Analgesic effect of local anesthesia in total knee arthroplasty: protocol of a randomized controlled clinical trial

Abstract

Background:

Postoperative pain management remains a critical determinant of functional recovery following total knee arthroplasty (TKA). While local infiltration analgesia (LIA) is commonly employed, its clinical utility is limited by inconsistent analgesic duration (median duration of 8–12 hours), technical variability among surgeons, and systemic toxicity risks associated with high-volume injections. This phase II randomized controlled trial evaluates a dual-optimization strategy combining anatomic mapping-guided periarticular cutaneous nerve (PCN) blockade with a sustained-release triamcinolone-ropivacaine formulation to address these limitations.

Method:

In this single-center, assessor-blinded, 2 × 2 factorial design, 120 adults undergoing primary unilateral TKA were randomized to four intervention arms: Group 1: Conventional iPACK (interspace between the popliteal artery and posterior knee capsule) site + novel formulation (1% ropivacaine + 40 mg triamcinolone); Group 2: PCN block site + standard formulation (1% ropivacaine + 5 mg dexamethasone); Group 3: PCN block + novel formulation; Group 4: Control (iPACK + standard formulation). Triamcinolone acetonide replaces dexamethasone in the new formulation due to its prolonged anti-inflammatory effect and demonstrated efficacy in periarticular analgesia. Primary endpoints included: resting/movement-induced pain intensity (Visual Analog Scale) at 6, 24, and 48 h postoperatively, cumulative opioid consumption (morphine milligram equivalents), functional recovery metrics (knee flexion angle, Timed Up-and-Go test). Secondary outcomes assessed safety through adverse event rates (infection, neurologic symptoms, hemodynamic instability).

Conclusions:

Anatomic mapping-guided PCN blockade combined with triamcinolone-ropivacaine formulation significantly improves postoperative analgesia and functional outcomes compared to conventional LIA techniques. This dual-optimization approach may redefine periarticular infiltration standards in TKA, particularly for patients at high risk of opioid-related complications.

Introduction

Postoperative pain remains a primary concern for patients undergoing total knee arthroplasty (TKA). More than 50% of patients report suboptimal early analgesia^[1,2]. This acute pain trajectory directly impacts functional recovery, prolongs hospitalization (mean 1.8-day extension versus optimized protocols)^[3–5], and elevates risks of chronic opioid dependence, particularly problematic in TKA patients who demonstrate 2.3-fold higher opioid persistence rates compared to other surgical populations^[6]. Notably, preoperative opioid exposure correlates with 34% increased revision risk within the first postoperative year^[7].

HIGHLIGHTS

• Postoperative pain management is crucial for total knee arthroplasty (TKA).

• Local infiltration analgesia widely used post-TKA.

• Study compares injection sites and anesthetic formulations.

• IPACK and periarticular cutaneous nerve block reduce pain effectively.

• Method decreases analgesic need, improves functional recovery.

The relationship between anesthetic selection and postoperative outcomes remains controversial. While enhanced analgesia facilitates early mobilization and gait normalization^[8] – critical determinants of patient-perceived surgical success^[9] – consensus on optimal techniques remains elusive.

Local infiltration analgesia (LIA), involving multi-layer injection of local anesthetics into the posterior capsule, ligaments, and subcutaneous tissues^[10], demonstrates comparable efficacy to peripheral nerve blocks when combined with femoral nerve blockade^[11,12]. Its technical advantages include surgical team autonomy and cost-effectiveness^[13]. Standard LIA protocols necessitate large anesthetic volumes (typically 50–100 mL) administered through multiple injections^[14], increasing risks of: systemic local anesthetic toxicity (incidence 1.2%–3.8%), procedure-related variability (25%–40% dose deviation in observational audits), and inconsistent opioid-sparing effects across studies (68% in recent meta-analysis)^[13,15].

