Background
Patients undergoing vaginal hysterectomy with native tissue pelvic reconstruction typically have low pain levels overall in the postoperative period. Notwithstanding, pain control immediately after surgery may be more challenging and a barrier to same-day discharge. Intrarectal diazepam has been used for acute and chronic pelvic pain and has a pharmacokinetic profile ideal for intermittent use. However, its use has not been investigated after the surgical intervention.
Objective
This study aimed to evaluate the effect of diazepam rectal suppositories on early postoperative pain after hysterectomy and vaginal reconstruction for pelvic organ prolapse.
Study Design
This was a double-blind, randomized, placebo-controlled trial comparing postoperative pain scores after vaginal hysterectomy with native tissue prolapse repairs. Patients were randomized to receive either an intrarectal 10-mg diazepam suppository or an identical placebo. Moreover, the participants completed the questionnaires at baseline, the morning of postoperative day 1, and 2 weeks after the operation. Surveys included visual analog scales for pain, a validated Surgical Satisfaction Questionnaire, and queries regarding medication side effects and postoperative recovery. The primary outcome was pain scores based on a visual analog scale approximately 3 hours after surgery. The secondary outcomes included total morphine equivalents after surgery, patient satisfaction with pain control, same-day discharge outcome, and overall satisfaction. The chi-square, Fisher exact, and Mann-Whitney tests were used. Based on a 10-mm difference in postoperative vaginal pain using the visual analog scale, sample size was calculated to be 55 patients in each arm to achieve 80% power with an alpha of.05.
Results
From February 2020 to August 2021, 130 participants were randomized. Of those participants, 7 withdrew, and 123 were analyzed: 60 in the diazepam group and 63 in the placebo group. The median age was 65 years (interquartile range, 27–80), the median body mass index was 27.9 kg/m 2 (interquartile range, 18.70–45.90), and 119 of 123 participants (96.7%) were White. There was no difference in the baseline characteristics, prolapse stage, or types of procedures performed between groups. Most participants had concurrent uterosacral ligament suspension with anterior and posterior repairs. Of note, 50 of 123 participants (41%) had midurethral slings. Moreover, 61 of 123 participants (50%) were discharged on the day of surgery. There was no difference in the primary outcome of vaginal pain 3.5 to 6.0 hours postoperatively (25 vs 21 mm; P =.285). In addition, the amount of rescue narcotics used in the immediate postoperative period (19.0 vs 17.0 MME; P =.202) did not differ between groups. At 2-weeks postoperatively, patients in the placebo group reported higher satisfaction with pain control in the hospital (31 vs 43 mm; P =.006) and pain control at home (31 vs 42 mm; P =.022). No difference was noted between same-day discharges and those who were admitted overnight.
Conclusion
The placement of a 10-mg diazepam rectal suppository immediately after pelvic reconstructive surgery did not improve pain or narcotic usage in the early postoperative period. Although the placebo group reported slightly higher satisfaction with pain control 2 weeks after surgery, overall pain levels were low. Therefore, we do not believe that the addition of diazepam to the postoperative regimen is warranted.
Introduction
In 2021, the American Urogynecologic Society published a Clinical Practice Statement recommending that patients not be discharged home with >15 opioid tablets after pelvic reconstructive surgery, suggesting that overall pain control after these procedures is good. Pain scores in the immediate postoperative period after minimally invasive hysterectomy are also generally low, with reported visual analog scale (VAS) scores between 13 and 40 mm at 4 hours after surgery. This information has been echoed by recent studies, highlighting low amounts of narcotics used postoperatively in the urogynecologic patient population. , However, this topic remains controversial as other reports have described up to 45% of women having inadequate pain control 3 days after vaginal hysterectomy, suggesting that further improvement would be beneficial.
Why was this study conducted?
This study aimed to compare intrarectal diazepam suppository vs placebo on short-term postoperative pain scores after total vaginal hysterectomy with native tissue prolapse repair.
