Secondary Logo

Journal Logo

Contents: Urogynecology: Original Research

Intravenous Acetaminophen Before Pelvic Organ Prolapse Repair

A Randomized Controlled Trial

Turner, Lindsay C. MD, MSc; Zyczynski, Halina M. MD; Shepherd, Jonathan P. MD, MSc

Author Information
doi: 10.1097/AOG.0000000000003102
  • Free

Pelvic organ prolapse (POP) is common, and women have a 12.6% lifetime risk of undergoing surgical repair to correct this condition.1 Older women tend to seek care more often than their younger counterparts.2 This is particularly relevant because the world population is rapidly aging, with 27% of the population estimated to be older than 60 years of age.3 In the United States, the population of 65 and older grew by 1.6 million since 2014.4 With such a significant increase in the number of elderly women, a large number are projected to undergo surgical repair of POP. Therefore, it is of particular importance to safely and effectively treat postoperative pain.

Preemptive analgesia involves introduction of pain medication regimens before a noxious stimulus (such as a surgical incision) to prevent amplification of pain by the nervous system.5 Enhanced recovery after surgery (ERAS) pathways using preoperative oral gabapentin, diclofenac, and acetaminophen along with preprocedure carbohydrate-loading and elimination of bowel preparation have resulted in significant improvements in recovery time, decreased pain, and reduced opioid use.6 Although nonsteroidal antiinflammatory drugs would be ideal for this indication owing to their reduction in pain and inflammation, they are used with caution in elderly patients because of interference with platelet and kidney function.7 There is no current standard of care for preemptive analgesia.

Acetaminophen administered via the intravenous (IV) route was approved for use in the United States in 2010.8 The recommended adult dosing is 1,000 mg IV administered every 6 hours, with a half-life of 2.4 hours.9 Compared with oral and rectal administration, IV acetaminophen has the shortest time to maximum blood concentration (15 minutes),9 highest plasma maximum concentrations,10 and highest postoperative plasma concentrations.11 Despite the fact that it has demonstrated effective postoperative analgesia across a wide variety of surgical procedures including gynecology, general surgery, orthopedics and ophthalmology,12,13 IV acetaminophen has not been well studied as single-agent preemptive analgesia. Studies to date in the obstetrics and gynecology literature report conflicting effects of preemptive acetaminophen.14–16 We sought to study the effect of preemptive IV acetaminophen in women undergoing surgical repair of POP. The objective of this study was to quantify the change in postoperative pain scores and narcotic requirements in patients receiving preemptive analgesia with IV acetaminophen compared with placebo. We hypothesized that women receiving preemptive IV acetaminophen before surgical correction of POP would have improved postoperative pain scores and reduced narcotic requirements, which may result in higher patient satisfaction, quality of life (QOL), and less postoperative side effects.

METHODS

Women were recruited at the University of Pittsburgh Medical Center and the Allegheny Health Network from July 2014 to August 2017. Women who were at least 18 years old and were planning minimally invasive surgery (vaginal, laparoscopic or robotic route) for symptomatic prolapse were eligible for recruitment if their anticipated hospital stay was at least 24 hours. Exclusion criteria included an allergy or intolerance to acetaminophen, hepatic dysfunction, or significant alcohol use—defined as patient-reported consumption of more than seven standard drinks per week or three drinks per day. This study was approved by the University of Pittsburgh and Allegheny Health Network institutional review boards and was registered on clinicaltrials.gov. The primary outcome was the change from baseline in patient-reported visual analog scale (VAS) pain scores at 24 hours after surgery. This was chosen as the primary outcome because of its use in prior studies of IV acetaminophen12 and ease of completion and scoring.17 Secondary outcomes included narcotic requirements, patient satisfaction, QOL, and postoperative side effects.

Patients were recruited from the outpatient urogynecology offices of the University of Pittsburgh Medical Center (192 participants) and the Allegheny Health Network (12 participants). Seven female pelvic medicine and reconstructive surgery physicians participated in the study. Stratified randomization was performed on the day of surgery in a 1:1 ratio using computer-generated fixed blocks of four stratified by surgical route (vaginal vs laparoscopic). Randomization was stratified by procedure type because it is likely that postoperative pain may vary by the type of incision (vaginal vs laparoscopic). Allocation concealment was maintained by the operating room pharmacist. The investigators as well as the surgical and anesthesia teams were blinded to the randomization sequence. The randomization log was maintained by the investigational pharmacist. Study drug and placebo were prepared by the operating room pharmacist and placed in identical appearing 250 cc glass bottles to maintain blinding of the physicians and research team. Bottles contained either 100 mL of acetaminophen (1,000 mg/100 mL) or sodium chloride 0.9%. Study drug was administered intravenously by preoperative nurses 10–30 minutes before incision on the day of surgery. No other preoperative pain medications were routinely administered to either group as part of ERAS pathways.

