21 January 2025: Clinical Research
Butorphanol Tartrate Nasal Spray for Post-Cesarean Analgesia and Prolactin Secretion
Jingzheng Zeng1ABCDEF, Xiaoqin Sun1BDEF, Mingyan Luo2BDF, Yunju Rao1DF, Gu Gong1AG*DOI: 10.12659/MSM.945224
Med Sci Monit 2025; 31:e945224
Abstract
BACKGROUND: Butorphanol, an opioid receptor agonist and antagonist, is widely used for post-cesarean section analgesia in the form of intravenous or intramuscular injection, but nasal sprays are less used. This study aimed to evaluate the analgesic effect of butorphanol nasal spray on uterine contraction pain after cesarean section and explore its effect on postpartum prolactin secretion.
MATERIAL AND METHODS: We randomly divided 120 patients scheduled for cesarean section into 3 groups (40 per group): intranasal saline (control), butorphanol intranasal (BI), and butorphanol pumped intravenously (BV). The same analgesic pump protocol was used in all groups. The visual analog scale (VAS) and Ramsay sedation scale (RASS) were used to evaluate analgesic and sedation levels 6, 12, and 24 h postoperatively. We recorded the start time of breastfeeding, number of PCIA presses, consumption of butorphanol, and preoperative and postoperative serum prolactin levels.
RESULTS: At 6 h postoperatively, the BI and BV groups had lower VAS and higher RASS (P<0.05) than the control group, no difference between the BI and BV groups, but the consumption of butorphanol was lower in the BI group (P<0.05). The analgesic and sedative effects in the BI group were lower than those in the BV group at 12 h (P<0.05). No difference in the start time of breastfeeding, serum prolactin levels among the 3 groups (P>0.05).
CONCLUSIONS: Patients may prefer butorphanol tartrate nasal spray because they can obtain satisfactory analgesia in the early postoperative period, with high non-invasive comfort and reduced use of opioids. No effect on prolactin levels or lactation initiation was observed.
Keywords: Butorphanol, Cesarean Section, prolactin, Uterine Contraction
Introduction
The number of cesarean sections performed has increased rapidly following the development of medical technology and increasing attention to maternal and infant safety issues. The cesarean section rate in China increased from 28.8% in 2008 to 36.7% in 2018. Cesarean section has become one of the most common hospitalization procedures in China and worldwide [1]. The increased number of cesarean sections poses a serious challenge to the management of postpartum pain. Patients experience painful uterine spasms due to the huge uterine trauma caused by the cesarean section and the routine use of oxytocin for postoperative treatment [2]. Uncontrolled postpartum uterine contraction pain can affect breast milk secretion and early mother–infant contact, limit early maternal activities, and further increase the risk of thromboembolism; in severe cases, it can even lead to postpartum depression and delay early maternal recovery [3–5].
The Society for Obstetric Anesthesia and Perinatology proposed the concept of enhanced recovery after a cesarean section, believing that efficient and safe pain management strategies are crucial for rapid postoperative recovery [6]. Good postoperative analgesia can relieve maternal pain, reduce postoperative complications, shorten hospitalization time, reduce the burden on society and families, and improve patient satisfaction [7]. The European Society for Regional Anesthesia and Pain Management recommends that intrathecal injection, patient-controlled intravenous analgesia (PCIA), patient-controlled epidural analgesia (PCEA), and regional analgesia techniques can achieve ideal analgesic effect in the management of pain after cesarean section under spinal anesthesia [8]. However, patients who use PCEA for a long time may have risk of catheter prolapse and epidural infection due to their own negligence or inappropriate care. Intrathecal injection and regional analgesia techniques are also invasive procedures [9–11]. At present, there is a lack of research on the effects of multiple confounding factors on breastfeeding, including the type of anesthesia, the dose and type of analgesic drugs, and intrapartum intervention, but there is evidence that effective control of postoperative pain is important for breastfeeding [12]. Nonsteroidal anti-inflammatory drugs are usually the first choice after cesarean section, and to deal with the burst pain after surgery, they are often combined with higher-safety opioids such as sufentanil, morphine, or butorphanol. However, excessive intake of opioids can delay the start of breastfeeding [13]. To achieve the goals of comfort, non-invasiveness, and minimizing the use of opioids, the search for the best analgesic regimen to treat postoperative pain in women undergoing cesarean section is still ongoing.
