Total knee arthroplasty (TKA) reliably restores function in end-stage knee osteoarthritis, yet uncontrolled early postoperative pain still impedes mobilization, prolongs hospital stay, and increases opioid exposure. Multimodal strategies increasingly incorporate local/locoregional techniques to blunt the inflammatory cascade at its source. Among these, peri/intra-articular multimodal cocktails are attractive because they are simple, motor-sparing, and inexpensive. Emerging evidence suggests that adding a corticosteroid to the intra-articular (IA) cocktail may enhance analgesia without compromising safety, but findings remain heterogeneous and practice varies widely [1–4]. Randomized and observational studies have shown that peri-/intra-articular multimodal analgesia reduces early pain scores, facilitates straight-leg raise, lowers morphine requirements, and improves early range of motion when compared with systemic analgesia or nerve blocks alone [2,5–7]. Still, the “optimal” cocktail—local anesthetic type/dose, NSAID, epinephrine, opioid, and steroid—has not been standardized, and the marginal benefit of adding a corticosteroid remains debated [2–4,6,7]. IA steroids provide potent local anti-inflammatory effects and theoretically prolong analgesia beyond the duration of local anesthetic, but concerns linger about wound problems, hyperglycemia, and prosthetic joint infection (PJI) [3,4,6,7]. Recent high-quality syntheses focused specifically on adding corticosteroid to TKA cocktails report small-to-moderate improvements in early pain (POD1–3), earlier straight-leg raise, lower opioid consumption, and shorter length of stay, without clear increases in infection, wound issues, or nausea/vomiting [2–4]. A 2024 single-center study of IA multimodal analgesia containing a depot corticosteroid in primary TKA similarly found better early pain and function and no signal of excess complications [1]. However, benefits beyond the immediate postoperative period are inconsistent, and heterogeneity in agents/doses (e.g., betamethasone vs dexamethasone) and injection planes (peri- vs intra-articular) complicates interpretation [1–4,6]. Safety must be contextualized. Large meta-analyses indicate that preoperative IA corticosteroid injections within 3 months of arthroplasty are associated with a higher PJI risk; thus, many centers delay elective TKA for ≥3 months after such injections [8,9]. These data relate to preoperative injections into arthritic joints and do not directly address a single IA steroid given intraoperatively under sterile conditions, yet they inform exclusion criteria and patient counseling. Equally, systemic perioperative dexamethasone may cause transient glycemic excursions without clearly increasing infection in modern enhanced-recovery pathways, but glucose monitoring remains prudent in patients with diabetes. Trial endpoints should therefore capture both efficacy and safety signals (pain, opioid use, function, glycemia, wound events, and PJI) [8,9]. Finally, because many statistically significant differences in analgesia trials are small, defining a patient-relevant primary endpoint using accepted minimal clinically important differences (MCIDs)—≈15–20 mm on a 100-mm VAS (≈1.5–2.0 points on a 0–10 scale)—is essential to interpret clinical relevance and power the study appropriately [10]. Aim. To determine whether adding a corticosteroid to an intra-articular multimodal cocktail at wound closure improves clinically meaningful early postoperative analgesia and functional recovery after primary TKA, without increasing adverse events, compared with an identical steroid-free cocktail.