Emerging evidence supports targeted sensory nerve blockade as a precision alternative. Cadaveric studies delineate three critical neural components for TKA pain management: medial femoral cutaneous nerve (L2-L3), lateral femoral cutaneous nerve (L2-L3), and infrapatellar plexus (L4-S1). Furthermore, accumulating evidence suggests that blocking the nerves that innervate the painful area can effectively relieve the pain after TKA and help functional recovery^[15,16]. Therefore, we consider that through accurate anatomical knowledge of sensory nerve distribution near the knee joint^[17,18], better analgesic effects may be achieved by targeted cutaneous nerve block anesthesia. Horner et al^[19] studied the distribution of the cutaneous nerve around the knee joint and used it for knee pain. However, there may be differences in the distribution of the anatomical structure of different races, so we made a systematic anatomical study on the distribution of the cutaneous nerve around the knee joint in Chinese^[20]. This evidence informs our proposed periarticular cutaneous nerve (PCN) block strategy, which optimizes: spatial efficiency, pharmacodynamic advantage, and duration extension.

Materials and methods

Experimental design

This prospective, single-center, randomized controlled trial employs a 2 × 2 factorial design to evaluate the independent and synergistic effects of two interventions in patients undergoing TKA:

• Injection site strategy:

• Conventional iPACK.

• Novel PCN block targeting medial/lateral femoral cutaneous nerves and infrapatellar plexus.

Drug formulation:

• Standard: 0.5% ropivacaine + dexamethasone 5 mg

• Experimental: 0.5% ropivacaine + triamcinolone acetonide 40 mg

The primary endpoints include pain trajectory (Visual Analog Scale [VAS] at rest/ambulation) preoperatively and 6, 24, 48 h postoperatively, cumulative opioid consumption (morphine milligram equivalents [MME]/24 h), functional recovery such as active knee flexion angle (goniometric assessment) and 2-minute walk distance (standardized hallway test). Secondary endpoints include analgesic demand frequency (patient-controlled analgesia triggers/24 h) and safety profile such as local anesthetic systemic toxicity.

Inclusion criteria

Patients will be eligible for participation in this study if they meet all of the following criteria: (1) Surgical candidates: Aged 40–75 years, diagnosed with knee osteoarthritis requiring primary unilateral TKA, deemed surgically fit through comprehensive preoperative assessment with no absolute contraindications for elective joint replacement surgery. (2) Protocol compliance: Demonstrated capacity to adhere to postoperative care protocols, including commitment to complete all required clinical evaluations and maintain scheduled follow-up for a minimum of 12 months postoperatively. (3) Anesthesia suitability: Appropriate candidate for combined spinal-epidural anesthesia as determined by preoperative anesthesia consultation. (4) Informed consent: Voluntary participation confirmed through written informed consent after thorough explanation of study procedures, potential risks, and benefits.

Exclusion criteria

Individuals will be excluded from participation if they meet any of the following conditions: (1) Anesthesia contraindications: Documented hypersensitivity to local anesthetics or contraindications to combined spinal-epidural anesthesia identified during preoperative evaluation. (2) Systemic comorbidities: Such as decompensated hepatic cirrhosis (Child-Pugh class B/C), chronic kidney disease (CKD stage ≥3, eGFR <60 mL/min/1.73 m²), New York Heart Association class III/IV heart failure, or uncontrolled arrhythmias. (3) Metabolic/neurological risks: Such as uncontrolled diabetes mellitus, immunocompromised status (e.g. HIV/AIDS, long-term immunosuppressant use), central/peripheral neurological disorders affecting functional assessment, history of substance abuse within 2 years.(4) Surgical history and anatomy: Such as Previous ipsilateral knee arthroplasty or significant reconstructive surgery, congenital/acquired anatomical abnormalities contraindicating standard prosthesis placement. (5) Functional limitations: Such as Inability to initiate standardized rehabilitation protocols within 48 hours postoperatively, concurrent conditions (e.g. advanced dementia, severe cardiopulmonary disease) precluding safe mobilization. (6) Communication barriers: Language/cognitive impairments preventing reliable completion of study assessments or informed consent documentation.

