Diclofenac Potassium Alone Versus Diclofenac Potassium with Hyoscine-N-butyl Bromide (HBB) in Reduction of Pain in Women Undergoing Office Hysteroscopy: A Double Blind Randomized, Placebo-Controlled Trial

Study Objective To compare between oral diclofenac potassium alone versus a combination of it with hyoscine-N-butyl bromide (HBB) in reduction of pain in women undergoing office hysteroscopy. Design Randomized, double-blind controlled trial. Setting Kasralainy hospital (a tertiary hospital). Intervention Sixty-Four patients undergoing office hysteroscopy were randomly divided into 2 groups (study group and placebo group) in the ratio of 1:1. Group 1 (study group = 32 participants) received two oral HBB tablets and one tablet of diclofenac potassium and group 2 (placebo group = 32 participants) received two oral placebo tablet similar in size, structure and color to buscopan in addition to the diclofenac tablet. The patient was given the drugs 30–60 min before the procedure.

There was statistically significant difference between the two groups in the pain score immediately during entry (p value = 0.001) and after 30 min of the procedure (p value = < 0.001). And there was a statistically significant difference as regards the side effects (gastric irritation) of the medications (p value = 0.04) between the women participating in the two groups.

The combination of diclofenac potassium and HBB helps a lot in decreasing the pain and discomfort during and after performing office hysteroscopy but with more gastric side effects.

Office hysteroscopy, Diclofenac potassium, Hyoscine-N-butyl promide, Analgesics, Pain

Hysteroscopy is considered nowadays the most useful tool for patients suffering abnormal uterine bleeding and infertility [1]. The outpatient or office hysteroscopy has always been related to higher acceptability to patients together with fewer complications, being more cost-effective and shorter recovery [2, 3]. It does not need anesthesia or an operating theater setting. There has been marked improvement and evolution in the office hysteroscopy settings due to the novelty of instruments and techniques [4]. Usually patients only experience minimal and tolerable discomfort with the procedure [5], but some may suffer intolerable pain [6]. Trials have been conducted to decrease the pain associated with office hysteroscopy using several medications, like nonsteroidal anti-inflammatory drugs (NSAIDs), local anesthetic drugs or even narcotics [7]. Diclofenac is one of the NSAIDs, with an anti-inflammatory, antipyretic and analgesic effect. It is effectively prescribed for the treatment of a wide spectrum of acute and chronic pain as well as inflammatory cases. Its mechanism of action is mediated through inhibiting prostaglandin synthesis via the inhibition of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) with relative equipotency [8]. Hyoscine-N-butylbromide (HBB) is an anticholinergic medication. It has high affinity for the muscarinic receptors in the gastrointestinal tract smooth muscles. It has an important spasmolytic effect causing smooth muscles relaxation, via its anticholinergic action. It is used to treat abdominal cramping by blocking muscarinic receptors in the gastrointestinal tract [9]. Hyoscine-N-butylbromide does not cross the blood–brain barrier, and also has a low plasma protein binding [10]. Despite having a large number of studies that aimed to evaluate the analgesic effect of the spasmolytic drugs during different gynecological outpatient maneuvers, as saline infusion sonohysterography (SIS) and hysterosalpingo-contrast sonography (HyCoSy), yet they could not demonstrate remarkable pain relief methods. This may be attributed to the small doses used [11, 12]. Hyoscine has been evaluated by many studies to detect its effect on facilitating cervical dilatation in patients undergoing gynecological procedures [13]. In this study, we aimed to reach an optimum pain relief in patients undergoing office hysteroscopy using a combination of oral diclofenac potassium with hyoscine-N-butyl bromide (HBB).

