Comparative Effects of Two Periarticular Analgesic Cocktails on Pain Reduction and Inflammatory Response After Unicompartmental Knee Arthroplasty

Summary

This study aimed to compare and analyze the analgesic effect, anti‑inflammatory activity, and safety of two ropivacaine‑based periarticular analgesic cocktails in patients undergoing UKA. Following propensity score-matching, the ropivacaine-ketorolac-epinephrine regimen provided better analgesia, anti-inflammatory effects, and functional recovery, with comparable safety.

Abstract

Unicompartmental knee arthroplasty (UKA) serves as the primary surgical treatment for isolated unicompartmental knee osteoarthritis. Clinical data of 108 patients who underwent UKA at Yueyang People’s Hospital from January 2020 to December 2024 were retrospectively screened. After strict case exclusion, 102 patients were categorized into Group A (ropivacaine combined with morphine and compound betamethasone, n = 52) and Group B (ropivacaine combined with ketorolac tromethamine and epinephrine, n = 50). Propensity score matching (PSM) was subsequently performed to balance baseline characteristics, resulting in 46 patients per group after matching. Primary outcomes consisted of resting and active visual analog scale (VAS) scores, 48 h postoperative opioid consumption, and inflammatory biomarkers, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cell (WBC), and neutrophil (NEUT) levels. Secondary outcomes covered knee range of motion (ROM), time to initial postoperative ambulation, Knee Injury and Osteoarthritis Outcome Score (KOOS), Barthel Index (BI), and postoperative adverse events. Baseline parameters were well balanced between the two groups following PSM (all P > 0.05). At 48 h postoperatively, Group B presented significantly decreased resting and active VAS scores, as well as lower 48 h opioid consumption (all P < 0.001). Milder elevations of CRP, ESR, WBC, and NEUT were observed in Group B (all P < 0.001). Additionally, Group B demonstrated superior knee functional recovery reflected by better ROM, higher KOOS and BI scores, and shorter time to first ambulation (all P < 0.001). No significant intergroup difference was detected in the incidence of adverse events (P = 0.503). In this single-center retrospective cohort, the ropivacaine–ketorolac–epinephrine cocktail demonstrates superior analgesic and anti-inflammatory properties with a noninferior safety profile. Limited by the single-center, retrospective design, this regimen is preliminarily considered a promising analgesic alternative for UKA patients, and further large-sample, multicenter, prospective studies are required for validation.

Introduction

The escalating global aging trend has driven a steady increase in the incidence of knee osteoarthritis (KOA), with the prevalence exceeding 10 % in individuals aged ≥ 60 years¹. Among these, approximately 30 % of patients present with isolated unicompartmental lesions, for which unicompartmental knee arthroplasty (UKA) has emerged as an ideal alternative to total knee arthroplasty², offering minimal invasiveness, reduced blood loss, near-physiological knee range of motion (ROM), and accelerated rehabilitation³.

However, postoperative pain remains a critical barrier to early functional recovery in UKA patients⁴. Unlike TKA, where pain arises from extensive soft tissue dissection and bone preparation across all compartments, UKA-specific pain mechanisms are distinct and more focal⁵. The surgical approach involves targeted incision and periosteal dissection confined to the affected compartment, with prosthesis implantation generating localized mechanical irritation and nociceptive signaling⁶. The preservation of cruciate ligaments and contralateral compartment structures maintains greater proprioceptive feedback, potentially amplifying pain perception from the operated compartment⁷. The minimally invasive nature of UKA, while reducing overall trauma, concentrates inflammatory mediators within a smaller surgical field, leading to intense localized inflammatory responses that directly stimulate free nerve endings and exacerbate pain⁸. Additionally, the proximity of the surgical site to the subchondral bone plate and retained meniscal rim in the contralateral compartment may heighten postoperative sensitivity to weight-bearing stress⁹. These UKA-specific pain characteristics necessitate highly effective periarticular analgesia that addresses both the focal nociceptive input and the concentrated local inflammatory cascade, rather than merely replicating TKA analgesic protocols¹⁰.