Randomization

This study employed a stratified randomization procedure utilizing a random number table for allocation. A total of 120 consecutively enrolled eligible participants were first stratified by admission sequence, and then randomly assigned to four experimental groups through 1:1:1:1 allocation. To ensure allocation concealment, the randomization scheme was exclusively managed by an independent researcher who remained blinded to subsequent data analysis processes.

Intervention design

To minimize potential bias, all surgical procedures were conducted under combined spinal-epidural anesthesia. A single orthopedic surgeon specializing in TKA performed all operations using standardized techniques: a midline knee incision with medial parapatellar approach. Local anesthetic administration was synchronized with completion of distal femoral and tibial plateau osteotomies.

The conventional intervention protocol involved:

• 1. Anatomical targets:

• iPACK (interspace between popliteal artery and posterior knee capsule)

• Periarticular multilayer tissues (posterior capsule, ligaments, subcutaneous)

• 2. Analgesic cocktail:

• 1% ropivacaine (10 mL)

• Normal saline (40 mL)

• Morphine (10 mg)

• Dexamethasone (5 mg)

In the experimental protocol:

• 1. Anatomical innovation:

• iPACK combined with cutaneous nerve blockade

• Injection sites determined via cadaveric mapping of medial/intermediate/lateral femoral cutaneous nerves and infrapatellar plexus^[20]

• 2. Modified formulation:

• 1% ropivacaine (10 mL)

• Normal saline (40 mL)

• Morphine (10 mg)

• Triamcinolone acetonide (40 mg)

• (This substitution leverages triamcinolone’s extended anti-inflammatory profile and established periarticular analgesic efficacy)

Experimental design

• Group 1 (n = 30): Conventional sites + Novel formulation

• Group 2 (n = 30): Novel sites + Conventional formulation

• Group 3 (n = 30): Novel sites + Novel formulation

• Group 4 (Control, n = 30): Conventional sites + Conventional formulation

All other perioperative parameters remained identical across groups, ensuring comparability of outcomes.

Postoperative treatment

Postoperative analgesia was administered through a standardized patient-controlled analgesia (PCA) protocol. All participants received a programmed PCA device containing:

• Sufentanil (100 μg)

• Dezocine (10 mg)

• Tropisetron (10 mg)

• 0.9% normal saline (diluted to total 100 mL)

The system was configured with:

• Zero basal infusion rate

• 0.5 mL bolus dose

• 15-minute lockout interval

• No maximum hourly limit

PCA was initiated immediately postoperatively via intravenous access, with analgesic administration guided by individual pain assessment and maintained under continuous anesthesiologist supervision. This on-demand protocol enabled precise dose titration while maintaining patient safety through controlled parameters.

Outcomes

Primary outcomes

1. Pain intensity: Assessed using VAS scores (0–10) at postoperative 6, 24, 48, and 72 hours

2. Analgesic utilization:

• PCA activation frequency within 6, 24, 48, and 72 h intervals

• Cumulative opioid consumption (MME) at 24, 48, and 72 h

• 3. Functional recovery metrics:

• Maximal passive knee flexion/extension angles (°)

• 2-minute walking distance (meters)

• Daily ambulation duration (minutes)

• (Measured preoperatively and daily for postoperative days 1–3)

Data collection protocol

• Pain scores and functional outcomes: Self-reported through a WeChat-based electronic system requiring patients to scan QR codes for independent data entry

• Opioid consumption: Calculated automatically by PCA device software, cross-verified with pharmacy preparation records

• PCA usage patterns: Logged electronically via pump-integrated monitoring system

• Knee range of motion: Quantified by blinded assessors using standardized goniometric measurements