After obtaining informed consent, baseline information was collected including age, race–ethnicity, general past medical history, parity, tobacco use, and current medications. Objective measurements including height, weight, body mass index (BMI, calculated as weight in kilograms divided by height in meters squared), and prolapse stage were collected from the electronic medical record (EMR). In the preoperative holding area, patients were instructed on how to record VAS pain scores and a baseline preoperative VAS pain score was completed (range 0–100 mm). A member of the anesthesia team recorded surgery start time, incision time, surgery end time, and anesthesia end time as well as medications given for induction, maintenance, reversal, and pain. Postoperatively, surgeons identified all procedures that were performed, amount and type of local anesthetic, estimated blood loss, urine output, IV fluids, and any complications. Visual analog scale pain scores were obtained every 4 hours throughout the first 24 hours of in-hospital recovery. Pain scores were independently performed by the patient. If the patient was discharged before the 24-hour time, she was sent home with VAS pain scores to complete and return via mail. Patients then were monitored for a total of 7 days. Dosages of narcotic and nonnarcotic pain medications were abstracted from the EMR. At discharge, patients were given a 7-day diary to record the time and dosage of all pain medications used (narcotic and nonnarcotic) and were instructed to return this via mail. Narcotics were converted to morphine milligram equivalents using published conversion tables.18

Twenty-four hours after surgery, patients completed the American Pain Society Patient Outcome Questionnaire. This is a validated questionnaire used to assess QOL and satisfaction with pain control over the 24 hours after an operation. It is preferred over more global measures of QOL because it is validated for acute pain in the setting of recent surgery. This questionnaire was designed to assess satisfaction with pain control and effect of pain on mood and emotional well-being. It contains 12 items across six subscales: pain severity and relief, effect of pain on mood–emotions, adverse effects, satisfaction, participation in decision making, and nonpharmacologic methods of pain management.19 Interference of pain with physical, mental, and social activities was measured using the Patient-Reported Outcomes Measurement Information System–Pain Interference Short Form, which is a patient-reported outcomes measure that queries the interference of pain over the previous week across eight items. Scores on this questionnaire range from 8 to 40, with higher scores indicating more interference of pain in activities of daily living.20 Patients completed this form at home on the 7th day after their surgery and returned it via mail.

Side effects were queried using the American Pain Society Patient Outcome Questionnaire, which contains four items on the side effects of pain medication including nausea, drowsiness, itchiness, and dizziness (items 6a-d). Respondents used a rating scale of 0–10 to indicate the severity of each side effect. Postoperative constipation was assessed using a bowel diary, which included the date and time of all bowel movements during the first postoperative week, and the classification of the stool using the Bristol Stool Scale.21 Validated measures of constipation are complicated by the fact that most are validated for chronic constipation.22 Therefore, we chose to survey constipation through the use of a self-reported bowel diary through postoperative day 7. Additionally, patients were asked to record all bowel medications used in the week after surgery. Surgical and postoperative complications were reviewed from the EMR for a period of 30 days postoperatively. Specifically, readmissions or telephone calls to the office for poor pain control or constipation were extracted.

Categorical data were expressed as n (%), parametric continuous data were expressed as mean±SD, and nonparametric continuous data were expressed as median and interquartile range. Because route of surgery likely contributes to the amount of postoperative pain, analyses were stratified by vaginal and laparoscopic–robotic surgery. Continuous variables including VAS pain scores and narcotic requirements measured in morphine milligram equivalents were compared by t tests. Both primary and secondary outcomes were compared in an intention-to-treat analysis. Univariable and multivariable logistic regression analyses were planned to identify independent risk factors that predict pain at 24 hours postoperatively. Two sample t tests were used to analyze results of individual American Pain Society Patient Outcome Questionnaire items and Patient-Reported Outcomes Measurement Information System–Pain Interference Short Form scores. The severity of side effects, as measured by the American Pain Society Patient Outcome Questionnaire adverse effects subscale (items 6a-d), were compared between IV acetaminophen and placebo groups using t tests. Constipation, measured in time (days) since surgery to first bowel movement, was compared between the groups. Two-tailed tests of significance are reported, and P<0.05 was considered significant.

