Hospital, KMU) for their excellent postoperative visit. This research was funded by Kaohsiung Municipal Siaogang Hospital (Grant number: KMHK-111-11) and Kaohsiung Municipal Ta-Tung Hospital (Grant number: KMTTH-111-025).