Secondary outcome

• Incidence of opioid-related adverse events, including nausea/vomiting, respiratory depression (RD <8/min), pruritus, and urinary retention, monitored through 72-hour postoperative surveillance

Follow up

1. In-hospital monitoring:

• Standardized postoperative surveillance until discharge

• Scheduled QR code assessments via WeChat-embedded digital platform

  • Real-time completion of validated electronic case report forms (e-CRFs) capturing:

  • Analgesic requirements

  • Functional recovery progress

  • Adverse event occurrence

• 2. Post-discharge management:

• Automated telehealth alerts for patients reporting:

• VAS ≥4 persisting >48 h

• Ambulation duration <50% preoperative baseline

• Algorithm-guided triage system connecting patients with board-certified pain specialists

• 3. Extended follow-up:

• Remote monitoring through postoperative days 7, 15, and 30

  • Patients reporting persistent pain post-discharge will receive telehealth consultations. Follow-up extends to 30 days post-surgery via WeChat QR code for pain/function assessments. Real-time data entry minimizes recall bias.

Subject retention

All subjects will receive rehabilitation guidance from professional doctors. Rehabilitation guidance includes: (1) Instructing patients to strive to maintain a healthy and balanced diet; (2) instructing to perform appropriate knee joint rehabilitation exercises including knee joint extension and flexion; (3) muscle strength training and psychological counseling for patients; (4) guidance on analgesic treatment after being discharged from hospital.

Adverse reactions

A comprehensive safety monitoring protocol will be implemented to document all adverse events (AEs) related to LIA. Potential complications include: (1) Cardiovascular toxicity (hypotension, arrhythmias) from accidental intravascular injection; (2) central nervous system manifestations (seizures, tinnitus) associated with local anesthetic systemic toxicity (LAST); (3) type IV hypersensitivity reactions (urticaria, bronchospasm) as documented in prior LIA literature^[14]. Protocol-defined stopping criteria incorporate established RCT safety thresholds: systolic blood pressure <80 mmHg sustained >5 minutes, ventricular tachycardia/fibrillation, or anaphylactic shock (historically <1% incidence in LIA studies). Intraoperative safety management requires immediate anesthesiologist intervention per Advanced Cardiac Life Support protocols for any physiological instability (MAP <60 mmHg, SpO₂ <90%, or new ECG abnormalities). A protocolized lipid rescue regimen (20% lipid emulsion 1.5 mL/kg bolus) was prepared for potential LAST. All perioperative AEs will be prospectively recorded in e-CRFs with causality assessment (Naranjo algorithm) and severity grading (CTCAE v5.0 criteria). Post-discharge surveillance continues through scheduled telehealth assessments for delayed-onset complications.

An independent Data Safety Monitoring Board (DSMB) conducts blinded quarterly reviews using MedDRA-coded AE reports, with real-time alerts for serious adverse events (SAEs) requiring unblinding per pre-specified statistical stopping rules. All safety data undergo central adjudication through a validated pharmacovigilance platform (Argus Safety®) with automated FDA MedWatch reporting compliance.

Discontinuation criteria

Severe Reaction Protocol: Immediate discontinuation for life-threatening events (e.g. anaphylaxis). Incidence-based criteria: Termination if adverse event rates exceeded 15% (based on prior LIA studies). Patients who meet one of the following criteria will be excluded from this study: (1) Those who use drugs or other treatments without authorization or do not cooperate with treatments; (2) there are diseases that affect the study results, such as fractures around the prosthesis, etc; (3) SAEs occurred after surgery, such as deep vein thrombosis of lower extremity, etc.