There is a paucity of information on mean VAS pain scores on postoperative day 1 after gynecologic surgery. Mean±SD 24-hour VAS pain scores after robotic sacral colpopexy have been published (44.0±20.8 mm),23 and VAS pain scores at 24 hours after vaginal prolapse repair are also available (19.3±14.8 mm).24 Previous studies of adult emergency department patients demonstrated a minimally clinically significant difference in VAS pain scores of 9, 12, and 18 mm.25–27 Unfortunately, minimally clinically significant differences have not been calculated in a gynecologic or urogynecologic surgical population. For this sample size analysis, we chose a minimally clinically significant difference in VAS pain score of 12 mm, as this is the median value of previously published values. We powered this study to detect a difference in mean change from baseline in VAS pain scores in both the vaginal and laparoscopic–robotic surgery groups. We performed separate sample size analyses using the larger of the two SDs (20.8 mm) from previously published studies of robotic and vaginal surgery to assure that there would be appropriate power to detect a difference in pain scores within each surgical route.23,24 Assuming a two-sided alpha of 0.05, 48 women in each group (laparoscopic acetaminophen, laparoscopic placebo, vaginal acetaminophen and vaginal placebo) would provide 80% power to detect a clinically significant difference in VAS pain scores after surgery in those receiving IV acetaminophen compared with placebo. After adjusting for a 5% loss to follow-up rate, 102 women undergoing laparoscopic–robotic surgery and 102 undergoing vaginal surgery were needed for a total of 204 patients. Therefore, this study was separately powered to detect differences within each surgical group (laparoscopic or vaginal). Statistical analyses were performed using IBM SPSS 24.0.

Authors' Data Sharing Statement

  • Will individual participant data be available (including data dictionaries)? No.
  • What data in particular will be shared: Not available.
  • What other documents will be available? Not available.
  • When will data be available (start and end dates)? Not applicable.
  • By what access criteria will data be shared (including with whom, for what types of analyses, and by what mechanism)? Not applicable.

RESULTS

A total of 204 patients were enrolled between July 2014 and August 2017. One patient was withdrawn owing to a lack of documentation from the pharmacy regarding allocation assignment, and one was withdrawn after her consent form was misplaced (Fig. 1). The remaining 202 women were randomized to IV acetaminophen (n=102; vaginal n=52, laparoscopic n=50), and placebo (n=100; vaginal n=49, laparoscopic n=51). Of those undergoing laparoscopic surgery, 25 patients (acetaminophen n=13, placebo n=12) underwent a robotic-assisted procedure, the remaining patients underwent traditional straight-stick laparoscopy. Three patients requested withdrawal from the study after allocation (acetaminophen n=2; placebo n=1). One patient in the IV acetaminophen group was withdrawn after her procedure was aborted before surgical incision owing to sustained ventricular tachycardia in the operating room. One patient in the laparoscopic placebo arm was converted to a vaginal sacrospinous ligament fixation secondary to dense pelvic adhesions diagnosed at time of laparoscopy. Data from 202 women were analyzed in an intention-to-treat fashion.

Fig. 1.
Fig. 1.:
Flow diagram.Turner. Intravenous Acetaminophen Before Prolapse Repair. Obstet Gynecol 2019.

Overall, the majority of patients were Caucasian (95.6%) and postmenopausal (96.3%), with a mean (±SD) age of 65.5±9.9 years and mean BMI of 27.8±4.3. Baseline characteristics, concomitant operative procedures, and intraoperative factors for the vaginal and laparoscopic arms are shown in Tables 1 and 2, respectively. In the vaginal surgery group, the majority of women underwent obliterative surgery (n=46, 45.5%) or native tissue apical suspension to the uterosacral ligament or sacrospinous ligament (n=44, 43.6%). Only eight women underwent vaginal mesh procedures. Concomitant vaginal hysterectomy was performed in 53 patients (52.4%). The majority of women undergoing laparoscopic surgery underwent sacral colpopexy (n=90, 89.1%) and nine underwent native tissue repair (8.9%). Concomitant laparoscopic hysterectomy (supracervical and total) was performed in 67 patients (66.3%). Among those patients undergoing surgery by vaginal route, there were no significant differences between those receiving IV acetaminophen and those receiving placebo, with the exception that more patients in the placebo group had a concomitant posterior repair (59.2% vs 36.5%, P=.02) compared with the IV acetaminophen group. Among those patients undergoing laparoscopic surgery, preoperative prolapse stage differed significantly between groups (P=.04).

