Effect of an Intravenous Acetaminophen/Ibuprofen Fixed-Dose Combination on Catheter-Related Bladder Discomfort: A Prospective, Randomized, Placebo-Controlled, Double-Blind Pilot Study

1. Introduction

Indwelling urinary catheterization is widely utilized in perioperative care, particularly for patients undergoing urological surgery. However, this intervention frequently triggers catheter-related bladder discomfort (CRBD), with reported incidences ranging from 47% to 90% following procedures [1,2]. Characterized by urinary urgency and suprapubic discomfort, CRBD is often poorly responsive to opioid analgesics and may contribute to postoperative complications including emergence agitation, impaired quality of recovery, challenges in pain management, and risks of physical injury or secondary infection [3,4]. Consequently, uncontrolled CRBD may hinder Enhanced Recovery After Surgery (ERAS) pathways by delaying early ambulation and reducing overall patient satisfaction [4].

The pathophysiology of CRBD involves involuntary detrusor contractions mediated by muscarinic receptors, alongside prostaglandin driven afferent sensitization resulting from local bladder irritation [5,6]. Maxigesic^® (Kyungbo Pharm, Asan, Korea), a fixed dose combination of 1000mg acetaminophen and 300mg ibuprofen, was recently released in South Korea and provides multimodal analgesia through complementary central and peripheral mechanisms [7,8]. This fixed dose combination has demonstrated favorable efficacy and safety in postoperative pain [9]. Ibuprofen inhibits prostaglandin mediated inflammation, which contributes to bladder afferent sensitization, while acetaminophen modulates central nociceptive processing. This dual mechanism may be particularly effective for CRBD, which involves both peripheral irritation and enhanced afferent signaling. Given the absence of clinical data evaluating this combination for CRBD, we hypothesized that the combined administration of acetaminophen and ibuprofen would significantly reduce the incidence and severity of symptoms of CRBD following urinary catheterization.

2. Materials and Methods

After receiving approval from the Institutional Review Board of our hospital (KYUH 2022-04-007-001), this prospective randomized study was registered at the Korea Clinical Research Information Service (permit number: KCT0007640). This prospective, randomized, placebo-controlled study was conducted from December 2022 through September 2025 in a single university hospital after obtaining written informed consent from all participants. During the informed consent process, patients were educated about the typical symptoms of CRBD, including urinary urgency, suprapubic discomfort, and a burning sensation, to facilitate accurate postoperative reporting.

This study was initially designed as a prospective randomized controlled trial to evaluate the effect of Maxigesic on the incidence of CRBD. However, due to slower-than-anticipated patient recruitment, the study was terminated early and subsequently considered a pilot randomized controlled trial aimed at assessing feasibility and estimating the potential effect size. Early termination was reported to and acknowledged by the Institutional Review Board.

We enrolled patients aged 19-70 years with an American Society of Anesthesiologists (ASA) physical status I–III, who were scheduled for urological surgery requiring urinary catheterization. A patient was excluded if any of the following criteria were met: (1) contraindication to acetaminophen or ibuprofen (e.g., history of hypersensitivity/anaphylaxis to acetaminophen or ibuprofen, gastrointestinal ulcers, severe renal impairment); (2) overactive bladder (OAB; urinary frequency > 3 times per night or > 8 times in 24 h); (3) bladder outlet and lower urinary tract obstruction; (4) benign prostatic hyperplasia; (5) active alcoholism; (6) neuropsychological disorder or cognitive impairment; (7) cases with factors that were judged to have an impact on postoperative outcomes, such as combined surgery.

Patients were randomly allocated to one of two groups (control or maxigesic group) at a 1:1 ratio using online randomization software (Researcher Randomizer; www.randomizer.org). The patient’s group allocation was concealed in a sealed opaque envelope, which was opened when the patient arrived in the operating room by the attending anesthesiologist responsible who administered the study drugs (saline 100 ml for the control group and Maxigesic 1vial [100 ml] for the maxigesic group). The study was conducted in a double-blinded manner. Patients, surgeons, and the anesthesiologist (resident) responsible for postoperative data assessment and collection were blinded to group allocation. The study drug was administered by the attending anesthesiologist, who was not involved in outcome assessment.

All patients fasted for at least 8 hours prior to surgery and were transferred to the operating room without premedication. Standard monitoring included pulse oximetry, electrocardiography, noninvasive blood pressure monitoring, the Patient State Index (PSI) (SedLine^®; Masimo Corp., USA) and neuromuscular train-of-four (TOF) acceleromyography on the adductor pollicis muscle. Anesthesia was induced with intravenous propofol (1.5-2mg/kg) and fentanyl (1–2 μg/kg), followed by rocuronium (0.6 mg/kg) to facilitate endotracheal intubation. Anesthesia was maintained with N2O：O2 (1：1) and desflurane (3–8 vol% end-tidal concentration) to keep the PSI at 25–50. The study drug was administered approximately 20 minutes before the anticipated end of surgery. Patients in the maxigesic group received an intravenous infusion of Maxigesic (1 vial), while those in the control group received 100 mL of normal saline. All infusions were administered over 15 minutes.