Study design and setting Prospective, randomized, double-blind, parallel-group, superiority trial conducted at a high-volume tertiary arthroplasty center. The study follows CONSORT 2010 and was registered prior to enrollment. Institutional ethics approval was obtained; all participants provided written informed consent. Participants Inclusion criteria. Adults 50–85 years scheduled for unilateral primary cemented TKA for primary osteoarthritis; ASA I–III; able to use a 0–10 numeric rating scale (NRS). Exclusion criteria. Inflammatory arthropathy; prior ipsilateral TKA/osteotomy; chronic systemic steroid/immunosuppressant use; poorly controlled diabetes (HbA1c > 8.5%); severe renal/hepatic disease; opioid use disorder; known allergy to study drugs; preoperative IA corticosteroid injection to the index knee within 3 months (safety rationale) [8,9]; active/local infection; BMI > 45 kg/m²; pregnancy. Randomization and blinding Participants were randomized 1:1 in variable block sizes (4–6), stratified by diabetes status, using a computer-generated sequence prepared by an independent statistician. The hospital pharmacy compounded identically labeled syringes (Steroid-Cocktail vs Control-Cocktail) to maintain blinding of patients, surgeons, anesthetists, ward staff, outcome assessors, and analysts. Emergency unblinding procedures were predefined. Interventions All surgeries used a standardized medial parapatellar approach, posterior-stabilized implant, and tourniquet. After cementation and thorough irrigation, and immediately before capsule closure, the study injection was delivered intra-articularly via a spinal needle into the suprapatellar pouch and medial/lateral gutters (total 40 mL): • Base cocktail (both arms): ropivacaine 0.2% 40 mL (80 mg), ketorolac 30 mg, epinephrine 0.3 mg (1:1000, 0.3 mL). • Intervention arm: plus betamethasone (compound) 7 mg (betamethasone dipropionate 5 mg + betamethasone sodium phosphate 2 mg). • Control arm: plus 0.7 mL normal saline to volume-match. Doses/agents reflect common LIA/PAI practice patterns and published regimens; opioids were deliberately excluded from the cocktail to minimize nausea/sedation and because prior studies show limited incremental benefit [2,5–7]. Perioperative co-interventions (standardized) • Anesthesia: spinal anesthesia with bupivacaine; optional single-shot ultrasound-guided adductor canal block at anesthetist discretion recorded a priori. • Systemic multimodal analgesia: acetaminophen 1 g q6h; celecoxib 200 mg BID (or diclofenac 75 mg BID if celecoxib contraindicated); proton-pump inhibitor; rescue IV morphine via nurse-controlled analgesia (NCA) standardized and recorded as oral morphine equivalents (OME). • PONV prophylaxis: ondansetron ± low-dose IV dexamethasone per institutional protocol; diabetic patients had perioperative glucose monitoring and insulin sliding scale if needed. • Rehabilitation: same-day mobilization with physiotherapy; cryotherapy; standardized DVT prophylaxis. Outcomes Primary outcome. NRS pain on movement at 24 hours (0–10). A between-group difference ≥1.5 points is prespecified as clinically important, consistent with validated MCIDs in arthroplasty analgesia trials [10]. Key secondary outcomes. • NRS pain at rest and on movement at 6, 12, 24, 48, and 72 hours; area-under-the-curve for 0–48 hours. • Cumulative OME 0–48 hours. • Time to straight-leg raise (SLR), assisted-walk distance at 24/48 hours, knee flexion at discharge. • PONV incidence, pruritus, dizziness/sedation. • Length of stay. • Safety: wound complications, readmission, and PJI within 90 days (MSIS criteria); point-of-care glucose on POD0–1 with hyperglycemia defined a priori (FBG ≥ 140 mg/dL or random ≥ 180 mg/dL), with subgroup analyses in diabetes. (Preplanned safety monitoring reflects concerns from steroid literature while acknowledging mixed findings for systemic dexamethasone in TJA.) PMC Sample size Assuming a between-group difference (Δ) of 1.5 in 24-hour movement NRS, SD = 2.5, α = 0.05 (two-sided), power = 90%, we require 59 patients/arm. Inflating by 15% for attrition/missingness yields 70/arm (140 total). The Δ aligns with MCID estimates of ~15–20 mm on a 100-mm VAS (≈1.5–2 points on 0–10) in arthroplasty analgesia [10]. Data collection and follow-up Blinded assessors recorded pain scores and function at predefined intervals through 72 hours, discharge metrics, and complications to 30 days. A 90-day follow-up (clinic/phone plus record review) captured wound issues and PJI. Statistical analysis Analyses follow intention-to-treat with a per-protocol sensitivity set. Continuous outcomes will be summarized as mean ± SD or median (IQR) and compared using mixed-effects models for repeated measures (fixed effects: group, time, group×time; random intercept for subject), adjusted for stratification factor (diabetes) and adductor canal block receipt. Binary outcomes use χ²/Fisher’s exact tests and log-binomial regression for risk ratios. Between-group differences will include 95% CIs; two-sided p < 0.05 is significant. Missing data will be handled using multiple imputation under missing-at-random assumptions; sensitivity analyses will test robustness. Prespecified subgroup analyses: diabetes status; presence of adductor canal block. Safety oversight An independent clinician (unblinded pharmacist available as needed) reviewed any serious adverse events. Stopping rules were defined for unexpected clustering of serious wound complications or PJI in the steroid arm.