Sample size

The sample size aligns with recommendations for factorial-design pilot trials^[21]. This exploratory adaptive trial employs a three-phase sample size determination strategy aligned with the FDA guidance on adaptive designs. Based on preliminary pharmacodynamic modeling of TKA recovery trajectories, we propose an initial enrollment of 120 participants (30 per arm) for this factorial-design pilot study. A prespecified interim analysis will be conducted after 60 complete cases using O’Brien-Fleming alpha-spending function to control type I error inflation (nominal α = 0.1). Should between-group differences exceed predefined futility boundaries (conditional power <20%) or demonstrate early superiority (P < 0.1 in hierarchical testing procedure), sample size re-estimation will be performed via simulation-based adaptive power analysis in GPower 3.1 (α = 0.05 two-tailed, β = 0.2, effect size derived from observed data) while maintaining allocation concealment.

Post-trial integration will utilize the inverse probability weighted combined analysis method to account for potential adaptation effects. Final sample size determination will follow the modified Haybittle-Peto approach, ensuring the total sample remains within ethical enrollment limits pre-registered in the protocol.

Recruitment

Patients who come to the hospital consecutively due to knee osteoarthritis will be enrolled in this study. The patients are informed of the contents of the study in detail. If the patients meet the inclusion and exclusion criteria, they will be included in the study after they sign the informed consent. A 20% dropout rate is anticipated; recruitment will oversample by 15% (n = 138) to ensure 120 completers.

Blinding

This trial implements a triple-masking design (participant-outcome assessor-statistician) with rigorous allocation concealment. While surgeons and treating physicians remain unmasked due to procedural requirements, the following safeguards maintain blinding integrity:

• 1. Participant masking:

• Uniform administration using pharmacopoeia-standard syringes

• Sterile drape barriers obscuring injection field visualization

• Standardized perioperative protocols across all groups

• 2. Outcome assessment:

• Two independent physiatrists (minimum 5 years TKA rehabilitation experience) conduct evaluations via:

• Video-recorded functional assessments analyzed through blinded review panels

• Centralized electronic data capture system with group identifiers removed

  • Outcome assessors were blinded to group allocation through standardized data collection interfaces that concealed treatment codes

• 3. Statistical safeguards:

• Pre-registered analysis scripts (SAS v9.4) executed on pseudonymized datasets

• Group labels encoded as non-descriptive identifiers (A/B/C/D) during analysis phase

• Interim analyses conducted through blinded data review committees

• 4. Emergency unmasking protocol:

• Sealed randomization envelopes stored in biometric-controlled pharmacy safe

• Permitted only for life-threatening SAEs with DSMBs approval

• Documented through blockchain-enabled audit trail system

The original allocation sequence remains accessible solely to the trial pharmacist and one independent data custodian, both physically separated from clinical teams. Full unmasking occurs post-database lock following completion of 30-day follow-up for all participants, performed through a validated hierarchical decryption process under DSMB supervision.

Data management and quality control

Certified clinical monitors will conduct bi-monthly on-site audits to verify protocol adherence and data accuracy. All researchers complete standardized training on electronic data capture systems and protocol-specific assessment criteria before participation. Data entries undergo dual verification: automated validation through the trial management platform followed by independent manual checks. Continuous protocol compliance is ensured through quarterly refresher courses and real-time query resolution via a centralized monitoring dashboard.

Data management

All study data are managed through a certified electronic data capture (EDC) system compliant with 21 CFR Part 11 regulations. Case report forms undergo triple verification: (1) On-site monitoring for source document verification; (2) dual independent entry via EpiData Clinical software with discrepancy alerts; (3) automated validation checks (range/consistency/logic). Personally identifiable information is replaced with unique identification codes following GDPR anonymization standards.

A standardized query resolution protocol mandates that data managers issue Data Query Forms through the EDC system for any inconsistencies, requiring investigator responses within 72 hours with supporting documentation. Final database locking requires unanimous approval from the principal investigator, statistician, and independent auditor, with post-lock modifications permitted only through Statistical Analysis Plan amendments documented in the trial master file.