Key findings
The placement of a 10-mg diazepam rectal suppository immediately after pelvic reconstructive surgery did not improve pain or narcotic usage in the early postoperative period.
What does this add to what is known?
The pain after vaginal hysterectomy with native tissue prolapse repair has been low overall, and the addition of intrarectal diazepam did not improve pain scores or expedite same-day discharge.
Hysterectomy in conjunction with pelvic reconstructive procedures is complex, often resulting in longer operating times and involves a larger field of dissection than other gynecologic surgery. Thus, pain with this procedure may be different from standard vaginal hysterectomy and includes a component of pelvic floor muscle dysfunction as well. Urogynecologists often treat pelvic floor muscle dysfunction and chronic pelvic pain with compounded medications, including suppositories. , Specifically, diazepam for pelvic floor dysfunction and urogenital pain has had reported success.
Rectal administration of medications is an attractive option in patients after pelvic surgery. Rectal analgesia avoids first-pass metabolism in the liver, leading to increased bioavailability of many medications and fewer side effects, such as nausea and vomiting. Belladonna and opium suppositories have been found to improve quality of life scores and decrease dysuria and urinary urgency in the urology literature but were not found to improve pain scores in patients after vaginal prolapse repair. Currently, we are lacking information regarding the efficacy of rectally administered diazepam for postoperative pain control.
This study aimed to assess the effectiveness of intrarectal diazepam suppository administration at the time of total vaginal hysterectomy with native tissue prolapse repair vs placebo on short-term postoperative pain. Moreover, we sought to compare surgical data, pain scores, and satisfaction scores at various other time points postoperatively. We hypothesized that the use of rectal diazepam suppositories after major vaginal reconstructive surgery would decrease pain in the interval between 3.5 and 6 hours postoperatively compared with placebo.
Materials and Methods
This randomized, double-blinded placebo-controlled trial was performed at TriHealth Good Samaritan Hospital and Bethesda North Hospital in Cincinnati, Ohio, between February 2020 and September 2021. The study was approved by the TriHealth Institutional Review Board (December 3, 2019) and registered with the National Clinical Trials registry (identification number NCT04198233). Compounded suppositories were provided by TriState Compounding Pharmacy (Cincinnati, OH). Funding was provided by the TriHealth Medical Education Research Fund.
Consented patients were randomized to receive either a compounded 10-mg diazepam rectal suppository (with fatty acid base) or an identical-appearing placebo, containing only fatty acid base, intraoperatively after surgery.
Eligible patients were women aged 18 to 80 years old who were planning a vaginal hysterectomy with native tissue prolapse repairs under general anesthesia performed by a fellowship-trained female pelvic medicine and reconstructive surgeon (FPMRS) assisted by fellow physicians. Patients were excluded if they were non–English-speaking, had medical contraindications to diazepam, or were having a concomitant procedure performed by another surgical specialty. In addition, patients with a history of chronic pain and/or daily use of narcotic medications were excluded from enrollment.
Patients were approached for enrollment at their preoperative appointment by their primary surgeon, FPMRS fellow, or clinical research nurse. Once enrolled, patients were randomized based on block randomization schedules created by a research statistician in conjunction with the corresponding compounding pharmacist. The pharmacist was the only team member unblinded to study allocation for purposes of medication production and did not reveal allocation to the remaining research team. The suppositories were compounded and appeared identical in form, color, and packaging.
Enrolled subjects were asked to fill out a baseline questionnaire before surgery. Furthermore, patients completed questionnaires on postoperative day zero (POD 0), the morning of POD 1, and at their 2-week follow-up appointment. These consisted of the following:
- •
The baseline questionnaire included 7 questions formatted as a 100-mm VAS:
- 1.
What is your pain level in your vagina or rectum right now?
- 2.
What is your pain level in your abdomen or belly right now?
- 3.
How satisfied are you with your pain control right now?
o Questions 4 to 7 included the validated surgical pain scale.