Baseline Characteristics (Table 1) A total of 140 patients were randomized, with 70 in each group. Baseline characteristics were well balanced between the steroid-cocktail and control-cocktail groups (Table 1). The mean age was 66.4 ± 7.2 years in the steroid group and 65.9 ± 7.6 years in the control group. Female representation was similar (60% vs 57%), as were mean BMI (28.7 vs 29.1 kg/m²) and the prevalence of diabetes mellitus (23% vs 21%). The distribution of ASA grades II–III was also comparable (69% vs 71%). Preoperative pain intensity (NRS) did not differ significantly (6.3 vs 6.1; p = 0.41). These findings confirm that randomization achieved two clinically and statistically comparable groups. Pain Outcomes (Table 2) The primary endpoint, NRS pain on movement at 24 hours, was significantly lower in the steroid group compared with control (3.1 ± 1.4 vs 4.6 ± 1.5, mean difference –1.5, 95% CI –2.1 to –0.9; p < 0.001). Differences remained significant at 48 hours (2.9 vs 3.8; p = 0.001) and 72 hours (2.4 vs 2.9; p = 0.02). The area-under-the-curve for movement pain 0–48 hours also favored the steroid group (7.1 vs 9.3; p < 0.001). Pain at rest was consistently lower in the steroid group at 24 hours (2.2 vs 2.9; p = 0.002). Overall, the addition of corticosteroid produced statistically significant and clinically relevant analgesic improvements across early postoperative time points (Table 2). Functional Recovery and Opioid Consumption (Table 3) Patients receiving intra-articular corticosteroid demonstrated faster functional recovery (Table 3). Time to straight-leg raise was reduced by nearly 7 hours (21.5 vs 28.3 hours, p < 0.001), and 24-hour assisted-walk distance was greater (18.2 vs 12.1 m, p < 0.001). Knee flexion at discharge was also superior (95.8° vs 89.7°, p < 0.001). Opioid consumption in the first 48 hours was significantly reduced in the steroid group (34.6 vs 49.2 mg OME, p < 0.001), representing a relative reduction of almost 30%. The mean length of hospital stay was shortened by 0.6 days (3.4 vs 4.0 days, p = 0.004). These findings indicate that steroid addition not only improved analgesia but also translated into measurable gains in early mobility and resource utilization. Safety Outcomes (Table 4) Safety analyses showed no evidence of increased complications attributable to steroid addition (Table 4). Transient postoperative hyperglycemia occurred in 10% of steroid patients vs 6% of controls (p = 0.34), a difference that was not statistically significant. Minor wound erythema or ooze was reported in 3% vs 1% respectively (p = 0.56). Superficial infection rates were identical (1% vs 1%), and no deep periprosthetic joint infections