Tranexamic acid (TXA), a synthetic derivative of the amino acid lysine, is well-known for its hemostatic properties, particularly in surgical settings. Initially employed to manage bleeding disorders, TXA works by inhibiting plasmin-mediated fibrinolysis, thereby stabilizing clots and minimizing bleeding ^[1]. Beyond its role in hemostasis, recent studies have illuminated TXA’s broader therapeutic potential, particularly in orthopedic surgery, with a focus on total knee arthroplasty (TKA). Emerging evidence suggests that TXA may offer significant anti-inflammatory benefits, likely through its ability to inhibit plasmin, a molecule implicated in various inflammatory pathways, including activation of the complement system and oxidative stress [2-6]. In addition, TXA has been shown to modulate immune responses, potentially reducing plasma levels of inflammatory markers such as C-reactive protein and interleukin-6 following TKA [7, 8]. This has led to growing interest in the potential analgesic properties of TXA, particularly in the context of postoperative pain management. With the ongoing opioid crisis highlighting the need for effective, non-opioid alternatives, TXA emerges as a promising adjunct to existing multimodal analgesia strategies ^[9]. Immediate post-operative pain relief is a critical factor in enhancing patient outcomes. Early control of pain not only improves patient comfort but also plays a crucial role in fostering trust in the healthcare system and in the treating physician. Effective pain management contributes to patient satisfaction, accelerates mobilization, and facilitates early discharge, which in turn optimizes the utilization of healthcare resources. Given these considerations, the ability to reduce opioid consumption, decrease post-operative pain, and expedite recovery is vital for improving both individual patient outcomes and overall healthcare efficiency. Despite the expanding body of literature on TXA’s hemostatic and anti-inflammatory effects, there is a paucity of randomized controlled trials that evaluate its analgesic impact in TKA patients. This prospective study seeks to address these gaps by investigating the analgesic efficacy of intra-articular TXA in TKA, exploring its potential to reduce opioid use, alleviate postoperative pain, and promote faster recovery. By evaluating TXA as an adjunct to traditional pain management approaches, this study aims to contribute to a more effective and resource-efficient model of post-operative care.

Trial design and study participants

This prospective, single-center study was conducted between April and May 2024. A total of 54 patients undergoing simultaneous bilateral TKA were enrolled following informed consent. All procedures were performed by a single, experienced surgeon. Baseline data, including sociodemographic characteristics, pre-operative laboratory investigations, any comorbid conditions, and American Society of Anesthesiologists (ASA) grading, were systematically collected using a standardized pro forma. Ethical approval was obtained from the institutional review board, and the study adhered to ethical principles outlined in the Declaration of Helsinki.

Inclusion and exclusion criteria

Patients were eligible for inclusion if they met the following criteria: (1) undergoing simultaneous bilateral TKA; (2) aged between 55 and 80 years; (3) ASA Grade I-III; (4) pre-operative hemoglobin levels >10 g/dL. There were no specific exclusions based on the presence of comorbid conditions such as a history of deep vein thrombosis (DVT), renal disease, or cardiac dysfunction. The sole exclusion criterion was a documented allergy to TXA.

Randomization

Randomization was performed using Stata version 12.1 (StataCorp LP, TX), with a generated list determining which knee would receive intra-articular TXA. Each patient served as their own control, with one knee receiving intra-articular TXA and the other serving as the control. Thus, there were 54 knees in each group (study and control), maintaining balanced sample sizes for within-subject comparisons.

Study intervention

All patients received 1 g of intravenous (IV) TXA 30 min before skin incision. In addition, 1 g (10 mL) of TXA diluted in 10 mL of normal saline (total volume 20 mL) was injected intra-articularly into one knee joint after wound closure. Closed suction drains were placed in both knees, initially clamped, and opened 2 h postoperatively. Two subsequent doses of 1 g IV TXA were administered at 3 h and 6 h after surgery. Patients with a history of DVT or renal/cardiac dysfunction were exempted from the 6-h postoperative IV TXA dose to minimize potential risks. Drains were removed 24 h post-surgery, and the output from both knees was measured and compared.

Outcome measures

The primary and secondary outcomes of the study were as follows:

1. Pain assessment: The Visual Analog Scale (VAS) scores were recorded at regular intervals: 48 h, 3 weeks, 6 weeks, and 12 weeks postoperatively, to assess pain levels in both the study and control knees.
2. Range of motion (ROM): Knee flexion was assessed at 48 h postoperatively and during subsequent follow-ups (3, 6, and 12 weeks). Knee flexion was categorized as follows:

• • <70° (poor)
  • 70–90° (average)
  • 90–110° (good)
  • >110° (excellent)

1. Functional outcomes: Functional outcomes were evaluated using two validated scores:

• Oxford knee score (OKS): Ranging from 0 to 48, where 0 represents the worst possible knee function and 48 represents the best.
• Knee injury and osteoarthritis outcome score for joint replacement (KOOS-JR): A score ranging from 0 to 100, where 0 indicates total knee disability and 100 signifies optimal knee health. These were assessed preoperatively and at 12 weeks post-surgery.

1. Blood transfusion criteria: Blood transfusions were administered according to clinical criteria: Patients with postoperative hemoglobin levels <10.0 g/dL and symptomatic anemia, or those with hemoglobin levels <7.0 g/dL, regardless of symptoms, were transfused.

Blinding

The study employed a double-blinded design, where both the patient and the assessing physiotherapist were unaware of which knee had received intra-articular TXA.

Statistical analysis

Descriptive statistics were used to summarize baseline and outcome variables, presented as mean ± standard deviation (SD), frequencies (n), and percentages, as appropriate. The normality of data distribution was assessed using the Kolmogorov–Smirnov test. For comparisons of quantitative variables, the Wilcoxon signed-rank test was employed for non-parametric data, given the within-subject design of the study. Statistical significance was set at a P < 0.05. All analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 21.0 (SPSS Inc., Chicago, IL, USA).