- 1.
- •
The POD 0 questionnaire included questions 1 to 3 as stated above
- •
The POD 1 questionnaire was identical to the baseline questionnaire
- •
The 2-week questionnaire was identical to the baseline and POD 1 questionnaire in addition to the following:
o One question regarding any medication side effects following surgery.
o Two questions regarding current voiding function.
o Two questions regarding bowel movements (BMs) after surgery, including day of their first BM and pain experienced during this event: 0 indicating “no pain” and 100 indicating “worst pain.”
o The Surgical Satisfaction Questionnaire (SSQ-8) was included.
A time frame between 3.5 and 6.0 hours postoperatively was chosen to assess short-term pain. Moreover, 2 pharmacokinetic studies have assessed intrarectal diazepam placement. The peak serum concentration of diazepam after rectal or vaginal administration is between 1.5 and 3.1 hours. , , This time frame would allow adequate time for medication absorption and recovery from anesthesia. The pharmacokinetic profile and absorption of the suppositories used in our study were not verified. This decision was made as suppositories were compounded by a reputable pharmacy and the rectal route of administration had been anecdotally successful in our practice.
After surgery, while still under general anesthesia, the rectal suppository was placed by either the attending surgeon or the FPMRS fellow. The time of placement was recorded. Vaginal packing and an indwelling Foley catheter were placed after surgery per standard practice. Intraoperative lidocaine 1% with epinephrine was injected along the surgical site to assist with hydrodissection and vasoconstriction in a standardized technique for all patients, as is common practice among all our providers.
Between 3.5 and 6.0 hours after suppository placement, the POD 0 questionnaire was administered by a study team member, followed by vaginal packing removal, depending on surgeon preference and discharge status. We did not deviate from the normal postoperative standard of care for our institution regarding multimodal pain control, quick advancement of diet, and early postoperative ambulation. Standard postoperative pain control for admitted patients included intravenous (IV) Toradol every 6 hours for 24 hours followed by 600 mg oral ibuprofen every 6 hours as needed, gabapentin 300 mg every 8 hours, 1000 mg acetaminophen every 6 hours as needed, IV hydromorphone 0.5 to 1.0 mg as needed (before oral intake), or oral oxycodone 5 mg every 6 hours as needed. Standard postoperative pain control at the time of discharge included ibuprofen, gabapentin, acetaminophen, and oxycodone. Any deviation from the standard pain control regimen was based on individual contraindications.
Discharge timing was determined by several factors and may have occurred on POD 0 or POD 1. Patients may have been admitted overnight because of pain, nausea, mobility concerns, familial anxiety, or transportation issues. In addition, the COVID-19 pandemic did occur during our study, and this did prompt an increase in same-day discharge (SDD) per hospital policy. The timing of the postoperative voiding trial was determined by discharge timing. Patients who were discharged on POD 0 had their voiding trial done before discharge. Those admitted overnight had their voiding trial in the morning before discharge. All voiding trials were done by backfilling the bladder with 300 mL of sterile water and allowing the patient to void after the catheter was removed. Patients who were unable to void at least 200 mL had an indwelling Foley catheter replaced. Patients were given the choice to either remove their catheter at home between 5 and 7 days postoperatively or have it removed in the office approximately 7 days postoperatively.
If patients were in the hospital on POD 1, the POD 1 questionnaire was administered by a study team member. If patients were discharged home on POD 0, the POD 1 questionnaire was administered over the phone by a study team member. Patient responses over the phone were collected as a numeric pain score of 0 to 10 and correlated to a VAS score of 0 to 100 mm on a 10-mm per 1-point scale. Finally, patients completed the 2-week postoperative questionnaire at their routine follow-up appointment. Patients were given standard postoperative restrictions, including no heavy lifting, pushing, pulling, or intercourse, for the first 6 weeks postoperatively. Clarification on questions was provided to patients at their request.
