Ropivacaine 75 mg versus placebo in perineal infiltration for analgesic efficacy at mid- and long-term for episiotomy repair in postpartum women – the ROPISIO study: a two-center, randomized, double-blind, placebo-controlled trials

Episiotomy is a surgical enlargement of the vaginal orifice performed with scissors and requires sutures to be repaired [1]. The midwife or the obstetrician can perform an episiotomy to facilitate childbirth in case of severe fetal heart rate anomaly, and it is occasionally conducted to prevent obstetric anal sphincter injury in vaginal delivery [2]. Considering all maternal consequences of episiotomy, its routine use has been questioned, and restrictive episiotomy policies are recommended by clinical practice guidelines [3]. Despite this restrictive policy, episiotomy is still a common surgical procedure [4].

Perineal pain is a common consequence of episiotomy and affects up to 97% of women on day 1 postpartum [5, 6] and up to 70% of women at days 7 to 10 postpartum [7‐9], and it may persist until at least 5 months postpartum [10, 11]. Pain after the perineal wound (apart from episiotomy) is also reported but less studied because of the high variability of the localization and the depth of the tear. Postpartum perineal pain may have a negative maternal impact, can affect the quality of life of the mother, and may be severe enough to disturb the postpartum period and the mother–infant dyad [5, 6]. Symptoms of postpartum depression affect 10–15% of women [12, 13]. An association between persistent perineal pain and symptoms of postpartum depression has been identified by several studies [14, 15]. After adjustment for covariates, an increased risk for depression was shown at 4–6 weeks and 6 months among women who had perineal pain compared with those without perineal pain [16]. In this prospective study, pain at 3–5 days postpartum was a predictor of symptoms of postpartum depression at 3 months [16]. Moreover, a dyspareunia rate of approximately 25% was observed in women who had an episiotomy [17]. Sexual disorders in women with postpartum perineal pain have previously been reported [10, 18, 19]. In addition, a clinical study showed that 12.8% of the women who underwent episiotomy presented with chronic perineal pain at 5 months, which was related to obstetric and postpartum factors (i.e., perineal pain in the first 48 h) [11].

Obstetric analgesia after a vaginal delivery received less attention than pain during labor or after a cesarean delivery. Epidural analgesia allows episiotomy to be performed without additional anesthesia. Therefore, local anesthetic injection at the time of the episiotomy may be necessary, even for women with epidural analgesia. Anesthetic perineal infiltration is the subcutaneous muscular aponeurotic space or serosal injection of analgesic drug next to the surgical site. Its effectiveness is based on the widest possible diffusion of the product and on the blocking of the most distal nerve endings [20]. The main property of local anesthetic drugs is to temporarily block pain message transmission from nociceptive terminations. Locally injected into an operative scar, the action of anesthetic drugs exceeds this framework. Local anesthetic drugs have an anti-inflammatory effect that limits self-maintenance of pain in peripheral lesions. Furthermore, clinical studies confirm that local anesthetic infiltration, even in a single postoperative injection, is beneficial over a period that exceeds the product’s persistence at the site of administration. Another prospective randomized study concerning groin hernia surgery showed that local anesthesia was superior to regional or general anesthesia in decreasing postoperative complications, duration of surgery and anesthesia, length of postoperative hospital stay, and time to normal activity [21]. For inguinal hernia repair, preoperative inguinal infiltration of ropivacaine provides benefits for patients in terms of faster recovery, less pain, better mobilization, and higher satisfaction throughout the first 7 days postoperatively [22]. For tonsillectomy under general anesthesia, preoperative infiltration of tonsils with bupivacaine showed that almost no constant pain occurred in the bupivacaine group at 5 days postoperatively compared with normal saline serum, and the difference in pain intensity was present even on the tenth postoperative day [23].

Ropivacaine is a drug already used in clinical practice for the treatment of acute pain in adults. For example, during childbirth (continuous or bolus epidural infusion), parietal infiltration or peripheral nerve blocks have been reported to be associated with a high rate of decreased pain [24]. Ropivacaine is an anesthetic with longer duration than lidocaine [25]. A complication of infiltration techniques is the systemic toxicity of local anesthetics. This results from large doses of anesthetic administration or from an injection into a space with important systemic resorption. In both cases, this can be prevented with knowledge of the products and injection sites and observing usual precautions when injecting a local anesthetic.