The mean age of the study patients was 63 (50–80) years. There were 14 male patients and 41 female patients. The average body mass index was 30.02 (18.40–45.40). Thirty-seven patients fell into ASA II while 17 patients belonged to ASA III grading. None of the study patients required blood transfusion as the criteria to determine transfusion was hemoglobin levels below 7 g/dL or if the patient is showing any sign of anemia. The average blood loss measured after 24-h closed suction drainage was 692.21 mL (Table 1). None of the patients had prior history of DVT, renal or cardiac dysfunction. In our study, no patient in the TXA group experienced complications and adverse events during the 3-month follow-up period.

Table 2 shows a statistically significant difference in favor of the study group (where intra-articular TXA was administered) where the mean 24 h closed suction output was 172.50 ± 69.01 mL as compared to that of the control group (192.50 ± 75.37 mL) with a P = 0.015.

Table 3 and 4 demonstrate the pain VAS scores and knee flexion gain at regular intervals (48 h, 3 weeks, 6 weeks, and 12 weeks). Mean VAS score 48 h postoperatively was 2.70 ± 0.96 in the study group as compared to 3.35 ± 2.84 in the control group which is a statistically significant result (P = 0.004). At the same time, mean knee flexion gain was also evaluated which showed majority of the study and control knees fell into 70–90° knee ROM (68.5% and 59.3% respectively). Though the study group had noteworthy better ROM, the difference was statistically non-significant (P = 0.132). On further follow-ups, no statistically significant difference was seen, though the patient showed clinical improvement in both knees.

We evaluated the functional scores of both knees of the patient preoperatively and at 12 weeks follow-up (Tables 5 and 6). The mean OKS increased from 12.07 ± 1.65 to 31.41 ± 2.17 in the study group and 12.09 ± 1.50–31.41 ± 2.17 in the control group. KOOS-JR score values increased from 44.89 ± 4.33 to 64.85 ± 2.85 in the study group while it increased from 44.94 ± 4.37 to 64.85 ± 2.85. We found the same functional outcome scores at 12-week follow-up in both study and control group knees.

The present study provides compelling evidence supporting the analgesic benefits of intra-articular TXA in reducing early post-operative pain following TKA. Our results demonstrated a statistically significant reduction in pain, as measured by the VAS, 48 h postoperatively in the TXA-treated group (P < 0.01). Although the improvement in knee ROM was not statistically significant, the trend toward better early ROM in the TXA group is notable and warrants further exploration in larger studies. Several studies have explored the role of intra-articular TXA in post-operative pain management. Guerreiro et al. reported significant pain relief at 24 and 48 h post-TKA in patients treated with intra-articular TXA, along with enhanced flexion at 24 h (P = 0.03) ^[10]. Laoruengthana et al. demonstrated that intra-articular TXA reduced post-operative opioid use in a large cohort of 228 patients ^[11]. Unlike these studies, which compared different patients across groups, our study uniquely compares both knees within the same patient undergoing simultaneous bilateral TKA, thereby minimizing patient-related confounders. This within-subject design strengthens the validity of our findings and underscores the reliability of intra-articular TXA as an effective analgesic adjunct. In terms of functional outcomes, we observed improvements in both the OKS and KOOS-JR at 3 months, though no significant differences between the TXA-treated and control knees were noted. The lack of statistical significance may be attributed to the limited sample size or the inherent variability in post-operative recovery. Previous studies on the effects of intra-articular TXA on functional outcomes are largely retrospective. For example, Moorthy et al. found no significant long-term functional improvement following unicompartmental TKA with intra-articular TXA ^[12], while Serrano Mateo et al. reported early improvements in knee function during the first 6 weeks, but these benefits diminished over time ^[13]. Our study contributes to this ongoing debate, highlighting the need for larger, prospective trials to better understand the long-term functional benefits of intra-articular TXA. In line with its well-established hemostatic properties, our study also confirmed intra-articular TXA’s role in reducing perioperative blood loss. The study group experienced significantly less blood loss (172.50 ± 69.01 mL vs. 192.50 ± 75.37 mL, P = 0.015), aligning with prior studies demonstrating the efficacy of intra-articular TXA in minimizing blood loss and transfusion requirements during TKA [14-16]. By reducing the need for blood transfusions, topical TXA helps mitigate the associated risks and enhances overall recovery, further improving patient outcomes. We did not encounter any thomboembolic event or any local wound complication pertaining to the usage of intra-articular TXA in our 3-month follow-up period, as also evidenced by various previous studies [15, 17, 18]. The clinical implications of our findings are substantial. Intra-articular TXA has the potential to serve as an effective adjunct to existing pain management protocols, particularly by reducing opioid consumption and minimizing opioid-related complications ^[9]. Moreover, its anti-inflammatory properties could further improve post-operative outcomes by promoting better wound healing and reducing the risk of inflammatory-related complications ^[6].

Our study provides robust evidence that intra-articular TXA significantly reduces early postoperative pain following TKA. As part of a multimodal analgesic strategy, intra-articular TXA could decrease opioid reliance, enhancing patient recovery and minimizing associated risks. Future research should focus on optimizing TXA dosing regimens and expanding its use to other surgical procedures, further elucidating its potential to improve post-operative pain management across a range of clinical contexts.

Apart from effectively achieving hemostasis, intra-articular TXA significantly reduces early post-operative pain following TKA. As an adjunct to pain management protocols, TXA may enhance patient recovery and reduce opioid-related complications. Further research is needed to optimize TXA dosing regimens and explore its potential benefits in other surgical procedures.