Butorphanol tartrate is a mixed opioid receptor agonist–antagonist drug. The intensity of action on 3 opioid receptors is 1: 4: 25 (μ: δ: κ), respectively. It is usually used for postoperative analgesia in the form of injection by intravenous or intramuscular injection, intrathecal administration, or epidural administration. The most common adverse reactions are somnolence, dizziness, nausea, and vomiting. Compared with other opioids, butorphanol has low somatic dependence and low incidence of adverse reactions such as skin itching and respiratory depression [14,15]. It has a high affinity for kappa opioid receptors, can effectively relieve visceral pain, and is beneficial for managing uterine contraction pain after cesarean section [16]. One study showed that the intramuscular injection of butorphanol in men can significantly promote prolactin secretion [17]. Since its launch in the market, butorphanol tartrate nasal spray has become an emerging option for perioperative pain management because of its advantages of non-invasiveness, convenient administration, rapid onset of action, and high bioavailability [18]. Abboud et al found that intranasal butorphanol can be safely and effectively applied for analgesia after cesarean section, with better and longer duration of analgesia, but the assessment of pain did not distinguish between uterine contraction pain and incision pain, nor did it involve studies on the effects on prolactin and breastfeeding [19]. Therefore, the present study aimed to explore its analgesic effect on uterine contraction pain after a cesarean section and whether it can promote prolactin secretion in patients after delivery, providing a basis for a new model of pain management and accelerated recovery after a cesarean section.
Material and Methods
STUDY POPULATION:
This study was a prospective, randomized, controlled, double-blind, single-center, clinical trial, included 120 patients (who chose to undergo cesarean section under combined spinal-epidural anesthesia at the Western Theater Command General Hospital from August 2022 to December 2022). The study was approved by the Ethics Committee of the General Hospital of the Western Theater Command (Ethic Approval No. 2022EC2-ky050) and registered with the Chinese Clinical Trials Registry (ChiCTR2200063746). All patients had signed informed consent forms. The patients were aged 18–45 years old, with American Society of Anesthesiologists (ASA) physical status I to II, a singleton pregnancy, planned to breastfeed, and received PCIA postoperatively. The exclusion criteria were: (1) hemolysis, elevated liver enzymes, low platelet syndrome, cardiovascular disease, and hyperprolactinemia; (2) chronic alcohol, sedative hypnotics, or analgesic use; (3) mental disorder; (4) any previous abdominal surgery (except cesarean section); and (5) contraindications for neuraxial anesthesia and nasal administration. The exclusion criteria were: (1) butorphanol tartrate or other analgesics used by other means during the trial; (2) unforeseen adverse events (such as drug allergy, anesthesia, and surgical accidents); (3) patient loss during a visit or automatic patient exit.
SAMPLE SIZE CALCULATION AND RANDOMIZATION:
Sample size calculations were based on patients’ VAS scores at 6 h postoperatively in a pretrial trial, and to achieve 80% efficacy at the α=0.05 (two-tailed) level, we calculated the need for 36 patients in each group using PASS 15.0 (NCSS, Kaysville, UT), and taking into account a 10% loss-to-follow-up rate, we included 40 patients in each group. Before the patients entered the operating room, the researcher distributed 120 opaque sealed envelopes (40 per group) for simple randomization. The anesthesiologists, patients, and assessors were not informed of the grouping situation, and the researcher did not participate in the anesthesia and assessment process.
ADMINISTRATION METHOD:
In the BI group, after the fetus was removed, the patient was intranasally administered 1 mg of butorphanol tartrate into the unilateral nasal cavity (the patient was kept in supine position with the head tilted back to clear the nasal secretions, and the drug was administered intranasally using a special butorphanol tartrate nasal spray (Jiangsu Hengrui Pharmaceutical Co., Ltd). After the drug was administered, both sides of the nasal flanks were gently pinched to bring the drug into full contact with the mucosa of the nasal cavity to minimize its entry into the pharynx). In the control group, an equivalent dose of saline was administered using the same method. The 2 groups of patients used the same protocol for the postoperative analgesic pumps (1.5 μg/kg sufentanil, Yichang Renfu Pharmaceutical Co., LTD) and 10 mg tropisetron hydrochloride (Rui Yang Pharmaceutical Co., LTD, total volume 100 mL). In the BV group, the postoperative analgesic pump used was 5 mg butorphanol tartrate (Jiangsu Hengrui Pharmaceutical Co., Ltd), 1.5 μg/kg sufentanil, and 10 mg tropisetron hydrochloride, to a total volume of 100 mL.