Table 1.
Table 1.:
Baseline and Intraoperative Characteristics—Vaginal Surgery Group (n=101)
Table 2.
Table 2.:
Baseline and Intraoperative Characteristics—Laparoscopic Surgery Group (n=101)

The change from baseline in VAS pain score at 24 hours was available for 162 patients (laparoscopic acetaminophen n=36, placebo n=41, vaginal acetaminophen n=41, placebo n=44) (missing in 15 patients receiving placebo [vaginal n=5, laparoscopic n=10] and 25 receiving IV acetaminophen [vaginal n=11, laparoscopic n=14]). The overall, mean 24-hour VAS pain score in the acetaminophen group was 30.5±23.7 mm and in the placebo group was 27.1±22.3 mm (P=.36). When stratified by route, mean 24-hour VAS pain scores were 30.5±26.0 mm for vaginal surgery and 26.9±19.3 mm for laparoscopic (P=.32). There were no significant overall or route of surgery differences in mean change from baseline pain scores at 24 hours postoperatively between acetaminophen and placebo (overall 25±26 vs 21±24 mm; vaginal 29±28 vs 21±23 mm; laparoscopic 20±26 vs 21±25 mm) (Table 3). Additionally, no differences were seen in change from baseline in VAS pain score for any other time point within the first 24 hours (data not shown).

Table 3.
Table 3.:
Visual Analog Scale Pain Scores, Narcotic Requirements, and Quality of Life Outcomes

Data on narcotics received during the hospitalization were available for all 202 patients. There were no overall or surgical group differences in total 24-hour narcotic use measured in morphine milligram equivalents between acetaminophen and placebo (overall 37.9±24.7 vs 40.1±25.4 mg, P=.54) even after stratifying by route of surgery (vaginal 31.6±23.6 vs 32.5±24.7 mg, P=.85; laparoscopic 44.5±24.2 vs 47.4±24.2 mg, P=.55) (Table 3). Similarly, narcotic requirements did not differ between groups, even after excluding narcotics received intraoperatively (Table 3). There was no difference between groups in dose of nonnarcotic pain medications during the first 24 hours after surgery, including acetaminophen, ibuprofen and ketorolac. Owing to a lack of significant differences between groups with respect to VAS pain scores and narcotic requirements, regression analyses to evaluate predictors of pain at 24 hours were not performed.

Pain diaries were completed by 155 patients (76.7%), with 18 women in the placebo group and 29 in the IV acetaminophen group failing to return the diaries. There was no significant difference in narcotic use throughout the first week postoperative as measured by the 7-day pain diary (Table 3). The median number of narcotic tablets prescribed to patients at time of discharge was 30 (range 0–50). At the end of the 7-day dairy, the median number of leftover narcotic tablets was 26 (range 0–49). This amounts to only 23.4% of all narcotic pills being consumed by patients by the end of the 7-day diary.

A total of 170 patients completed the American Pain Society Patient Outcome Questionnaire questionnaires (80 acetaminophen and 90 placebo). There were no differences in individual item scores on any questions on the American Pain Society Patient Outcome Questionnaire between the groups (data not shown). A total of 158 patients completed the Patient-Reported Outcomes Measurement Information System–Pain Interference Short Form questionnaire (73 acetaminophen and 85 placebo). No differences were seen between the two groups (Table 3).

No differences were seen in side effects of nausea, drowsiness, itching or dizziness on the American Pain Society Patient Outcome Questionnaire between groups (data not shown). Urinary retention occurred in 15 women undergoing laparoscopic surgery and in 44 undergoing vaginal surgery. Rates were similar between acetaminophen and placebo among those undergoing laparoscopic surgery (10.4% vs 20.0%, P=.19); however, rates of urinary retention were significantly higher among those receiving acetaminophen in the vaginal arm (59.2% vs 33.3%, P=.01). In an unplanned logistic regression analysis of those women undergoing vaginal surgery, IV acetaminophen remained a significant predicator of urinary retention even after controlling for known contributors of urinary retention including total 24-hour narcotic requirements (morphine milligram equivalents), urine output and IV fluids (P=.01, OR 3.5, 95% CI 1.4–8.7). When posterior repair was added to the model because the number of women undergoing this concomitant procedure differed at baseline, IV acetaminophen again remained a significant predictor of postoperative urinary retention (P=.003, OR 4.3, 95% CI 1.6–11.6).

Bowel diaries were completed by 155 patients (76.7%) with 18 women in the placebo group and 29 in the IV acetaminophen group failing to return the diaries. Median time to first bowel movement was 3 days for both the laparoscopic and vaginal routes (interquartile range 2–4 days). There was no difference in the total number of bowel movements recorded on the 7-day postoperative diary between those receiving acetaminophen or placebo (data not shown).

