A critical review on the role of perioperative pregabalin in ureteroscopy for urolithiasis

Urolithiasis continues to increase in prevalence worldwide, with ureteroscopy a mainstay in the surgical management of kidney and ureteral stones (1). Unfortunately, ureteral stents, which are often temporarily placed after ureteroscopy, are associated with significant side effects and patient discomfort. Non-opioid pain management after ureteroscopy has emerged to combat the opioid epidemic. Among these alternatives, pregabalin, a gamma-aminobutyric acid (GABA) agent, has been shown to be effective in reducing pain intensity and opioid consumption after surgery and is 2–4 times more potent as an analgesic than gabapentin (2). Its mechanism of action is via voltage-dependent calcium channels, which are distributed throughout the central and peripheral nervous system (2).

Specifically, pregabalin has been studied extensively for use in post-ureteroscopy stent discomfort. Falahatkar et al. performed a randomized controlled trial in 256 ureteroscopy patients looking at pregabalin and solifenacin for stent-related symptoms (3). Pregabalin, whether administered alone or in combination with solifenacin, was associated with significantly superior USSQ scores 4 weeks post-operatively compared to the control group. A similar randomized controlled trial by Ragab et al. evaluating 500 patients undergoing ureteroscopy with stent insertion showed similar results (4). In this cohort, once again, patients assigned to pregabalin alone or pregabalin in combination with solifenacin had significantly improved pain symptoms at 15 days-post-operatively. Importantly, in both trials, pregabalin was prescribed for prolonged post-operative courses.

On a larger scale, a recent systematic review and meta-analysis of the pharmacological management of stent-related symptoms looked at 26 studies including 2,900 patients (5). Of those, 188 patients were treated with pregabalin and 186 with combined anticholinergic and pregabalin. The combination and pregabalin alone were noted to be among the highest performers in the rankings for pain control.

Contrary to the above studies, in their recently published manuscript titled “Randomized Controlled Trial of Single-dose Perioperative Pregabalin in Ureteroscopy”, Rosen et al. performed a single institution, blinded, placebo-controlled trial evaluating a single dose of pregabalin pre-operatively prior to ureteroscopy and found the opposite effect (6). Study participants were given either 300 mg pregabalin or placebo to take 1 hour preoperatively. The primary outcome was postoperative pain defined via the visual analogue scale (VAS) 1-hour post-surgery. A total of 118 patients were enrolled over 2 years. Interestingly, they found that postoperative pain was higher in the group that received pregabalin than the placebo cohort (P=0.004). Participation in surveys was low, less than 50% across all dates. The only significant outcome was a larger proportion of patients in the pregabalin group was satisfied with their pain control at day 7 (P=0.01).

There are several limitations to this study. First, the study was likely underpowered. The power analysis does not appear to be based on literature evaluating acute post-operative VAS scores and therefore the validity is uncertain. The trial was designed for 200 subjects, but due to significant dropout, enrollment was discontinued at 59 patients per group. Importantly, more than 600 patients were excluded because they were not approached for the study, suggesting the 118 patients consented and randomized were handpicked for the study. These results cannot be generalized to the larger population undergoing ureteroscopy. Additionally, only 44 to 49 patients total completed the follow-up postoperative surveys, making findings beyond post-operative day 0 difficult to interpret.

Among the group of patients included, it is difficult to minimize the potential impact of confounders within the study. While the authors point out the trial is indicative of a pragmatic approach, and there are certainly merits to pragmatic trials, the lack of standardization likely impacts the outcomes. First, 1-hour post-operative pain can be impacted by intra-operative anesthetic which was not standardized within this protocol. Additional confounding factors included the proportion of patients pre-stented or with stents placed post-operatively—a known contributor to post-operative pain. Although the rates of these factors did not vary significantly between groups, they were not included on multivariate analysis for formal assessment—likely reflective of sample size limitations. Lastly, as the editorial commentors pointed out in the Journal of Urology, the study should have included timepoints between 1 hour and 3 days, given the half-life of pregabalin and the known peak post-ureteroscopy pain at 2 days (7,8).

We commend the authors for evaluating the effectiveness of preoperative pregabalin administration on post-ureteroscopy in a randomized controlled trial. However, with a small study size standardization of multiple factors would have significantly strengthened the design. While preoperative pregabalin is not part of my regular preoperative prescribing routine, the findings of this study do not deter me from including it in the future. I hope the authors or other researchers will use this study as a stepping point to future research in a more controlled manner.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-39/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-39/coif). K.M.W. reports consulting fee from BD, Coloplast, Boston Scientific and Applaud Medical. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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