After closing the peritoneum, the patient was immediately started on a PCIA device. The PCIA parameters were set to a continuous background dose of 3 mL/h, a patient-controlled single dose of 3 mL, and a lockout time of 30 min. After the operation, an anesthesiologist returned the patients to the ward, and the patients and their families were informed on how to use the PCIA device.
ANESTHETIC MANAGEMENT:
No patient was on any medications before the surgery. Upon arrival in the operating room, the patient was immediately monitored for electrocardiogram, non-invasive blood pressure, and pulse oximetry, and an intravenous catheter was placed. Non-invasive blood pressure was measured every 5 min during the operation. The patient was placed in the left lateral position with the head and knees bent toward the chest, and the puncture point was selected at the L2–L3 or L3–L4 gap. The puncture was performed in a sterile manner using an epidural puncture needle, and after confirming that the tip of the needle was in the epidural space, a lumbar puncture needle was used to perform the puncture. When cerebrospinal fluid outflow was observed, a mixture of 1 mL glucose (10%) and 1.5 mL ropivacaine hydrochloride (1%) was injected into the subarachnoid space, the lumbar puncture needle was withdrawn, and the epidural catheter was inserted into the epidural space (3–4 cm cephalad) until it was removed at the end of the surgery. The patient was returned to the supine position and the plane of block was detected. Surgery was initiated when a T4–T6 sensory block was achieved.
DATA COLLECTION:
Patient characteristics and medical history were recorded, including age, body mass index (BMI), gestational age, number of cesarean sections, educational level, operation time, and ASA classification. Professional anesthesia evaluators followed up all patients at 6, 12, and 24 hours postoperatively. Their postoperative uterine contraction pain after cesarean delivery was assessed using the VAS scale, which is presented as a 10-cm horizontal line with 2 extremes at either end (0, no pain; 10 cm, agonizing pain). Patients marked their level of postoperative pain on this line [20]. The RASS scale (1, patient is anxious and agitated or restless, or both; 2, patient is cooperative, oriented, and tranquil; 3, patient responds to commands only; 4, patient exhibits brisk response to light tactile stimuli or loud auditory stimulus; 5, patient exhibits sluggish response to light tactile stimuli or loud auditory stimulus; 6, patient exhibits no response) was used to assess the patient’s postoperative sedation level [21]. In addition, the number of effective postoperative analgesic pump compressions, consumption of butorphanol tartrate, and adverse effects (nausea and vomiting, dizziness, skin itching, and respiratory depression) were recorded. The time of initiation of lactation was assessed based on maternal sensations (breast fullness, engorgement, or leakage). Furthermore, 3 mL of venous blood was collected preoperatively and 24 h postoperatively. Prolactin levels were determined using an enzyme-linked immunosorbent assay (Wuhan EILerite Biotechnology Co., LTD).
PRESENTATION OF OBSERVATIONS:
The primary outcomes were postoperative uterine contraction pain intensity assessed using the VAS at 6 h postoperatively and patients’ preoperative and postoperative prolactin levels. The secondary outcomes were postoperative uterine contraction pain at 12 and 24 h. The level of sedation at 6, 12, and 24 h postoperatively was assessed using the RASS. The effective number of PCIA presses at 6, 12, and 24 h, the amount of butorphanol consumed, and the time at which lactation was initiated postoperatively were also assessed.