Currently, multiple analgesic modalities are clinically available for postoperative pain management following UKA, each possessing inherent advantages and drawbacks that complicate standardized analgesic selection. Common alternative techniques include peripheral nerve block, systemic intravenous analgesia, and simple single-agent local anesthetic infiltration. Peripheral nerve block provides reliable moderate-to-severe pain relief but carries unavoidable risks of motor nerve paralysis, delayed ambulation, nerve injury, and additional ultrasound-guided operation costs, which are inconsistent with the rapid rehabilitation concept of UKA. Systemic intravenous analgesia dominated by opioids can relieve generalized pain, yet it frequently triggers systemic adverse reactions such as nausea, vomiting, dizziness, and respiratory depression, with poor control of localized inflammatory pain in the surgical compartment. Conventional single-drug periarticular infiltration adopts a simple administration method, but its short analgesic duration and weak anti-inflammatory capacity often fail to sustain effective pain control within 48 h after UKA, resulting in rebound pain during early weight-bearing activities. In comparison, multi-drug combined periarticular infiltration anesthesia (PIA) stands out with its simple intraoperative administration, localized drug action, negligible systemic side effects, and balanced analgesic and anti-inflammatory properties, making it the most adaptable analgesic method for minimally invasive UKA.

Periarticular infiltration anesthesia (PIA) has been widely adopted in joint replacement surgeries due to its ease of administration, direct analgesic effect, and minimal systemic adverse reactions¹¹. Ropivacaine, a long-acting amide local anesthetic with low cardiac toxicity and favorable sensory-motor separation, serves as the cornerstone of PIA analgesic cocktails¹². Among clinically used combinations, ropivacaine + morphine + compound betamethasone represents an earlier established regimen, whereas ropivacaine + ketorolac tromethamine + epinephrine has garnered increasing attention for its NSAID-based anti-inflammatory mechanism and prolonged duration of action through epinephrine-induced vasoconstriction. The two regimens above represent representative mainstream strategies in periarticular analgesia with fundamentally distinct mechanisms. One relies on central opioid and corticosteroid effects, while the other focuses on peripheral anti‑inflammatory action and vasoconstriction. A direct comparison of these two regimens can provide evidence to guide optimal analgesic selection in UKA patients.

Postoperative inflammatory response is closely intertwined with pain and constitutes another key factor influencing UKA recovery. The concentrated local inflammatory cascade not only directly stimulates nerve endings to exacerbate pain but also causes joint swelling and effusion, hindering ROM recovery and potentially impairing periprosthetic tissue healing¹³. Therefore, evaluating analgesic cocktail efficacy requires integration of both pain scores and inflammatory markers to comprehensively reflect their dual analgesic and anti-inflammatory effects.

Notably, the two PIA regimens have clear applicable populations and clinical limitations to guide practical clinical application. The ropivacaine-morphine-compound betamethasone regimen is suitable for elderly patients with poor tolerance to NSAIDs, patients with mild preoperative gastrointestinal and renal dysfunction, and individuals requiring long-term mild pain relief without early aggressive ambulation. Nevertheless, this regimen is limited by opioid-related side effects and delayed local inflammatory regression, which is not recommended for young, highly active patients pursuing rapid rehabilitation. By contrast, the ropivacaine-ketorolac tromethamine-epinephrine regimen is preferred for middle-aged and young patients with unimpaired gastrointestinal and renal function, patients with obvious preoperative inflammatory hyperalgesia, and those undergoing accelerated postoperative rehabilitation protocols. Its primary limitations lie in contraindications for patients with NSAID allergies, peptic ulcers, and coagulation disorders, and the vasoconstrictive effect of epinephrine requires cautious use in patients with severe peripheral vascular disease. Given the single-center, retrospective design and the non-randomized grouping of this study, the stratified application of the two regimens should be based solely on individual patient comorbidities, physical tolerance, and rehabilitation expectations, to avoid a blind, universal approach.

Through retrospective analysis, this study systematically compares these two ropivacaine-based PIA regimens. The study hypothesized that the ropivacaine-ketorolac tromethamine-epinephrine regimen would yield superior analgesic and anti-inflammatory effects, facilitate earlier functional recovery, and exhibit a safety profile similar to that of the ropivacaine–morphine–betamethasone regimen. This study aims to provide evidence‑based guidance for optimizing postoperative analgesia in UKA and promoting functional recovery.

Protocol

This study was reviewed and approved by the Medical Ethics Committee of Yueyang People’s Hospital (Ethical Approval No.: ky2025012), and all procedures were performed in strict accordance with the Declaration of Helsinki¹⁴.