Demographics such as age, body mass index (BMI), medical and surgical history, preoperative pelvic organ prolapse quantification, surgical procedure details, and postoperative complications were collected.
Our primary outcome was the difference in POD 0 vaginal or rectal pain scores based on VAS between groups. The secondary outcomes included level of pain at other time points, satisfaction with postoperative pain control, nurse recorded pain score (based on 0–10 scale) at 4 hours, total morphine equivalents (Meq), surgical procedure details, postoperative complications, and factors associated with SDD and inpatient admission.
Our sample size was based on a similar study by Long et al who found a difference in VAS scores 3 hours after vaginal surgery with preemptive analgesia. In their study, a difference in mean pain score at 3 hours postoperatively was 12 mm by VAS: 36 mm (standard deviation [SD], 20 mm) in the control group and 24 mm (SD, 24 mm) in the intervention group. Our sample size calculation was performed with a 2-group Satterthwaite t test of equal means and demonstrated a need to enroll 55 subjects in each arm to detect a 10-mm difference in VAS scores with a power of 80% and significance level of.05. Assuming a loss to follow-up rate of 15%, the number of patients per arm was set to 65, for a total of 130 patients.
The chi-square test or Fisher exact test was employed to examine an association between categorical variables and treatment groups. A Shapiro-Wilk test was used for testing normality, and the Mann-Whitney rank-sum test was implemented to test for significant differences in pain between the diazepam and placebo groups and between those with SDD and those without. Sample size and power calculation were completed with nQuery (2017; Statsols; Statistical Solutions Ltd, Cork, Ireland). Statistical analysis was performed using IBM SPSS Statistics for Windows (version 27; IBM Corp, Armonk, NY).
Results
Between February 2020 and August 2021, a total of 215 patients were screened for eligibility, and 130 patients were randomized. Moreover, 65 patients were allocated to each study arm. Before surgery, 7 patients withdrew, including 5 from the diazepam group and 2 from the placebo group. Final data analysis was performed on 123 participants: 60 received intrarectal diazepam suppository and 63 received placebo ( Figure ).
The median age of the participants was 65 years (interquartile range [IQR], 27–80), median BMI was 27.9 kg/m 2 (IQR, 18.7–45.9), and 119 participants (96.7%) were White. No patient had a history of prolapse repair, and most patients had stage 2 or 3 prolapse (n=114 [93%]). There was no were no differences between group demographics ( Table 1 ).
| Characteristics | Diazepam group (n=60) | Placebo group (n=63) | P value a |
|---|---|---|---|
| Smoker | 5 (8.3) | 3 (4.8) | .484 b |
| Sexually active | n=52 22 (39.3) | n=55 31 (50.8) | .265 |
| Past medical history | |||
| Anxiety | 5 (8.3) | 5 (7.9) | >.999 b |
| Endometriosis | 1 (1.7) | 2 (3.2) | >.999 b |
| Asthma | 3 (5.0) | 5 (7.9) | .718 b |
| COPD | 1 (1.7) | 0 (0.0) | 0.98 |
| Fibromyalgia | 0 (0.0) | 1 (1.6) | >.999 b |
| Arthritis (RA) | 5 (8.3) | 1 (1.6) | .113 b |
| Depression | 10 (16.7) | 9 (14.3) | .908 |
| GERD | 5 (8.3) | 8 (12.9) | .6 |
| Arthritis (OA) | 9 (15.0) | 13 (20.6) | .562 |
| Diabetes mellitus | 9 (15.9) | 4 (6.3) | .205 |
| Hypertension | 26 (43.3) | 27 (42.9) | >.999 |
| Other | 42 (70.0) | 40 (64.5) | .651 |
| Past surgical history | |||
| Salpingo-oophorectomy | 1 (1.7) | 0 (0.0) | .488 b |
| Sling | 1 (1.7) | 0 (0.0) | .488 b |
| Other pelvic surgery | 23 (38.3) | 23 (36.5) | .834 |
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