All patients underwent surgery in the lithotomy position. At the end of the surgery, urinary catheterization was performed using a Foley catheter lubricated with 2% lidocaine jelly (Instillagel^®; Farco-Pharma GmbH, Cologne, Germany) and the balloons of the catheter were inflated with normal saline. The size of the Foley catheter and volume of the balloon were determined at the discretion of the urologist. After urinary catheterization, the patients were placed in the supine position. Subsequently, to reverse the neuromuscular block, sugammadex was administered intravenously according to the depth of the block, and the patients were transferred to the post-anesthetic care unit (PACU) after extubation. All patients were observed for at least 1 h in the PACU.

CRBD was assessed at 0, 1, 2, and 6 hours after the patient arrived in the PACU. The severity of CRBD were evaluated using a 4-point scale (none = patient did not complain of any CRBD symptoms even when asked, such as urge to urinate or discomfort in the suprapubic region, mild = complaint of CRBD symptoms only on direct questioning, moderate = spontaneous complaint by the patient of CRBD symptoms without any behavioral responses [e.g., attempts to pull out the catheter, flailing limbs, or a loud vocal response], and severe = spontaneous complaint by the patient of CRBD symptoms with behavioral responses) [10] and 11-point numeric rating scale (NRS, 0 = no catheter-related bladder discomfort, 10 = worst catheter-related bladder discomfort imaginable) by the anesthesiology resident. CRBD incidence was defined as the presence of mild or greater symptoms. At each assessment time point, patients with moderate or severe CRBD received intravenous tramadol (25–50 mg) as rescue medication.

The primary endpoint was the incidence of CRBD immediately after the patient arrived at the PACU. Secondary endpoints included the incidence of CRBD at 1, 2, and 6 hours, the severity of CRBD (categorized as none, mild, moderate, or severe) at each time point, and the CRBD NRS assessed at PACU arrival and at 1, 2, and 6 hours.

Statistical Analyses

Based on prior data, the study was originally designed to enroll a total of 106 patients to detect a clinically meaningful difference in CRBD incidence. However, due to slower-than-expected recruitment, enrollment was discontinued early after enrolling 25 patients and the study was completed with a substantially smaller sample. Accordingly, the present trial should be considered a pilot randomized study. Given the limited sample size, the analyses focused on estimation of effect size and confidence intervals rather than formal hypothesis testing.

SPSS Statistics software (ver. 27.0 for IBM Corp., Armonk, NY, USA) was used for the statistical analyses. The distribution of continuous variables was assessed with the Kolmogorov–Smirnov test; normally distributed variables were analyzed using Student’s t-test and Non-normally distributed variables were analyzed using the Mann–Whitney U-test. Categorical data were compared using the χ2 test, the χ2 test for trends (linear-by-linear association), or Fisher’s exact test as appropriate. Cohen’s effect sizes d and h were used to compare the continuous and categorical data, respectively. A P-value < 0.05 was considered significant.

3. Results

A total of 25 patients were enrolled and randomized. Two patients were excluded from the final analysis (one in each group) because they underwent additional intraoperative surgical procedures that were considered likely to affect postoperative CRBD assessment, resulting in 23 patients included in the outcome analysis (Figure 1). The characteristics and perioperative data of the patients in the two groups were comparable (Table 1).

Incidence and severity of postoperative CRBD are presented in Table 2. The incidence of CRBD upon arrival at the PACU, the predefined primary endpoint, was significantly lower in the maxigesic group compared with the control group (54.5% vs. 100%; relative risk 0.333, 95% CI 0.2 to 0.6; mean difference 45.5%, 98% CI 11.2% to 72.0%; effect size h 1.481, p = 0.014). However, no significant differences were observed at 1, 2, or 6 hours following PACU admission.

Overall CRBD severity differed significantly between groups at PACU arrival (p = 0.002), but not at later postoperative time points. When severity categories were analyzed separately, the incidence of moderate PONV was significantly lower in the maxigesic group at 0 hour (66.7% vs.18.2%; mean difference 48.5%, 98% CI 8.1% to 72.0%; effect size h 1.030, p = 0.036) and at 1 hour (41.7% vs.0%; mean difference 41.7%, 98% CI 7.5% to 68.5%; effect size h 1.404, p = 0.037) following PACU admission.

CRBD NRS scores were significantly lower in the maxigesic group at 0, 1 and 2 hours after patient arrival in the PACU (effect size d = 1.481, 1.070, and 0.929, respectively; p = 0.002, 0.011, and 0.023, respectively).