This randomized, double-blind controlled trial (Clinical-Trials.gov identifier NCT 04125771 conducted at a tertiary Hospital in Egypt between February and October 2020. The hospital’s Institutional Research Ethics committee approved the protocol of the study. The patients received counseling provided written informed consent before enrollment in the study. In our study, we recruited patients aged 20 to 40 years of age, and indicated for diagnostic hysteroscopy including infertility, bleeding, suspected intrauterine pathologies (e.g., polypi, septea). The patients were scheduled for the procedure during the postmenstrual days (between day 6 and 11 of the cycle [except in irregular bleeding]). Exclusion criteria included menopausal and amenorrhic patients, contraindications to office hysteroscopy (e.g., pelvic inflammatory disease, marked cervical stenosis or pregnancy) as well as previous cervical surgery (e.g., cauterization or conization). We also excluded patients in whom vaginoscopic approach was not enough and where a tenaculum had to be used, patients with peptic ulcers or other contraindications to NSAIDs or hyoscine, and patients who refused or asked to be excluded from the study after enrollment. In addition, patients who needed an office operative procedure were excluded. Recruited women were randomly divided into two equal groups. Group 1 (study group = 32 participents) received two oral HBB tablets (buscopan 10 mg, Boehringer Ingelheim) and one tablet of diclofenac potassium (Cataflam 50 mg, Novartis) and Group 2 (placebo group = 32 patients) received two oral placebo tablet similar in size, structure and color to buscopan in addition to the diclofenac tablet. The manufacturing of the placebo tablets and packaging of all medications into sterile boxes labeled as 1 or 2 was assigned to the same pharmacist. Both the study team and patients were blinded to the allocation groups, whereas the pharmacist was aware of the medication type in the sterile boxes. Sample Size Calculation Sample size calculation was done using the comparison of visual analog scale (VAS) score during office hysteroscopy between women pretreated with diclofenac potassium and those pretreated with hyoscine-N-Butyl bromide (HBB), as it was the primary outcome of our study. As reported in previous publication [14], the mean ± SD of VAS in diclofenac group was approximately 2.12 ± 1.03, while in HBB group it was approximately 3.02 ± 1.55. Accordingly, we calculated that the minimum proper sample size was 32 participants in each group to be able to reject the null hypothesis with 80% power at á = 0.05 level using Student’s t test for independent samples. Sample size calculation was done using PS Power and Sample Size Calculations software, version 3.0.11 for MS Windows (William D. Dupont and Walton D., Vanderbilt University, Nashville, Tennessee, USA). Randomization The patient, operator and the observer were not aware of the patients’ allocation. A third party generated the allocation sequence using online generated random numbers. Study Intervention Patients included in this study were subjected to history taking (especially for contraindications to NSAIDs), examination and TVUS. An informed written consent was provided by each participant. The procedure was done in the lithotomy position with a 30°angle 2.9 mm rigid hysteroscopy. The feeling of pain by ladies was evaluated for each group on 3 settings: During the hysteroscopy (after introduction of hysteroscopy in the uterus), immediately after the hysteroscopy when the hysteroscope was removed from the uterus, and 30 min after finishing the maneuver. Pain was calculated using a 10 cm visual analog scale (VAS). VAS of 0 indicated no pain and VAS of 10 indicated the worst possible pain. Women were asked to report any side effects and were asked about the general acceptability of the procedure whether acceptable, difficult, or not acceptable at all. The total procedure time was recorded in seconds and the ease of procedure (easy or difficult) was recorded by the operator. Study Outcomes The main study outcome was the pain sensation difference during the procedure between the two groups. The level of pelvic pain was rated according to a 10-point visual analog scale (VAS). Secondary outcome parameters included the intensity of pain immediately and 30 min after the procedure, prominent side effects as gastric pain, procedure time and ease of entry as reported by the operator, and overall acceptability of the procedure by the patient whether acceptable, difficult or not acceptable at all. Statistical Analysis Pre-coded data were then transferred and entered into the Statistical Package of Social Science Software program, version 26 (SPSS) to be statistically analyzed. For quantitative variables (Using Kolmogorov–Smirnov Z test) normally distributed variables were described as mean and standard deviation and compared using independent t test, where p value is significant if less than 0.05. While, not normally distributed variables were described as median and IQR (interquartile range) then compared using Mann Whitney U test, where p value is significant if less than 0.05. For qualitative variables, they were described as frequency and percentage and compared using Chi-square test or fisher exact test accordingly where p value is significant if less than 0.05.