1. Patients and methods

1. Retrieve medical records of 108 patients who underwent UKA at Yueyang People’s Hospital from January 2020 to December 2024.
2. Enroll 102 patients after exclusions.
   1. Divide them into Group A (ropivacaine + morphine + compound betamethasone, n = 52) and Group B (ropivacaine + ketorolac tromethamine + epinephrine, n = 50) by intraoperative periarticular analgesic cocktail type.
3. Perform 1:1 propensity score matching (PSM) with a 0.02 caliper width to minimize baseline confounding effects.
   1. Include 46 patients per group, with well-balanced baseline characteristics, for subsequent analysis. (Figure 1)
4. Inclusion Criteria
   1. Confirm that patients meet the diagnostic criteria for unicompartmental knee osteoarthritis.
      1. Verify isolated medial or lateral compartment lesions via imaging and ensure contralateral compartment cartilage wear is no higher than Kellgren-Lawrence grade II.
      2. Exclude patients with obvious patellofemoral osteophytes or cartilage damage¹⁵.
   2. Enroll patients aged 18–75 years without gender restriction.
      1. Confirm the ASA physical status of I–II, and ensure normal baseline blood, hepatic, renal, and coagulation indicators.
      2. Exclude patients with severe cardiopulmonary or visceral organic dysfunction.
   3. Screen patients with persistent pain or recurrent symptoms after no less than six months of standardized conservative treatment.
      1. Include only patients scheduled for unilateral unicompartmental knee arthroplasty.
   4. Perform all surgical procedures in Yueyang People’s Hospital.
      1. Administer one of the two standardized periarticular infiltration analgesic cocktails intraoperatively and collect complete clinical data from all enrolled patients.
5. Exclusion Criteria
   1. Screen patients for joint-related diseases and surgical history.
      1. Exclude individuals with various inflammatory arthritis and multicompartmental knee lesions, and eliminate candidates with congenital knee deformity, traumatic arthritis, or prior knee revision surgery.
   2. Evaluate preoperative physical activity and medication history.
      1. Exclude patients with knee motion limitation below 90° or severe muscle contracture and rule out individuals using opioids or glucocorticoids within 14 days before surgery.
   3. Assess systemic organ function and mental status.
      1. Exclude patients with severe cardiopulmonary, hepatic, renal, and hematological diseases or advanced malignancies, and eliminate those diagnosed with irreversible mental and cognitive disorders.
   4. Confirm lower extremity conditions and surgical records.
      1. Exclude patients with severe vascular or poor neuromuscular function, recent knee invasive procedures, concomitant orthopedic surgery, and those requiring secondary postoperative intervention¹⁶.

2. Analgesic regimen

1. Use a 20 mL disposable syringe equipped with a 22 G needle 38 mm in length for all injection procedures.
   1. Use normal saline as the diluent to standardize the total volume of each cocktail to 20 mL.
   2. Inject the mixed solution uniformly at multiple sites in the following fixed order: periarticular capsular tissue, quadriceps tendon insertion, pes anserine tendon, and periligamentous regions of the collateral ligaments, allocating an equal injection volume to each anatomical site.
   3. After completing the multi-point injection, close the surgical incision with layered suturing, and apply compressive bandaging using sterile dressings.
      NOTE: Cocktail A (ropivacaine + morphine + compound betamethasone): Cocktail A consisted of 10 mL of 1 % ropivacaine hydrochloride injection, 10 mg of morphine sulfate injection, and 1 mL of compound betamethasone injection, and the mixture was further diluted with 0.9 % sodium chloride injection to a standardized total volume of 20 mL. Cocktail B (ropivacaine + ketorolac tromethamine + epinephrine): Cocktail B was composed of 10 mL of 1 % ropivacaine hydrochloride injection, 30 mg of ketorolac tromethamine injection, and 0.1 mg of epinephrine hydrochloride injection, and 0.9 % sodium chloride injection was added as diluent to make up a total injection volume of 20 mL for standardized local infiltration¹⁷.

3. Data collection

1. Draw study data from the hospital’s electronic and paper-based medical record archives. Assign two uniformly trained physicians to independently perform data extraction and entry to ensure data reliability.
2. Define the data collection period as January 2020 to December 2024.
3. Collect baseline preoperative data within 24 h of admission and 1 day before surgery; collect postoperative outcome data at 48 h postoperatively (starting from the moment of skin suture completion at the end of surgery).
   NOTE: Two trained investigators independently and blindly extracted all data; discrepancies were adjudicated by a senior attending physician using the original medical records. Inter-rater reliability was excellent, with Kappa = 0.89 for categorical variables and ICC = 0.92 for continuous variables.