Fewer patients in the maxigesic group required rescue tramadol compared with the control group (9.1% vs 41.7%; effect size h = 0.791); however, this difference was not statistically significant (p = 0.155) (Table 2).

4. Discussion

In this study, we found that Maxigesic administration significantly decreased the incidence and overall severity of CRBD at PACU arrival in patients undergoing urological surgery. This corresponded to an absolute risk reduction of 45.5% and a number needed to treat of approximately 3. Additionally, CRBD NRS scores were significantly lower in the maxigesic group than in the control group at 0, 1, 2 hours, but not at 6 hours. Although not statistically significant, fewer patients in the maxigesic group required rescue tramadol. This pilot randomized trial suggests that the combination of acetaminophen and ibuprofen contributes to a clinically relevant reduction in CRBD.

The significant reduction in the incidence and severity of CRBD observed in this study supports our initial hypothesis and can be interpreted through the multifactorial pathophysiology of the condition. CRBD remains a common and clinically significant challenge in urological surgery requiring urinary catheterization, manifesting as a distressing triad of urinary urgency, suprapubic pain, and agitation [1,2,3]. As our results indicate, Maxigesic effectively targets these symptoms by addressing both the peripheral and central components of the discomfort.

The beneficial effect of this regimen lies in its ability to modulate the complex pathways of bladder irritation. Mechanical irritation from the catheter induces involuntary detrusor contractions mediated primarily via M3 muscarinic receptors [11]. In parallel, the resulting local inflammatory response triggers the release of prostaglandins, which enhances afferent sensory signaling and sensitizes the bladder mucosa [12]. Ibuprofen exerts its effect through cyclooxygenase inhibition, thereby reducing prostaglandin synthesis and attenuating this inflammation driven afferent sensitization [13]. Acetaminophen complements this by acting primarily at the central level, modulating nociceptive transmission through central prostaglandin inhibition and the activation of descending inhibitory pathways [14]. This multimodal approach would be mechanistically superior to single agent therapy, as it simultaneously reduces peripheral inflammatory input and modulates the central perception of urgency.

While antimuscarinics like oxybutynin and gabapentinoids such as pregabalin have been the mainstay of CRBD prevention, their clinical utility is often hampered by a restrictive side effect profile, including sedation, dizziness, cognitive dysfunction, and postoperative delirium [15,16,17,18]. Previous studies have shown that single-agent therapy with either intraoperative paracetamol [19] or NSAIDs such as ketorolac [20] can effectively reduce the incidence and severity of CRBD without significant adverse events. These findings suggest that targeting prostaglandin-mediated pathways and nociceptive processing is a viable strategy for managing catheter-related distress while avoiding the anticholinergic burdens associated with conventional treatments.

The safety of the acetaminophen and ibuprofen combination is thus a key consideration, especially as it involves the simultaneous administration of two different pharmacological classes. While a fixed-dose combination could theoretically carry the side effect profiles of both agents including gastrointestinal, renal, and hepatic concerns. Extensive safety data from Cochrane reviews [9] and large-scale multi-center studies [8] demonstrate that short term perioperative use of this combination is remarkably well tolerated. Specifically, the incidence of serious adverse events remains below 1%, with no significant increase in hepatic or renal toxicity compared to placebo [8,9]. In alignment with these established safety profiles, no serious drug-related adverse events, such as gastrointestinal bleeding or acute kidney injury, were observed in our study. These findings suggest that the multimodal benefits of this combination can be achieved safely, supporting its use as a reliable alternative for perioperative CRBD management.

From a clinical perspective, effective CRBD control is essential for optimizing perioperative outcomes. Beyond improving patient comfort, reducing CRBD helps mitigate emergence agitation and decreases the requirement for rescue medications, including opioids which themselves may contribute to urinary retention and delayed discharge [21]. By ensuring a smoother transition from the PACU and facilitating early mobilization, this combination aligns with the core principles of ERAS protocols.

Several limitations of this study should be noted. The trial was terminated early due to recruitment difficulties. Consequently, the study was underpowered to detect statistically significant differences. Nevertheless, this pilot trial provides preliminary estimates of the potential effect of the intervention. In addition, our findings may inform the sample size calculation for future adequately powered trials. Furthermore, we utilized a fixed dose regimen, which precludes the determination of an optimal dose response relationship. The timing of administration may also have influenced the results, and future studies should explore different dosing schedules.

5. Conclusions

This pilot randomized trial suggests that the combination of 1000 mg acetaminophen and 300 mg ibuprofen reduces early postoperative CRBD burden, as reflected by lower incidence, reduced severity, and decreased CRBD NRS during the early recovery phase. While limited by a small sample size, these results demonstrate the potential of this multimodal approach as an effective and well tolerated strategy for perioperative CRBD management. Future large scale randomized controlled trials are warranted to confirm these benefits and optimize its clinical implementation.