A total of 84 patients indicated for diagnostic hysteroscopy were recruited from Cairo University Hospital office hysteroscopy clinic. Two patients refused participation, eight patients proceeded to operative procedure (e.g., polypectomy), four patients had cervical stenosis, three patients were menopausal and another three had history of peptic ulcer which contraindicated NSAIDs use. Those twenty patients were excluded (Fig. 1). There was no statistically significant difference between both groups as regard patients’ age (p value = 0.84), gravidity (p value = 0.43), and history of abdominal surgery (p value = 0.4) (Table 1). Table 1. | Variable | Study group (n = 32) | Placebo group (n = 32) | p value | | |---|---|---|---|---| | Age (years) [mean ± SD] | 30.2 ± 5.7 | 29.9 ± 5.4 | 0.84 | | | Gravidity | Nulligravida [No., (%)] | 12 (37.5%) | 15 (46.9%) | 0.43 | | Multigravida [No., (%)] | 20 (62.5%) | 17 (53.1%) | || | H/o of abdominal surgery [No., (%)] | 11 (34.4%) | 8 (25.0%) | 0.4** | SD Standard deviation, No. Number The administration of diclofenac potassium (50 mg) in combination with HBB (20 mg) was associated with a statistically significant lower pain score when compared with diclofenac only either immediately during entry (4.3 ± 1.6 versus 5.7 ± 1.6, respectively, p value = 0.001) and after 30 min of the procedure (1.8 ± 0.9 versus 3.3 ± 1.5, respectively, p value < 0.001) (Table 2). There was no statistically significant difference between both groups neither in the duration of the procedure (p value = 0.26) nor in the procedure difficulty (p value = 0.18) (Table 3). There was no statistically significant difference between both groups as regards patient satisfaction to the procedure (p value = 0.16), however, gastric irritation was significantly more frequent in the study group compared to the placebo one (p value = 0.04) (Table 4). Table 2. | Pain score | Study group (n = 32) | Placebo group (n = 32) | p value | | |---|---|---|---|---| | At zero time | Mean ± SD | 4.3 ± 1.6 | 5.7 ± 1.6 | 0.001* | | Median (min–max) | 4 (1–8) | 6 (1–9) | || | After 30 min | Mean ± SD | 1.8±0.9 | 3.3 ± 1.5 | < 0.001* | | Median (min–max) | 2 (0–3) | 3.5 (0–6) | SD Standard deviation Table 3. | Variable | Study group (n = 32) | Placebo group (n = 32) | p value | | |---|---|---|---|---| | Procedure duration (in seconds) | Mean ± SD | 220.6 ± 105.4 | 253.8 ± 126.8 | 0.26 | | Procedure difficulty [No., (%)] | Very easy | 3 (9.4%) | 1 (3.1%) | 0.18 | | Easy | 15 (46.9%) | 10 (31.3%) | || | Fair | 11 (34.4%) | 13 (40.6%) | || | Difficult | 3 (9.4%) | 4 (12.5%) | || | Very difficult | 0 (0.0%) | 4 (12.5%) | SD Standard deviation, No. Number Table 4. | Variable | Study group (n = 32) | Placebo group (n = 32) | p value | |---|---|---|---| | Patient satisfaction [No., (%)] | 26(81.3%) | 21(65.6%) | 0.16 | | Side effects (Gastric irritation) [No., (%)] | 22(68.8%) | 13(40.6%) | 0.04** | SD Standard deviation, No. Number