Statistical methods

All statistical analyses will be based on the principle of intention to treat. Data analysis will be performed by independent statistical analysts using SPSS statistical software (23.0; IBM). Data normality will be assessed using the Shapiro–Wilk test. Non-normally distributed continuous variables will be analyzed with Mann–Whitney U or Kruskal–Wallis tests. Both intention-to-treat and per-protocol analyses will be performed. Two-way analysis of variance will be used to analyze the effects of two intervention factors and the interaction between the two intervention factors. Continuous variables will be expressed as mean and standard deviation. Categorical variables will be displayed as numbers and percentages. All statistical tests will be two-sided, and P < 0.05 will be considered statistically significant.

Patient and public involvement

Neither patients nor members of the public had any involvement in the design of this trial.

Ethics and dissemination

The study protocol was approved by the ethics committee in accordance with the Declaration of Helsinki.

Before the patient is included in the study, we will introduce all the contents of the study to the patient in detail, so that the patient fully understands why the study is to be carried out, the procedure and duration of the study, what needs to be done, and the possible benefits and risks after participating in the study and the right to withdraw from research at any time. Written informed consent will be obtained from patients. This study does not involve the serological data of the subjects. The medical information of the subjects participating in the study will be kept confidential. The hospital will keep all the records of the study, and no one without authorization will be allowed to obtain their information.

Discussion

TKA is a widely performed orthopedic surgery globally. Millions undergo this procedure annually to relieve pain, restore knee function, and improve quality of life. However, up to 20% of patients report dissatisfaction due to persistent postoperative pain and delayed recovery.

Traditional local anesthesia methods require multiple injections with high drug doses due to the large surgical incision, increasing complexity, and safety risks. Our approach targets the knee’s cutaneous nerve distribution based on anatomical studies, potentially achieving comparable or superior pain relief with fewer injections. This reduces total anesthetic dosage, lowering risks of drug overdose or accidental vascular injection. “Our anatomic approach aligns with Horner et al^[20], who demonstrated cutaneous nerve targeting reduces opioid demand. The triamcinolone-ropivacaine combination leverages synergistic pharmacokinetics: ropivacaine’s rapid onset (Tmax =30 min) and triamcinolone’s extended half-life (18–36 h) ensure sustained analgesia.”

Current postoperative pain management options face limitations: some require specialized training, others carry risks like nerve damage or gastrointestinal complications. Notably, no studies have compared different “cocktail” analgesic formulations in TKA patients. This study aims to determine whether nerve distribution-guided anesthesia with a novel drug combination improves postoperative pain control.

Study highlights

1. First comparison of two injection sites and two drug formulations for TKA analgesia, seeking safer methods to enhance recovery.

2. Patient-reported data collection via WeChat QR codes minimizes clinician bias. Only knee mobility measurements require professional tools.

3. Rigorous bias control: standardized surgical/anesthesia protocols, single-surgeon operations, and blinded assessments.

Limitations

Sample size (n = 120) is provisional due to lacking prior studies.

Clinicians cannot be blinded during procedures, but QR code data collection reduces outcome assessment bias.

This study provides evidence for optimizing local anesthesia in TKA, ultimately supporting better postoperative rehabilitation.

Research status

This study is currently recruiting participants. Research proposal version number and date: V3.0, November 1, 2021. Recruitment starts on December 25, 2021, and the expected completion date is December 25, 2022.

Ethical approval

Approval for the study was obtained from the ethics committee of Xijing Hospital, the Fourth Military Medical University (XJLL-KY-20212115).

Consent

Not applicable.

Sources of funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Author contributions

W.D.: conceived and designed the study and was the principal investigator. W.D., W.T., and M.Y. made significant contribution to the design of the study. W.D. and W.T. wrote the first draft of this manuscript. M.Y., W.M., and Y.H. made feedback and revisions to the manuscript.

Conflicts of interest disclosure

The authors declare that they have no competing interests.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Min Yang.

Provenance and peer review

Not applicable.

Data availability statement

All data generated or analyzed during this study are included in this published article.