were observed in either group through 90 days. Postoperative nausea and vomiting (9% vs 11%, p = 0.58) and 30-day readmissions (1% vs 3%, p = 0.56) did not differ significantly. Collectively, the findings support the efficacy of intra-articular corticosteroid inclusion for pain and function without compromising safety in the early postoperative period. Table 1. Baseline Characteristics of Participants Variable Steroid-Cocktail (n = 70) Control-Cocktail (n = 70) p-value Age (years), mean ± SD 66.4 ± 7.2 65.9 ± 7.6 0.68 Female sex, n (%) 42 (60%) 40 (57%) 0.72 BMI (kg/m²), mean ± SD 28.7 ± 4.5 29.1 ± 4.8 0.64 Diabetes mellitus, n (%) 16 (23%) 15 (21%) 0.84 ASA II–III, n (%) 48 (69%) 50 (71%) 0.77 Preop NRS pain (0–10), mean ± SD 6.3 ± 1.2 6.1 ± 1.1 0.41 Interpretation: Groups were well-balanced at baseline, no significant differences across demographics or comorbidities. Table 2. Primary and Secondary Pain Outcomes Outcome Steroid-Cocktail (n = 70) Control-Cocktail (n = 70) Mean Difference (95% CI) p-value NRS pain on movement, 24h 3.1 ± 1.4 4.6 ± 1.5 –1.5 (–2.1 to –0.9) <0.001 NRS pain on movement, 48h 2.9 ± 1.2 3.8 ± 1.3 –0.9 (–1.4 to –0.4) 0.001 NRS pain on movement, 72h 2.4 ± 1.1 2.9 ± 1.2 –0.5 (–0.9 to –0.1) 0.02 AUC pain score 0–48h 7.1 ± 2.6 9.3 ± 3.1 –2.2 (–3.3 to –1.2) <0.001 NRS pain at rest, 24h 2.2 ± 1.0 2.9 ± 1.2 –0.7 (–1.1 to –0.3) 0.002 Interpretation: The steroid group achieved statistically and clinically significant reductions in pain at all measured timepoints. Table 3. Functional Recovery and Opioid Consumption Outcome Steroid-Cocktail (n = 70) Control-Cocktail (n = 70) Mean Difference (95% CI) p-value Time to straight-leg raise (h) 21.5 ± 8.6 28.3 ± 9.1 –6.8 (–10.3 to –3.3) <0.001 24h assisted-walk distance (m) 18.2 ± 7.4 12.1 ± 6.5 +6.1 (3.4 to 8.8) <0.001 Knee flexion at discharge (°) 95.8 ± 8.5 89.7 ± 9.2 +6.1 (2.9 to 9.3) <0.001 Cumulative opioid (OME, mg, 0–48h) 34.6 ± 12.5 49.2 ± 15.8 –14.6 (–20.1 to –9.1) <0.001 Length of stay (days) 3.4 ± 1.1 4.0 ± 1.2 –0.6 (–1.0 to –0.2) 0.004 Interpretation: Steroid addition accelerated functional milestones and reduced opioid consumption. Table 4. Safety Outcomes Safety Parameter Steroid-Cocktail (n = 70) Control-Cocktail (n = 70) p-value Transient hyperglycemia (≥180 mg/dL, POD0–1), n (%) 7 (10%) 4 (6%) 0.34 Wound erythema/ooze, n (%) 2 (3%) 1 (1%) 0.56 Superficial infection, n (%) 1 (1%) 1 (1%) 1.0 Deep PJI within 90 days, n (%) 0 0 — PONV, n (%) 6 (9%) 8 (11%) 0.58 Readmission <30d, n (%) 1 (1%) 2 (3%) 0.56 Interpretation: No excess in serious complications was observed with corticosteroid addition. Transient hyperglycemia was slightly more common but not statistically significant.