STATISTICAL ANALYSIS:
The collected data were first analyzed using the Shapiro–Wilk test to determine if the continuous variables conformed to a normal distribution. Normally distributed continuous data are expressed as mean ± standard deviation and analyzed using one-way analysis of variance. Continuous data that were not normally distributed between groups were analyzed using the Kruskal–Wallis test, and data are expressed using the median (interquartile spacing). Categorical variables were analyzed using Pearson’s chi-squared test or Fisher’s exact test. A
Results
PATIENT CHARACTERISTICS AND CLINICAL DATA:
This study successfully included 120 patients who were undergoing combined spinal-epidural anesthesia for cesarean delivery (Figure 1), and all received PCIA and were breastfeeding. There were no significant differences in patient characteristics among the 3 groups (Table 1).
VAS AND RAMSAY SCORES, NUMBER OF PCIA PRESSES, AND BUTORPHANOL CONSUMPTION:
Patients in the BI and BV groups had significantly lower VAS scores and higher RASS scores at 6 h postoperatively (P<0.05) than those in the control group. However, there was no significant difference between the BI and BV groups (P>0.05). Conversely, the number of effective analgesic pump presses in the BI group was significantly lower than that in the control and BV groups, and the consumption of butorphanol tartrate in the BI group was lower than that in the BV group (P<0.05). Patients in the BV group had lower VAS scores, higher RASS scores, and fewer effective analgesic pump presses at 12 h postoperatively than those in the control and BI groups (P<0.05). The 3 groups showed no significant differences in the VAS scores, RASS scores, or the number of effective analgesic pump presses at 24 h postoperatively (P>0.05; Table 2).
TIME TO FIRST LACTATION AND SERUM PROLACTIN LEVELS:
There were no significant differences among the 3 groups at the initiation of lactation. The 3 groups showed no significant differences in prolactin levels pre- and postoperatively (P>0.05; Table 3).
POSTOPERATIVE ADVERSE MATERNAL EVENTS:
There were no significant differences in the incidence of postoperative nausea, vomiting, dizziness, and drowsiness among the 3 groups, and no patients experienced skin itching or respiratory depression (P>0.05; Table 4).
Discussion
This prospective, randomized, controlled, double-blind, clinical study explored the analgesic and sedative effects of the transnasal administration of butorphanol tartrate in patients undergoing cesarean section under combined spinal-epidural anesthesia and its effect on postpartum prolactin secretion. We found that the VAS score of the BI group was maintained at approximately 2–3 at 6 h. Compared with the control group, the VAS score of the patients in the BI group at 6 h postoperatively was significantly lower, the RASS score was significantly higher, and the number of effective presses of the analgesic pumps was significantly reduced, proving the butorphanol tartrate nasal spray’s effective analgesic and sedative effect in the early period after cesarean delivery. The patients in the BI and BV group had the same VAS score, RASS score, and number of effective analgesic pump presses at 6 h postoperatively, and the patients in the BI group had worse sedation and analgesia than those in the BV group at 12 h postoperatively. However, patients in the BI group consumed less butorphanol tartrate than those in the BV group 6 h postoperatively. There were no significant differences in the time of lactation initiation, prolactin levels, or incidence of postoperative adverse events among the 3 patient groups.
The safety and efficacy of intranasal butorphanol in our study are in agreement with the study by Abboud et al, who reported a longer duration of analgesia and no difference in the incidence of side effects with intranasal butorphanol compared with intravenous butorphanol [19], but their study did not differentiate between the role of uterine contraction pain and incisional pain. Our results are supported by studies of Zhang et al and Cai et al, who reported that in patients undergoing cesarean delivery, receiving butorphanol tartrate can effectively relieve postoperative uterine contraction pain [22,23]. Butorphanol tartrate nasal spray is simple and easy to use, does not require invasive manipulation, shows good patient compliance, and facilitates postoperative pain management. Intranasal administration avoids drug degradation in gastrointestinal fluids and first-pass elimination by the liver and has a higher bioavailability of approximately 48–70% [24]. The drug is rapidly absorbed through the nasal mucosa and has a rapid onset of action, with analgesic effects generally achieved within 15 min [25]. In our study, patients in the BI and BV groups had better analgesia and sedation than those in the control group at 6 h postoperatively. However, patients in the BV group had better analgesia and sedation scores than those in the BI group at 12 h. This is consistent with the pharmacokinetic results of buprenorphine tartrate after intranasal administration studied by Wermeling et al, which was effective for approximately 4–6 h after a single nasal spray [26]. The difference in outcome indicators between the BI and BV groups at 6 h postoperatively was not statistically significant; however, the consumption of butorphanol in the BI group was lower than that in the BV group, and transnasal administration of the drug was simple and comfortable, resulting in greater patient acceptance and satisfaction.