Postoperative phone calls related to pain, constipation, nausea, and vomiting were similar between groups (acetaminophen n=5, placebo n=5, P=.95). Readmission rates were similar between groups (acetaminophen n=4, placebo n=1, P=.37). In the IV acetaminophen group, the diagnoses at time of readmission included hydroureter, pulmonary embolism, partial small bowel obstruction, and urinary retention related to severe constipation. The patient readmitted from the placebo group was diagnosed with a diverticulitis flare.

DISCUSSION

This double-blind, randomized placebo-controlled trial of preemptive IV acetaminophen did not demonstrate a difference in 24-hour VAS pain scores, narcotic consumption, or patient satisfaction in women undergoing vaginal or laparoscopic pelvic reconstructive surgery. Side effects were similar between groups, with the exception of increased urinary retention among women receiving acetaminophen in the vaginal arm. Return of bowel function was no different between groups.

Previous studies of preemptive analgesia with a single dose of IV acetaminophen have been completed in women undergoing open abdominal hysterectomy14,15 and cesarean delivery.16 In women undergoing abdominal hysterectomy, a 2009 study reported that preemptive IV acetaminophen significantly lowered 24-hour postoperative pain scores at rest and with movement when compared with placebo.14 However, in a 2011 study, there was no significant difference in pain scores at rest or with movement between acetaminophen and placebo.15 Interestingly, both studies reported significantly lower postoperative opioid narcotic consumption in the IV acetaminophen group compared with placebo. In women undergoing cesarean delivery, preemptive IV acetaminophen did not significantly reduce postoperative opioid narcotic consumption, pain scores, or length of stay as compared with placebo.16

A PubMed search was conducted from 1966 to August 2018 using key terms such as “acetaminophen,” “paracetamol” and “gynecology.” We were not able to locate studies of single dose IV acetaminophen that have been performed in women undergoing pelvic reconstructive surgery; however, a combination of preoperative and postoperative IV acetaminophen has been studied in a urogynecologic population undergoing vaginal reconstructive surgery.28 In that double-blind study, 90 patients were randomized to either placebo (saline) or 1,000 mg of IV acetaminophen which was administered within 60 minutes of anesthesia and then at six hours intervals postoperatively for a total of four doses. Similar to our study, no significant differences were seen in narcotic requirements, postoperative VAS pain scores, satisfaction, or side effects between those receiving IV acetaminophen or placebo. One explanation posited by these authors is the minimally invasive nature of urogynecologic procedures may result in postoperative pain scores which may not be high enough to demonstrate a significant effect with IV acetaminophen. However, power calculations for this study were based on previously reported mean VAS pain scores from robotic and vaginal pelvic reconstructive surgery. In our study, mean 24-hour VAS pain scores for vaginal procedures were slightly higher than those previously reported by Roovers et al (19.3±14.8 mm).24 Women undergoing laparoscopic surgery in our study had slightly lower VAS pain scores than those previously reported by Collins et al in women undergoing robotic sacral colpopexy (44.0±20.8 mm).23 Narcotic consumption is difficult to compare with prior studies in female pelvic reconstructive surgery owing to the variability in morphine milligram equivalent conversion factors and time points at which this was assessed28–30; in general, narcotic use was relatively low in this study. Ultimately, comparison of our primary and secondary outcomes to other studies is limited by the lack of available data on single dose IV acetaminophen in a urogynecology population.

More recently, postoperative narcotic use has been associated with long-term continuation of opioids, with approximately 3% of patients requiring opioids for more than 90 days after major elective surgery.31 In a recent cross-sectional survey administered to a national sample of American College and Obstetricians and Gynecologists fellows and junior fellows, 179 obstetrician-gynecologists responding to the survey (60%) reported prescribing a median of 25 (range 6–60) opioid pills per patient for minimally invasive surgeries such as laparoscopic and vaginal hysterectomy.32 In our study, the median number of prescribed opioid pills was 30, which is slightly higher than reported in the American College and Obstetricians and Gynecologists survey. Similar to previous studies of cesarean delivery and hysterectomy for benign indications, our study demonstrated excessive prescribing of opioids for postoperative pain control.33,34 By postoperative day 7, patients in this study had consumed only 23.4% of prescribed narcotics. Although this data is limited by patient reporting bias, and not all patients returned pain diaries, it is still concerning given the potential for opioid addiction and misuse, distribution of unused tablets into the community and escalation to illicit drug use.35