4. Outcome measures

1. Primary Outcome Measures
   1. Resting and activity visual analog scale (VAS) scores: Use a standard 0–10 point VAS ruler, with higher scores indicating more severe pain¹⁸.
   2. Extract sufentanil consumption data from the patient-controlled intravenous analgesia pump's built-in metering system.
      1. Convert additional oral or intravenous opioids to sufentanil-equivalent doses using the Clinical Practice Guidelines for Postoperative Pain Management in Adults¹⁹.
      2. Calculate the total cumulative opioid consumption within 48 h postoperatively.
   3. C-reactive protein (CRP): Detect CRP via immunoturbidimetry.
      1. Collect 3 mL fasting venous blood and place samples in sterile serum separation tubes.
      2. Separate serum at 3000 × g for 10 min under 4 ℃.
      3. Test supernatant with an automatic biochemical analyzer²⁰.
      4. Set the detection wavelength at 546 nm and reaction temperature at 37 ℃.
      5. Calibrate reagents before each batch of tests and follow factory default parameters.
   4. Erythrocyte sedimentation rate (ESR): Measure ESR using the Westergren method.
      1. Aspirate 1.6 mL anticoagulated blood into disposable ESR tubes.
      2. Conduct detection with an automatic ESR analyzer²⁰.
      3. Maintain a constant temperature of 18–25 ℃ for 60 min.
      4. Keep tubes vertically stationary and calculate sedimentation height via automatic optical tracing without manual parameter modification.
   5. White blood cell (WBC) and neutrophil (NEUT): Collect fasting venous blood samples.
      1. Detect WBC and NEUT counts with an automated hematology analyzer²¹.
      2. Apply factory default whole-blood mode at a 1:250 dilution ratio.
      3. Adopt Westgard quality control rules without manual adjustment.
      4. Set the sampling volume at 20 µL and perform daily blank calibration for detection accuracy.
2. Secondary Outcome Measures
   1. Knee ROM: Use a standard goniometer for all measurements.
      1. Position the patient supine.
      2. Align the goniometer with the lateral femoral condyle as the fixed point.
      3. Place the fixed arm parallel to the femoral long axis and the movable arm parallel to the tibial long axis.
      4. Instruct the patient to perform active maximum knee flexion.
      5. Repeat the measurement three times and calculate the mean value²².
   2. Time to first ambulation postoperatively: Define this index as the time when patients first stand and walk 3 steps with a walker after surgery, and verify the specific times using nursing records²³.
      NOTE: Knee injury and Osteoarthritis Outcome Score (KOOS): The KOOS is a validated patient-reported outcome instrument consisting of 42 items across five domains: pain, symptoms, activities of daily living, sport and recreation function, and knee-related quality of life. Each item is rated on a 0-4 Likert scale, with domain scores converted to a normalized range of 0-100, where a higher score indicates fewer symptoms and better knee function²⁴.
   3. Barthel Index (BI): Assess patients' independence in activities of daily living (ADLs) using the BI scale, which covers 10 ADL items, including feeding, washing, dressing, and toileting, with a total score of 100. Note that higher scores reflect greater independence in daily activities²⁵.
   4. Adverse events: Evaluate adverse reactions, including gastrointestinal reactions, urinary system reactions, central nervous system reactions, local tissue reactions, infection risk, cardiovascular reactions, and bleeding risk.
      1. Document adverse events based on medical records and calculate the incidence of adverse events²⁶.
         NOTE: Intermuscular thrombosis was defined as intramuscular or intermuscular deep vein thrombosis (DVT), excluding superficial thrombophlebitis. All thrombotic events were diagnosed by bilateral lower extremity compression Doppler ultrasound according to standard criteria. All adverse events were attributed to the combination of analgesic regimen.
3. Biosafety Protection and Waste Disposal Specifications
   1. Provide biosafety training for all operating staff.
      1. Wear gloves, masks, and isolation gowns during operations.
      2. Use sterile disposable medical devices for puncture and injection.
      3. Equip sharp instruments with anti-puncture sleeves.
      4. Transport sealed blood samples in biosafety transfer boxes. Complete all specimen manipulation in a Class II biological safety cabinet.
   2. Classify medical wastes in accordance with hospital and national laboratory guidelines.
      1. Place sharp waste into puncture-proof boxes and contaminated waste into sealed hazardous bags.
      2. Mark waste information clearly for unified collection, disinfection, and incineration.
      3. Store residual samples at −80 °C for retrospective detection.
      4. Sterilize expired samples via high-temperature steam before centralized disposal.