Three studies have already studied the analgesic efficacy of ropivacaine in perineal infiltration after episiotomy [26‐28]. Gutton et al. [26] found a significant decrease of pain measured using a visual analogue scale (VAS) at 24 h in a cohort of 102 women in the ropivacaine group (3; 95% CI, 1.5 to 4) versus lidocaine group (4; 95% CI, 2 to 6) (p = 0.004). Moreover, the proportion of patients with a VAS ≤ 4 was significantly higher in the ropivacaine group (70.6% versus 43.1%; p = 0.009). These results remained at 48 h. In an unblinded study, Sillou et al. [28] compared the injection of ropivacaine in the margin of the episiotomy (n = 31) with the absence of infiltration (n = 31). The pain evaluated by NPRS was significantly lower in the ropivacaine group at hour 4 (H4) (1.9 ± 0.3 versus 3.6 ± 0.5; p = 0,006), H8 (3.3 ± 0.4 versus 5.2 ± 0.4; p = 0.003), H12 (2.8 ± 0.4 versus 5.2 ± 0.4; p = 0,0001), and H24 (2.6 ± 0.4 versus 4.3 ± 0.4; p = 0.006). However, in a cohort of 154 women, Schinkel et al. [27] compared the injection of ropivacaine versus lidocaine versus normal saline serum and did not find differences at 24 h in terms of time to first oral analgesic request (13.9 h versus 17.0 h versus 16.6 h; p = 0.104), proportion of patients who did not request oral analgesics (35% versus 54% versus 53%; p = 0.09), and VAS score (ropivacaine 16.8 ± 11.6; lidocaine 12.4 ± 9.7; saline 16.2 ± 11.5; P = 0.08). These studies focused on 24 and 48 h after childbirth, and no analysis of the mid- and long-term pain levels, dyspareunia, or depression occurrence was conducted. If the mother has less pain at midterm (7–10 days postpartum), it could increase mother–infant interaction and bonding.

Mediolateral episiotomies in the early and midterm postpartum period are associated with perineal pain. Both theoretical arguments and results of previous studies indicate that ropivacaine has promise in the prevention of perineal pain. Nevertheless, there are not enough well-conducted studies to reach any definitive conclusion. We therefore designed the present randomized controlled trial (Study of the Analgesic Effect of the Perineal Infiltration of Ropivacaine 0.75% versus Placebo in Post-episiotomy Perineal Pain [ROPISIO]). This study is a superiority study of ropivacaine 75 mg versus placebo in perineal infiltration for women receiving episiotomy. The primary endpoint is analgesic efficacy at day 7 (D7) postpartum (midterm) measured with the Numeric Pain Rating Scale (NPRS). The patients will be recruited at two centers.

The ROPISIO study will assess the efficacy of ropivacaine infiltration to reduce perineal pain in the postpartum period at midterm and long term and increase in the quality of life. This analgesic management could improve the women’s quality of life in the postpartum period (earlier mobilization, better interaction with the baby, decrease in analgesics used). In the long term, we expect a decrease in dyspareunia and a better overall quality of life for the women.

Most studies on analgesic management of pregnant patients focused on pain during labor or following a cesarean section. Perineal pain in association with an episiotomy has been much less studied and is often underestimated. Ropivacaine is a promising candidate drug, inexpensive and easy to administer, and infiltration with this analgesic could be added to the routine management of all women after episiotomy worldwide. The evidence currently available is too limited to justify its widespread use for perineal pain prevention in the postpartum period. This adequately powered, multicenter, randomized, placebo-controlled trial aims to determine if the risk/benefit ratio favors the systematic use of ropivacaine after episiotomy to prevent postpartum perineal pain.

Enrollment having started on 24 October 2017. As of 10 May 2020, all the 272 patients were included in the ROPISIO trial and the follow-up will last until October 2020. Three data safety and monitoring committees have confirmed the continuation of the study, in January 2018, February 2019 and March 2020 respectively. The current protocol version used for ROPISIO study is 8.0, dated 22 February 2019. Enrollment was completed in April 2020. The total duration of the trial will be 43 months, including 37 months of inclusion and 6 months of follow-up in the postpartum period (assessment of quality of life, pain characteristics, sexual function, and postpartum symptoms of depression).