In this study, there were no significant differences in side effects of constipation, nausea, drowsiness, itching, and dizziness; however, more patients experienced urinary retention in the vaginal arm receiving IV acetaminophen. This finding has not been demonstrated in prior studies of acetaminophen. In a metanalysis of randomized controlled trials that compared morphine patient-controlled analgesia with morphine patient-controlled analgesia in addition to IV or oral acetaminophen, no differences were seen in nausea, sedation, retention, pruritus, or respiratory depression.36 Because increased narcotic use is associated with urinary retention,37 it would be hypothesized that preemptive analgesia such as IV acetaminophen would decrease instead of increase rates of urinary retention. The increased rates of urinary retention with IV acetaminophen in women undergoing vaginal surgery are surprising, because more women in the placebo group underwent posterior repair, which historically has been thought to increase risks of postoperative urinary retention.38 One explanation for this finding is the medium in which IV acetaminophen is suspended. Per the package label, IV acetaminophen is suspended in 3,850 mg mannitol.9 This dose of diuretic could potentially lead to increased urine output and contribute to increased bladder distention. However, in our study intraoperative urine output was similar between groups. Even after correcting for narcotic requirements, urine output, and intraoperative IV fluids, IV acetaminophen remained a significant predictor of urinary retention. Further study of this interaction is needed.

Although preoperative IV acetaminophen is included in many extended recovery pathways owing to its improvement in pain scores and reduction in narcotic use after many other types of procedures, the use of IV acetaminophen alone before surgery for POP is not supported by this study. Perhaps when used in conjunction with other principals of extended recovery, it may improve pain or reduce narcotic use in a urogynecology population. In a trial of women undergoing pelvic reconstructive surgery, 70 women were randomized to usual care or multimodal pain regimens, which included preoperative and postoperative celecoxib, gabapentin, IV and oral acetaminophen, ibuprofen, and narcotics. Compared with placebo, women receiving multi-modal pain regimens required less narcotics postoperatively. However, similar to our study, no significant differences in postoperative day 1 pain scores, side effects, or length of stay were demonstrated, which may be related to the minimally invasive nature of procedures performed in these studies.29

The IV formulation of acetaminophen for prevention of pain amplification was selected owing to its quick onset of action and high plasma maximum concentration compared with oral and rectal administration9,10; however it should be noted that IV acetaminophen is considerably more expensive than oral formulations with an average wholesale cost of $48/1,000-mg dose in comparison with $0.02–$0.16/1,000-mg tablet.39 Oral acetaminophen in conjunction with gabapentin, ketamine and dexamethasone has demonstrated a reduction in pain scores and narcotic use in a population of patients undergoing anorectal surgery,40 and in conjunction with gabapentin and diclofenac has resulted in lower pain scores and opiate use in women undergoing gynecologic oncology surgery,6 but to our knowledge has not been studied as a single agent preemptive analgesic in women undergoing gynecologic surgery. Although oral acetaminophen is a cheaper alternative to IV acetaminophen and a likely effective component of multi-modal ERAS pathways, we chose to use IV acetaminophen in this study given its quicker onset in a setting where highest tissue concentrations were prudent for prevention of pain amplification.

Strengths of this study include the randomized placebo-controlled design that accounted for both routes of urogynecologic surgery—laparoscopic and vaginal. Additional strengths include the use of patient centric satisfaction questionnaires and nonstandardized postoperative care, such as patient and provider driven postoperative pain and bowel regimens. The use of a more pragmatic design, multiple surgeons and institutions, and minimal exclusion criteria make our results more generalizable. It should be noted; however, that the majority of patients were recruited from one institution and that the population was quite homogenous with 96% of patients being Caucasian and postmenopausal.

Limitations of the study include missing primary outcome data for 40 patients and the lack of consistency in patient completion of postoperative bowel and pain diaries. Our initial power calculation assumed a 5% loss to follow-up. Because the actual loss to follow-up exceeded this, the lack of primary outcome data decreases the power of the study to detect a difference between IV acetaminophen and placebo. However, when the vaginal and laparoscopic surgery groups were combined (Table 3), statistical power was met and there continued to be no difference between IV acetaminophen and placebo groups. The study was conducted before institutional adoption of ERAS clinical pathways. As such, the intraoperative and postoperative care teams were less sensitized to the current agenda of reducing opioids in both settings. The study protocol did not proscribe parameters for opioid administration, and as such, standard practices may have blunted differences in observed outcomes. Current ERAS protocols include multi-modal, nonnarcotic preemptive medications that commonly include acetaminophen. It is possible that together they have a synergistic effect that we were unable to quantify.

