Office hysteroscopy (OH) and endometrial biopsy (EMB) is increasingly performed for evaluation of various gynecologic conditions. It has replaced traditional dilatation and curettage for evaluation of intrauterine pathology. It is more acceptable to most women as it is quick, safe and cost effective with higher diagnostic accuracy. However, pain encountered at the time of procedure is a major limitation and at times lead to incomplete procedure. The variables that influence women's experience of pain during these procedures are nulliparity, menopausal status, pre-existing anxious state, use of tenaculum, presence of synechiae in the cervical canal, and duration of procedure.

The average pain score recorded at the end of procedures when OH and EMB were performed simultaneously was 7 on a 10 cm VAS scale (Visual analogue scale) 5 among pre and post menopausal women who received pre-procedure analgesia in the form of oral Non-Steroidal Anti Inflammatory drug (NSAID) and application of local anesthetic gel. Among patients where only intracervical topical anesthetic injection was used, the pain score at the end of OH and EMB was 9.22 (low pain) and 11.52 (moderate pain), respectively, on a 20cm VAS. Most women describe EMB as "moderately" or "severely" painful6. A significant source of pain during endometrial sampling is placement of tenaculum on the cervix. Interventions that have been studied to reduce pain with EMB include misoprostol for cervical ripening, intrauterine lidocaine infusion, paracervical block, and pre-procedure NSAIDs. The results are variable with modest benefit on pain with only an intrauterine lidocaine infusion with or without NSAID or/and misoprostol. Similarly, during OH also, there are multiple points where women experience pain. It can be during tenaculum placement, introduction of the hysteroscope, distension of uterine cavity, intrauterine procedures, and withdrawal of scope. Out of many interventions evaluated, local anesthesia via paracervical block provided consistent decreases in intraoperative and postoperative pain scores. There were mixed data on efficacy of intracervical blocks and no evidence to support the use of intrauterine anesthesia or topical gels, sprays, or creams. Premedication with opioid analgesics or NSAIDs do not confer benefit in pain management during office hysteroscopy. Misoprostol for cervical ripening prior to diagnostic hysteroscopy neither reduce pain nor facilitate the procedure for hysteroscopes with diameters of less than 6 mm in premenopausal women, but there may be a benefit in postmenopausal women. In contrast, another systematic review examining use of misoprostol before hysteroscopy found that misoprostol given to premenopausal women reduced the need for cervical dilatation and the incidence of cervical laceration.

Misoprostol is a prostaglandin E1 analog that was first marketed in the 1980s to prevent gastric ulcer. It can be administered sublingually, orally, vaginally, or rectally. Peak serum levels are achieved after vaginal administration. The plasma concentration increases gradually after vaginal administration, reaching its maximum level after 70-80 minutes. Misoprostol is commonly used in gynecology for inducing dilatation of the cervix for termination of pregnancy and removing retained products of conception. It helps in non-pregnant women to dilate the cervix and provides easy access to the uterine cavity for transcervical procedures such as hysteroscopy and intrauterine device placement. To evaluate the optimal dose of vaginal misoprostol for cervical priming before operative hysteroscopy, low dose (200mcg) and high dose (400 mcg) misoprostol was compared in a recent randomized control trial. They found no difference in perioperative dilatation time, and subjective difficulty of cervical dilatation assessed by surgeons. However, the incidence of misoprostol related adverse events such as abdominal pain, pre-insertion nausea and cramping were less in the group who received 200 mcg misoprostol. But it is important to note that even 200 mcg misoprostol is associated with 50% incidence of abdominal cramping. Since we would be conducting outpatient diagnostic procedures only, we propose that use of 50 mcg misoprostol would lead to adequate cervical dilatation to successfully complete the OH and EMB with lower incidence of associated complications (abdominal cramping, vaginal bleeding, and nausea). Moreover, it is important to note that the standard operating procedure of the fibroid and endometriosis center has been the administration of 50 mcg misoprostol to patients undergoing simultaneous OH and EMB. This practice that has been ongoing for over 12 months has provided very favorable results. No other study has evaluated the efficacy of such a low dose and it would be interesting to explore the minimal effective dose, which can be used for simultaneous OH and EMB to yield effective results in terms of lower pain scores and lower incidence of associated complications. As mentioned previously, studies evaluating the role of misoprostol in alleviating overall pain during OH and EMB had mixed reviews. But those studies have been performed in the general population. It is important to note that there are subgroups of women (previous cesarean section, nulliparous, postmenopausal, previous loop surgery) who more often need dilatation of the cervix to facilitate passage of the hysteroscope. Therefore, this trial will focus on these subgroups to assess whether the use of prostaglandin analogue provides clinically significant reduction in pain, reduces the need for dilatation and incidence of genital trauma and whether these benefits outweigh the potential harms (bleeding, laceration, abdominal cramping, fever etc.)