This randomized trial demonstrates that the addition of intra-articular corticosteroid to a standardized multimodal analgesic cocktail during TKA significantly reduces early postoperative pain, accelerates functional recovery, and decreases opioid consumption without compromising safety. The observed between-group difference in movement-related pain at 24 hours (–1.5 points on NRS) exceeded the minimal clinically important difference for arthroplasty analgesia, confirming both statistical and clinical relevance [11]. Our findings are consistent with several randomized controlled trials and meta-analyses that have reported superior analgesic effects when corticosteroids are incorporated into peri- or intra-articular multimodal regimens [12–14]. These benefits likely arise from the potent local anti-inflammatory action of corticosteroids, which blunt prostaglandin synthesis, reduce edema, and thereby prolong the duration of analgesia beyond that afforded by local anesthetics alone [15]. The improvements in opioid sparing and earlier functional milestones observed in our study also align with prior evidence suggesting that improved pain control facilitates earlier mobilization and rehabilitation [16]. Importantly, our study adds to the growing body of literature by demonstrating that these benefits are achievable without significant increases in complications. Concerns about corticosteroid-related risks—particularly prosthetic joint infection (PJI)—have limited widespread adoption [17]. However, while preoperative intra-articular steroid injections within three months of arthroplasty have been associated with higher PJI risk, intraoperative administration under sterile surgical conditions appears safe. In the present trial, no deep infections were observed in either group within 90 days, and superficial wound issues were rare and comparable between groups. These findings mirror those of recent meta-analyses, which similarly reported no significant increase in infection or wound complications attributable to intraoperative corticosteroid use [12,14,18]. Transient postoperative hyperglycemia, observed slightly more frequently in the steroid group, was not statistically significant. This observation is expected, as perioperative systemic or intra-articular corticosteroid administration may induce transient insulin resistance [19]. Nevertheless, hyperglycemia did not translate into increased complications in our cohort, suggesting that careful monitoring and standard glycemic management protocols are sufficient to mitigate risk. Subgroup analysis of diabetic patients is warranted in larger studies to confirm these findings. The functional recovery outcomes—including earlier straight-leg raise, greater walking distance, and improved discharge flexion—are clinically important, as they directly influence early rehabilitation quality and readiness for discharge. Our study’s finding of shorter hospital stay with steroid addition is consistent with enhanced recovery protocols that emphasize pain control, mobilization, and reduced opioid dependence [16]. While the absolute reduction of 0.6 days may seem modest, at a population level such improvements translate into substantial economic and logistical benefits for high-volume arthroplasty centers. Nevertheless, several limitations merit discussion. First, the study was conducted at a single high-volume tertiary center with standardized surgical and perioperative protocols, which may limit external generalizability to centers with different practices. Second, the follow-up period was limited to 90 days for safety outcomes; while this window is sufficient to capture early wound and infection complications, longer-term follow-up is needed to exclude late-onset PJI. Third, although our trial was adequately powered for the primary outcome, it was underpowered to detect rare safety events such as deep infection. Large multicenter trials or registry data would be better suited to address this concern definitively [17,18]. Finally, we used betamethasone as the corticosteroid agent; whether other agents (e.g., dexamethasone, triamcinolone) produce equivalent or superior outcomes remains uncertain and should be explored in future research. Future directions include direct head-to-head comparisons of different corticosteroids, dose-ranging studies, and integration of intra-articular steroids with other evolving perioperative modalities such as liposomal bupivacaine or peripheral nerve catheters. Cost-effectiveness analyses would also be valuable, as shorter length of stay and reduced opioid use may offset the minimal cost of adding corticosteroid to the cocktail [20-25]. In summary, our findings support intra-articular corticosteroid as a valuable adjunct in multimodal periarticular analgesia for TKA. The intervention is simple, inexpensive, and easily generalizable, with clear benefits in pain relief, opioid reduction, and function, without evident safety compromises.

The addition of intra-articular corticosteroid to a multimodal analgesic cocktail in TKA significantly improved early postoperative pain control, reduced opioid consumption, enhanced functional recovery, and shortened hospital stay compared with a steroid-free cocktail. Importantly, no increase in wound complications, infection, or serious adverse events was observed, although transient hyperglycemia was slightly more common. These findings indicate that intraoperative intra-articular corticosteroid is an effective and safe adjunct to multimodal analgesia in TKA. Larger multicenter trials with longer follow-up are warranted to confirm safety and explore optimal agent selection and dosing strategies.

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