Our study showed that the administration of diclofenac potassium (50 mg) in combination with HBB (20 mg) was associated significantly lower pain score when compared with diclofenac only either immediately during entry or after 30 min of the procedure. There was no significant difference between both groups in the time of the procedure, in the procedure difficulty or as regards patient satisfaction to the procedure; however, gastric irritation was significantly more frequent when HBB was used. Pharmacological and non-pharmacological methods were studied to decrease pain felt during hysteroscopy. Several classes of medications have been tried as NSAIDs, narcotics and local anesthetics [15]. Local anesthetics were used either; intrauterine, paracervical injection, topical spray, cream and gel. In addition, oral or intravenous analgesia; either opioid or non-opioid (NSAIDs and paracetamol) were also evaluated, but finally the previous studies that were concerned with pain relief during OH reported no agreement on a certain efficient method [7]. To the best of our knowledge, the current study was the first study that assessed the effect of using oral diclofenac potassium combined with hyoscine-N-butyl bromide (HBB) in reduction of pain in ladies undergoing office hysteroscopy. The failure of office hysteroscopy procedure or the unsatisfactory patient experience is mainly related to pain, during introduction of instruments into the genital tract, such as speculum insertion, placement of a tenaculum, cervical dilatation, as well as distension of the uterine cavity and the removal of the intrauterine pathology [16]. Patients may experience pain at different timings during the hysteroscopy procedure. Almost 50% of the pain is related to hysteroscope insertion or to cervical dilatation [17]. Many researches investigated the medications for pain reduction in hysteroscopy, however, there is no Several publications have discovered treatments for controlling pain in hysteroscopy, but there is no definite agreement in the literature about the best way of relieving pain during OH, so the novelty of our study is that it presents a previously overlooked drugs (Diclofenac and Buscopan) but in a combination form which is never tried before. In agreement with our study, Sharma and his colleagues [18] allocated 120 women undergoing hysteroscopy and endometrial biopsies, and were randomized into 3 groups, drotaverine hydrochloride (80 mg) + mefenamic acid (250 mg) which is our same combination (NSAID with spasmolytic) versus group II (lignocaine paracervically) versus group III intravenous diazepam. The combination of NSAID with spasmolytic was associated with statistically significant lower pain scores when compared with the 2 other groups during the procedure and 30 min later and 60 min later and accordingly they concluded that Oral drotaverine with mefenamic acid is efficient in ladies during hysteroscopy and endometrial biopsy. In a similar concept but with different methodology, Abbas and his coworkers they concluded that diclofenac potassium or HBB oral administration reduced pain during OH but oral diclofenac potassium intake 1 h prior to diagnostic OH minimizes the pain (more effectively than HBB) with subsequent easier procedure and shorter OH duration. [14] Desilva and his colleagues [19] made a systematic review and meta-analysis to find the best analgesia records for control of pain in office diagnostic and operative hysteroscopy. The results of the meta-analysis demonstrated a marked reduction in pain both during and after office hysteroscopy and that NSAIDs is the most safe and efficient way of analgesia for relieving pain during and after office hysteroscopy. The effectiveness of HBB in reducing pain was recently evaluated by Gokmen and her colleagues [20] who recruited 28 women scheduled for operative hysteroscopy and were randomly divided into 3 groups, group 1 received placebo treatment, group 2 received rectal misoprostol and group 3 received rectal HBB. All medications were given 2 h before the procedure. They also investigated the ease of cervical dilation and duration of the procedure in addition to the post procedure pain. This difference was nearly statistically significant (p value = 0.06). The only statistically significant difference among groups was that patients who received HBB needed less postoperative analgesia in comparison to Group 1 (placebo treatment) (p = 0.001). In contrast to Gokmen study [20] and our results, Jareethum and his coworkers [11] assessed the effectiveness of HBB (10 mg) in reducing pain in 141 nulliparous women undergoing saline infusion sonohysterography (SIS). The evaluation was performed during and after the procedure. They reported no difference in pain scores between HBB and placebo during saline infusion sonohysterography (SIS). Likewise, Moro and his colleagues [12] reported the same findings in SIS. We assume that the conflicting results were due to the difference in study population, sample size, the procedure and dosage of the HBB. The current study showed no statistically significant difference between both groups in the duration of the procedure (p value = 0.26), in the procedure difficulty (p value = 0.18) or patient satisfaction to the procedure (p value = 0.16). This was in agreement with the reports of both Abbas [14] and Gokmen [20]. In the current study, gastric irritation was significantly more frequent when HBB was used (p value = 0.04). The same was reported by Abbas and his colleagues [14]. In contrast to our results, Gokmen and her coworkers [20] reported that the use of HBB was not significantly associated with gastric upset, however, this discrepancy in results may be justified by the different route of administration (oral in the current study versus the rectal route in Gokmen’s one). Adverse effects of hyoscine after oral usage include gastric irritation which is dose dependent [21]. The randomized double-blind controlled trial is the main point of strength in our study [22]. Other points of strength were including a single operator to perform all the OH procedures and a single investigator to interview the patients and collect the VAS score results to avoid any bias. Furthermore, we were able to recruit our calculated sample size for achieving enough power to determine a significant difference in our primary outcome. Also, one of the strengths of our the study was the strict selection of study population, including only uncomplicated, medically free, in reproductive age and post menstrual, undergoing diagnostic office hysteroscopy, so we were clearly able to determine the role of the medications studied in affection of pain perception as the first outcome in our study. The main limitation of the study was the small sample size together with the subjectivity in recording pain through VAS score as there are no objective factors to assess pain. Further researches using different doses and routes of administration of HBB are warranted. In conclusion, oral administration of diclofenac potassium 50 mg combined with oral HBB 20 mg significantly reduces the pain sensation during and after the office hysteroscopy procedure, same as the ease of entry which was much easier with that combination in comparison to diclofenac only and placebo. The medications of the study, being safe, effective and less costly, could be of great benefit to reduce pain during office hysteroscopy and improve better chances for the procedure results and patient satisfaction to the procedure. We recommend the further more comparative studies including more combinations of different classes or methods of decreasing pain for achieving the least pain and more satisfaction about the procedure, and we recommend also the further more comparative studies with objective pain evaluation methods for more accurate pain assessment and also PPI may be added to the HBB in other studies may be more useful to decrease the possible gastric side effects. Declarations Conflict of interest All authors declare that there are no any financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work. Ethical approval Local Scientific and ethical Committee (an Institutional Review Board) approval was obtained before the start of the study. Footnotes Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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