In conclusion, in women undergoing vaginal and laparoscopic prolapse repair, preoperative IV acetaminophen alone did not reduce pain scores or overall opioid use and had no effect on patient satisfaction or QOL measures when compared with placebo. Owing to its lack of clinical benefit, routine use of IV acetaminophen as the sole preemptive analgesia agent is not supported by this study. Further study of preemptive acetaminophen is warranted when used in combination with other principles of ERAS pathways in a urogynecologic population.

REFERENCES

1. Wu JM, Matthews C, Conover MM, Pate V, Funk MJ. Lifetime risk of stress incontinence or pelvic organ prolapse surgery. Obstet Gynecol 2014;123:1201–6.
2. Luber KM, Boero S, Choe JY. The demographics of pelvic floor disorders: current observations and future projections. Am J Obstet Gynecol 2001;184:1496–501.
3. United Nations. Population ageing and development 2012. Available at: http://www.un.org/en/development/desa/population/publications/pdf/ageing/2012PopAgeingandDev_WallChart.pdf. Retrieved July 10, 2013.
4. United States Census Bureau. Facts for features: older Americans month: May 2017. Available at: https://www.census.gov/newsroom/facts-for-features/2017/cb17-ff08.html. Retrieved July 26, 2018.
5. Gottshalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician 2001;63:1979–84.
6. Chapman JS, Roddy E, Ueda S, Brooks R, Chen L, Chen L. Enhanced recovery pathways for improving outcomes after minimally invasive gynecologic oncology surgery. Obstet Gynecol 2016;128:138–44.
7. Park KE, Qin Y, Bavry AA. Non-steroidal anti-inflammatory drugs and their effects in the elderly. Aging Health 2012;8:167–77.
8. U.S. Food and Drug Administration. FDA approved drug products. Available at: https://na01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.accessdata.fda.gov%2Fscripts%2Fcder%2Fdaf%2Findex.cfm%3Fevent%3Doverview.process%26ApplNo%3D022450&data=02%7C01%7Cemily.moore%40wolterskluwer.com%7Cc25367ea305c4073b3e508d677289937%7C8ac76c91e7f141ffa89c3553b2da2c17%7C0%7C0%7C636827413590797701&sdata=tz8kBpLWveYoKUDrE%2B%2BT2kmH%2F5f477RU0ma%2B48OPma8%3D&reserved=0. Retrieved July 26, 2018.
9. U.S. Food and Drug Administration. OFIRMEV: highlights of prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022450lbl.pdf. Retrieved July 26, 2018.
10. Singla NK, Parulan C, Samson R, Hutchinson J, Bushnell R, Beja EG, et al. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral or rectal acetaminophen. Pain Pract 2012;12:523–32.
11. Brett CN, Barnett SG, Pearson J. Postoperative plasma paracetamol levels following oral or intravenous paracetamol administration: a double-blind randomized controlled trial. Anaesth Intensive Care 2012;40:166–71.
12. Marcario A, Royal MA. A literature review of randomized clinical trials of intravenous acetaminophen for acute postoperative pain. Pain Pract 2011;11:290–6.
13. Altenau B, Crisp CC, Deviaiah CG, Lambers DS. Randomized controlled trial of intravenous acetaminophen for postcesarean delivery pain control. Am J Obstet Gynecol 2017;217:362.e1–6.
14. Arici A, Gurbet A, Turker G, Yavascaoglu B, Sahin S. Preemptive analgesic effects of intravenous paracetamol in total abdominal hysterectomy. Agri 2009;21:54–61.
15. Moon YE, Lee YK, Lee J, Moon DE. The effects of preoperative intravenous acetaminophen in patients undergoing abdominal hysterectomy. Arch Gynecol Obstet 2011;284:1455–60.
16. Towers CV, Shelton S, van Nes J, Gregory E, Liske E, Smalley A, et al. Preoperative cesarean delivery intravenous acetaminophen treatment for postoperative pain control: a randomized double-blinded placebo control trial. Am J Obstet Gynecol 2018;353:e1–4.
17. McCormack HM, Horne JD, Sheather S. Clinical applications of visual analogue scales: a critical review. Psychol Med 1988;18:1007–19.
18. Johns Hopkins Medicine. Hopkins opioid program. Available at: https://www.hopkinsmedicine.org/apps/all-apps/hopkins-opioid-program. Retrieved July 26, 2018.
19. Gordan DB, Polomano RC, Pellino TA, Turk DC, McCracken LM, Sherwood G, et al. Revised American Pain society Patient Outcome Questionnaire (APS-POQ-R) for quality improvement of pain management in hospitalized adults: preliminary pyschometric evaluation. J Pain 2010;11:1172–86.