5. Sample size calculation

NOTE: Referring to the previous study results²⁷, among 61 patients who underwent UKA, the modified analgesic cocktail group had significantly lower resting and activity VAS scores at 24 h postoperatively compared with the unmodified group (resting: 3.70 vs. 4.38, P = 0.007; activity: 4.23 vs. 5.68, P < 0.001), yielding an estimated Cohen’s d of 0.62. With α = 0.05 (two-tailed) and β = 0.20, the calculated sample size required 42 patients per group. Given the potential loss of data in retrospective studies and the actual number of patients in the hospital, 46 patients per group were included in the final analysis after PSM, meeting the sample size requirement.

6. Statistical analysis

1. Perform propensity score matching (PSM) using the nearest neighbor matching algorithm with a caliper width of 0.02 without replacement.
   1. Establish a logistic regression model to calculate propensity scores by incorporating all demographic and clinical baseline covariates.
   2. Adopt the standardized mean difference (SMD) to evaluate post-matching baseline balance and define SMD < 0.1 as acceptable between-group balance.
2. Test the normality of data using the Shapiro-Wilk test.
   1. For normally distributed continuous data, use the paired t-test for intra-group comparisons and the independent samples t-test for inter-group comparisons, and present results as mean ± standard deviation (mean ± SD).
   2. For non-normally distributed continuous data, present results as median (interquartile range) [M (Q1, Q3)], and use the Wilcoxon signed-rank test for intra-group comparisons and the Mann-Whitney U test for inter-group comparisons.
3. Present categorical data as n (%) and perform inter-group comparisons using the Chi-square test.
4. Define all statistical tests as two-tailed and regard a P value < 0.05 as statistically significant.
   NOTE: All statistical analyses were performed using statistical analysis software. No missing primary outcome data were identified. Thus, no data imputation or sample exclusion was applied to key variables. All analyses used original, complete observations.

Results

Baseline characteristics of patients

Table 1 shows baseline characteristics before and after PSM. Before matching, Group A included 52 patients and Group B 50 patients. PSM was performed using a logistic regression model with age, gender, BMI, ASA classification, lesion site, K-L grading, hypertension, diabetes, and CHD as covariates; only main effects were included without interaction or nonlinear terms. Prior to PSM, gender, BMI, and hypertension differed si...

Discussion

UKA represents a precision surgical procedure for the treatment of unicompartmental knee osteoarthritis. Currently, multimodal analgesia regimens based on ropivacaine are widely adopted in clinical practice, achieving synergistic analgesic effects through the combination of drugs with distinct mechanisms of action. However, differences in postoperative analgesic intensity, anti-inflammatory efficacy, and safety persist among analgesic cocktails with varying drug combinations²⁸. This retrospective ...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
1% ropivacaine hydrochloride injection	AstraZeneca Pharmaceuticals LP	H20140763	drug
morphine sulfate injection	Shenyang No.1 Pharmaceutical Co., Ltd.	H21022436	drug
compound betamethasone injection	Merck Sharp & Dohme Corp.	H20180023	drug
ketorolac tromethamine injection	Shandong New Times Pharmaceutical Co., Ltd.	H20052634	drug
epinephrine hydrochloride injection	Shanghai Hefeng Pharmaceutical Co., Ltd.	H31021170	drug
VAS ruler	Shanghai Medical Devices Co., Ltd.	SY-VAS-01	scale
patient-controlled intravenous analgesia pump	Zhuhai Funia Medical Equipment Co., Ltd.	FCS-6000	Instrument
automatic biochemical analyzer	Roche Diagnostics	Cobas 8000	Instrument
automatic Erythrocyte sedimentation rate analyzer	Beijing Succeeder Technology Co., Ltd.	ESR-600	Instrument
automatic hematology analyzer	Mindray	BC-6800	Instrument
standard goniometer	Guilin Guanglu Digital Measurement & Control Co., Ltd.	GL-100	Instrument
G*Power	Heinrich - Heine - Universität Düsseldorf	3.1.9.7	software
SPSS software	IBM	SPSS 27.0	software
Doppler ultrasonography	Philips Healthcare	EPIQ 7	Instrument
20 mL disposable syringe	Becton, Dickinson and Company	300613	syringe
22G long needle of 38 mm in length	Terumo Medical Corporation	NN-2238R	syringe
0.9% sodium chloride injection	China National Biotec Group	S20053046	drug