Ureteroscopy is one of the most frequently performed procedures in urology. Pain leading to unplanned visits and persistent opioid use (approximately 6% of opioid-naïve patients will become new persistent opioid users after ureteroscopy) represents a significant burden after this procedure.^1-3

Gabapentenoids (gabapentin and pregabalin) have been shown to be beneficial adjuncts in multimodal regimens to prevent and treat postoperative pain in multiple surgical specialties.⁴ Enhanced recovery after surgery protocols in ureteroscopy have begun to employ gabapentinoids, though assessment of use in this specific arena is limited, and no prior work independently evaluates the role of single-dose perioperative gabapentinoid in ureteroscopy.^5,6

We performed a blinded, placebo-controlled, randomized trial evaluating the use of single-dose perioperative pregabalin in ureteroscopy, hypothesizing that this would decrease postoperative pain without significantly increasing adverse events.⁷

After approval by our Institutional Review Board (IRB No. MU2017676) and trial registration (ClinicalTrials.gov, NCT04122196), we enrolled 118 patients undergoing ureteroscopy for any indication from June 2020 to July 2022 at a single institution. We excluded patients with renal insufficiency, chronic indwelling ureteral stent (>30 days), or history of chronic opioid or gabapentinoid use. The study was powered at 80% to detect a difference in visual analogue scale (VAS) of 1 unit between groups with a significance level of .05.

Participants were randomized on the day of surgery and were administered either pregabalin 300 mg or identical placebo by mouth with a sip of water 1 hour before predicted surgical start time. Blinding of all research and clinical staff as well as patients was maintained until assessment of the primary outcome was completed.

Prior to medication administration, patients were asked to complete a VAS of pain and a Watson clock drawing test. Patients repeated the VAS and Watson test 1 hour after arriving in the postanesthesia care unit. Follow-up questionnaires were distributed via email at 3, 7, and 30 days after their procedure.

The primary outcome was postoperative pain (VAS in postanesthesia care unit), and secondary outcomes included Watson clock test scores, opioid prescribing, and clinical outcomes in the 30 days following surgery.

Most of the patients (92%) underwent ureteroscopy for urolithiasis, and 79% of patients had a stent placed. The groups who received placebo and pregabalin were well matched with respect to clinical and demographic factors other than age, with those who received placebo being older than those who received pregabalin (median 57 vs 44 years).

Contrary to our hypothesis, postoperative pain was found to be higher in the group that received pregabalin (placebo median [IQR]: 2.0 [0.6,4.2], pregabalin: 3.7 [1.5,6.3], mean difference [95% CI] 1.4 [0.5-2.4], P = .004; see Figure). There was no statistically significant difference in postoperative Watson clock test scores (P = .8). The rate of adverse events was similar in both groups (P = .7).

Figure. Change in pain score from pre- to postoperatively for those getting placebo (A) and pregabalin (B). Dashed line represents the median change in each group.

While there was no difference in satisfaction with pain control 3 days or 30 days after surgery, it was significantly higher at postoperative day 7 among those receiving pregabalin (P = .01). However, VAS of pain was similar between the 2 groups at all time points. Oral morphine equivalents prescribed in the 30 days following surgery were similar between those in the pregabalin and placebo groups (median 90 vs 110 placebo and pregabalin). Nine (15%) patients who received placebo and 10 (17%) who received pregabalin had an emergency department visit or admission in the first 30 postoperative days. This totaled 29 visits in which 23 were for chief concern of pain. Sixteen (27%) patients who received placebo and 8 (14%) of those who received pregabalin (P = .06) had an unplanned interaction with the urology team (outside of an emergency department visit or admission), 15 of which were regarding pain.

Given the difference in age between the groups, we performed post hoc analyses controlling for age and other predictors. ANCOVA demonstrated that there continued to be a statistically significantly higher VAS among those who received pregabalin (adjusted P = .02, coefficient 1.1 [0.1-2.0]), accounting for patient age and preoperative VAS. Accounting for these variables, there continued to be no statistically significant difference in VAS at postoperative day 3 (adjusted P = .8), postoperative day 7(adjusted P = .8), or postoperative day 30 (adjusted P = .6). Accounting for age and preoperative Watson test score, there was no statistically significant difference in postoperative Watson test scores (adjusted P = .8).

This was a single-center pragmatic study, which may limit applicability at other centers that use different anesthetic regimens. Age was unbalanced between the groups. In ureteroscopy, younger age has been shown to be associated with increased postoperative pain, with a 0.4-point difference for every 10 years of age.⁸ Therefore, our primary outcome is likely biased toward demonstrating more of a difference than there would be had the groups been balanced (essentially a type I error).

In this appropriately powered, single-center, blinded, randomized, placebo-controlled trial evaluating the safety and efficacy of a single dose of 300 mg pregabalin before ureteroscopy, we failed to detect an improvement in pain scores among patients who received pregabalin. At the same time, we did not detect increased risk of cognitive issues using our proxy measure. Urologists should not routinely use perioperative gabapentinoid in ureteroscopy, as it is unlikely to provide benefit.

Full results of this trial are available online and in the September 2023 issue of The Journal of Urology^®.⁷