Objective To explore the clinical effect and safety of intravenous and epidural administration of butorphanol in the analgesic effect of combined spinal‑epidural anesthesia for labor anesthesia. Methods A total of 297 primiparous women in full‑term spontaneous delivery who requested labor analgesia were selected. According to the random number table method, they were divided into three groups: a non‑butorphanol group (group Ⅰ, n=98), a butorphanol epidural administration group (group Ⅱ,n=100), and a butorphanol combined intravenous and epidural administration group (group Ⅲ, n=99). All three groups of parturients underwent combined spinal‑epidural anesthesia for labor analgesia: 2 μg of sufentanil was administered in the subarachnoid, and 3 ml (the test volume) + 10 ml of different mixed solutions were given in the epidural space (group Ⅰ: ropivacaine 150 mg+sufentanil 48 μg; group Ⅱ and group Ⅲ: ropivacaine 150 mg+sufentanil 48 μg+butorphanol 2 mg; and all the above solutions were diluted to 200 ml with normal saline). Next, 5 ml of normal saline were given to group Ⅰ and group Ⅱ, while group Ⅲ was intravenously given 0.5 mg/5 ml of butorphanol via a Murphy style dropper. The mixture was pumped into the epidural space at 7 ml/h until 12 h after delivery of the placenta. The Visual Analogue Scale (VAS) score, Ramsay Sedation score and Bromage Modified score were used to evaluate the degree of pain, sedation and motor nerve block in the lower limbs, immediately before the opening of the uterus to 3 cm for labor analgesia (T0), 20 min immediately after the administration of total epidural volume (T1), immediately after the opening of the uterus (T2), immediately after the delivery of the fetus (T3), immediately after the delivery of the placenta (T4), 4 h after the delivery of the placenta (T5), and 8 h after the delivery of the placenta (T6). Meanwhile, the mean arterial pressure (MAP), heart rate, pulse oxygen saturation (SpO2) and respiratory rate were recorded. The levels of substance P, 5‑hydroxytryptamine (5‑HT), leu‑enkephalin and β‑endorphin (β‑EP) in venous blood were detected at T0, T4 and T6. The duration of the first, second, and third stages of labor, and the number of cases of oxytocin use were recorded. The neonate 1 min, 5 min, 10 min Apgar scores and umbilical artery blood gas analysis [pH, arterial partial pressure of carbon dioxide (PaCO2), arterial partial pressure of oxygen (PaO2), and lactic acid (Lac)] were recorded. The maternal adverse reactions were observed and recorded, including changes in the mode of delivery, respiratory depression, lethargy, hypotension, nausea, vomiting, chills, urinary retention, and itchy skin. Results At T2 and T3, groups Ⅱ and Ⅲ showed lower VAS scores than group Ⅰ, where decreased VAS scores were found in group Ⅲ, compared with group Ⅱ (all P<0.05). At T1 and T2, Ramsay Sedation scores in groups Ⅱ and Ⅲ were significantly higher than that in group Ⅰ, where Ramsay sedation score in group Ⅲ was higher than that in group Ⅱ (all P<0.05). Compared with those at T0, VAS scores in the three groups decreased at T1‒T6 (all P<0.05), while Ramsay Sedation scores increased (all P<0.05); and the Bromage Modified score in the three groups was 0. At T3, group Ⅲ showed lower MAP than groups Ⅰ and Ⅱ (all P<0.05). Compared with those at T0, the three groups presented remarkable decreases in MAP, heart rate and respiratory rate at T1‒T6 (all P<0.05). At T4, group Ⅱ showed less amounts of substance P than group Ⅰ, while leu‑enkephalin and β‑EP contents in groups Ⅱ and Ⅲ were significantly higher than those in group Ⅰ (all P<0.05). Compared with those at T0, the contents of substance P and 5‑HT in the three groups significantly decreased at T4 and T6, while the contents of leu‑enkephalin and β‑EP significantly increased (all P<0.05). Compared with those at T4, the amounts of substance P, leu‑enkephalin and β‑EP in the three groups significantly decreased at T6 (all P<0.05). There was no statistical difference in other indicators at other time points (all P>0.05). There were no statistical differences in the first, second and third stages of labor, the number of cases of oxytocin use, the neonate 1 min, 5 min, 10 min Apgar scores and umbilical artery blood gas analysis (pH, PaCO2, PaO2 and Lac) among the three groups (all P>0.05). No adverse reactions such as changes in the mode of delivery, respiratory depression, lethargy, hypotension, chills, and urinary retention occurred in the three groups during delivery. Group Ⅲ showed lower incidences of nausea, vomiting and itchy skin than groups Ⅰ and Ⅱ (all P<0.05), while decreases in the incidences of nausea, vomiting and itchy skin were seen in group Ⅱ, compared with group Ⅰ (all P<0.05). Conclusions Intravenous and epidural administration of butorphanol during combined spinal‑epidural anesthesia for labor anesthesia can minimize organic pain and psychological stress, improve maternal comfort during natural childbirth, and achieve good clinical results in labor analgesia.