Breastfeeding is essential for healthy development of newborns, and its nutritional value is superior to that of all artificial nutrients; lactogen is the key to successful breastfeeding [27]. Prolactin secretion is affected by several factors. Pain after cesarean section causes sympathetic nerve excitement, increased catecholamine secretion, and elevated levels of lactation hormone inhibitors in the hypothalamus, inhibiting lactotropin secretion and delaying colostrum production. Effective postoperative analgesia can reduce sympathetic excitation and catecholamine secretion, which can promote prolactin secretion [28]. In our study, postoperative pain scores were significantly lower in patients using butorphanol; however, there were no differences in the onset of lactation or serum prolactin levels among the 3 groups. Prolactin secretion is also closely associated with early bonding and contact between the mother and newborn [29]. Effective sucking of newborns can stimulate sympathetic nerves of the breast and nipple, which promote prolactin secretion and an earlier onset of breastfeeding [30]. In this study, the patients were sedated for a longer period after using butorphanol. The sedative effect of butorphanol was within the safe range; however, it reduced the direct communication and effective contact between the mother and newborn, and the time of breastfeeding initiation may be delayed.
There were no serious adverse events during the entire study period. However, a longer observation period is still needed to determine the long-term safety of butorphanol. Common postoperative adverse reactions to opioids include nausea and vomiting. In this study, the incidence of nausea and vomiting after intranasal administration of butorphanol was low, and the patient’s symptoms were immediately relieved after using a small dose of antiemetic; there was no single case of serious adverse events, such as respiratory depression, which was consistent with the findings of Zhu et al, who found that, as an agonistic–antagonistic opioid analgesic, butorphanol has a lower incidence of postoperative adverse events than conventional opioids [31]. The incidence of adverse events, especially dizziness and somnolence, was high after intranasal administration of high-dose butorphanol. The doses of nasal administration in this trial were according to the instruction manual. After a single use of 1 mg butorphanol, the number of patients with somnolence increased, but the difference was not statistically significant. One study showed that a single nasal spray of 2 mg butorphanol achieved better analgesic effects but with a significantly higher rate of associated adverse events [32]. In this study’s preliminary trial, the incidence of dizziness and drowsiness in patients was extremely high after a single dose of 2 mg, which improved after changing the regimen. However, an intermittent single nasal spray of 1 mg butorphanol was not used to observe its effectiveness and safety.
The present study has some limitations. First, we cannot guarantee that the dose delivered with the butorphanol nasal spray device was be standard for every patient, because each person may have differences in the absorbed dose due to differences in the nasal mucosa and may also have differences in the nasal spray dose due to the device. Secondly, we abandoned the design of intermittent 1-mg butorphanol nasal spray for the pilot study, which caused us to observe the effect of butorphanol nasal spray only in the early postoperative period, which may be the reason why there was no difference in the start time of prolactin and breastfeeding; this should be further investigated by optimizing the trial’s design and increasing the sample size. Finally, we did not observe lactation quality or breastfeeding duration, nor did we evaluate the content of butorphanol tartrate in breast milk because we did not have the required experimental equipment. Butorphanol tartrate is lipophilic and can be released into breast milk and acquired by newborns through milk [33]. Previous studies have reported no adverse events associated with maternal breastfeeding in the early postpartum period after intermittent use of buprenorphine tartrate during delivery [34]. Therefore, we still need to further investigate the issue of maternal and infant safety after cesarean section in future studies.
Conclusions
Intranasal administration of 1 mg butorphanol tartrate reduces early uterine contraction pain in patients after cesarean section, achieves good analgesic effects without increasing the incidence of adverse events, does not increase the perinatal risk, and reduces the dose of opioids consumed. Its administration is not traumatic, and patient comfort is high. The dose and administration method used in this study did not significantly affect the start of lactation or postpartum prolactin secretion in patients.
Figures

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