20. Amtmann D, Cook FK, Jensen MP, Chen WH, ChoiI S, Rervicki D, et al. Development of a PROMIS item bank to measure pain interference. Pain 2010;150:173–82.
21. Probert CJ, Emmett PM, Heaton KW. Intestinal transit time in the population calculated from self made observations of defecation. J Epidemiol Community Health 1993;47:331–3.
22. McCrea GL, Miaskowski C, Stotts NA, Macera L, Hart SA, Varma MG. Review article: self-report measures to evaluate constipation. Aliment Pharmacol Ther 2008;27:638–48.
23. Collins SA, Tulikangas PK, OSuliivan DM. Effect of surgical approach on physical activity and pain control after sacral colpopexy. Am J Obstet Gynecol 2012;206:438.e1–6.
24. Roovers JP, Bom JG, Vaart CH, Shagen van Leeuwen JH, Scholten PC, Heintz AP. A randomized comparison of post-operative pain, quality of life, and physical performance during the first six weeks after abdominal or vaginal surgical correction of descensus uteri. Neurourology and Urodynamics 2005;24:334–40.
25. Kelly AM. Does the clinically significant difference in visual analog scale pain scores vary with gender, age, or cause of pain? Acad Emerg Med 1998;5:1086–90.
26. Kelly AM. The minimum clinically significant difference in visual analogue scale pain score dose not differ with severity of pain. Emerg Med J 2001;18:205–7.
27. Todd KH, Funk JP. The minimum clinically important difference in physician-assigned visual analog pain scores. Acad Emerg Med 1996;3:142–6.
28. Crisp CC, Khan M, Lambers DL, Westermann LB, Mazloomdoost DM, Yeung JJ, et al. The effect of intravenous acetaminophen on postoperative pain and narcotic consumption after vaginal reconstructive surgery: a double-blind randomized placebo-controlled trial. Female Pelvic Med Reconstr Surg 2017;23:80–5.
29. Reagan KML, O'Sullivan DM, Gannon R, Steinberg AC. Decreasing postoperative narcotics in reconstructive pelvic surgery: a randomized controlled trial. Am J Obstet Gynecol 2017;217:325.e1–10.
30. Yeung J, Cirsp CC, Mazloomdoost D, Kleeman SD, Pauls RN. Liposomal bupivacaine during robotic colpopexy and posterior repair. Obstet Gynecol 2018;131:39-46.
31. Clarke H, Soneji N, Ko DT, Yun L, Wijeysundera DN. Rates and risk factors for prolonged opioid use after major surgery: population based cohort study. BMJ 2014;348:g1251.
32. Madsen AM, Start LM, Has P, Emerson JB, Schulkin J, Matteson KA. Opioid knowledge and prescribing practices among obstetrician-gynecologists. Obstet Gynecol 2018;131:150–7.
33. Osmudson SS, Schomack LA, Grasch JL, Zuckerwise LC, Young JL, Richardson MG. Postdischarge opioid use after cesarean delivery. Obstet Gynecol 2017;130:36–41.
34. As-Sanie S, Till SR, Mowers EL, Lim CS, Skinner BD, Fritsch L, et al. Opioid prescribing patterns, patient use, and postoperative pain after hysterectomy for benign indications. Obstet Gynecol 2017;130:1261–8.
35. Theisen K, Jacobs B, Macleod L, Davies B. The United States opioid epidemic: a review of the surgeon's contribution to it and health policy initiatives. BJU Int 2018;122:754–9.
36. Remy C, Marret E, Bonnet F. Effects of acetaminophen on morphine side-effects and consumption after major surgery: meta-analysis of randomized controlled trials. Br J Anaesth 2005;94:505–13.
37. Patel JA, Kaufman AS, Howard RS, Rodriguez CJ, Jessie EM. Risk factors for urinary retention after laparoscopic inguinal hernia repairs. Surg Endosc 2015;29:3140–5.
38. Book NM, Novi B, Novi JM, Pulvino JQ. Postoperative voiding dysfunction following posterior colporrhaphy. Female Pelvic Med Reconstr Surg 2012;18:32–4.
39. Lexicomp Clinical Drug Information. Available at: https://online.lexi.com/lco/action/doc/rectrieve/docid/patch_f/6264. Retrieved November 23, 2018.
40. Van Backer JT, Jordan MR, Leahy DT, Moore JS, Callas P, Dominick T, et al. Preemptive analgesia decreases pain following anorectal surgery: a prospective, randomized, double-blinded, placebo-controlled trial. Dis Colon Rectum 2018;61:824–29.
Figure
Figure

Supplemental Digital Content

© 2019 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.