Association of Pre-operative Genicular Nerves Cryoneurolysis With Improved Pain and Function in Patients Undergoing Total Knee Arthroplasty
Phase: NA
Conditions: Arthroplasty, Replacement Material, Knee Arthritis Osteoarthritis, Knee Arthroplasty, Total, Genicular Nerves, Chronic Pain
Sponsor: Attikon Hospital

Cover Page for ClinicalTrials.gov 
Document: 
Study Protocol & Statistical Analysis Plan 
 
Official Study Title: 
Association of Pre-operative Cryoneurolysis of the Genicular Nerves with 
Improved Pain and Function in Patients Following Total Knee Arthroplasty 
Date: 
December 20, 2025 
 
 
NCT Number: Not yet assigned 
 
 
 
 
 
 
 
 
 
 
 
 

 
Administrative Information 
Protocol version: 1.0  
Ethics approval: Approved by the Institutional Review Board of the National and 
Kapodistrian University of Athens (Approval ID: A9, 10/09/2025). 
Sponsor: Attikon Hospital 
Funding: No external funding. Supported by institutional resources. 
Introduction 
Persistent postoperative pain following total knee arthroplasty (TKA) remains a significant 
clinical problem, affecting approximately 20–30% of patients despite advances in surgical 
technique and perioperative analgesia. Cryoneurolysis, a percutaneous image-guided 
technique that temporarily interrupts peripheral nerve conduction by inducing axonal 
degeneration through extreme cold, has emerged as a promising modality for pain 
management. Preoperative cryoneurolysis of the genicular nerves may reduce 
postoperative pain intensity, enhance mobility, and improve quality of life outcomes 
following TKA. 
Objectives 
The primary objective of this study is to evaluate whether preoperative CT-guided 
cryoneurolysis of three genicular nerves (upper medial, upper lateral, and lower medial) 
improves postoperative pain, mobility, and quality of life compared with standard care in 
patients undergoing total knee arthroplasty. 
Primary hypothesis: Preoperative cryoneurolysis of genicular nerves will result in superior 
postoperative pain control, enhanced mobility, and improved life quality scores compared 
with control patients. 
Trial Design 
This is a prospective, randomized, comparative, single-center, two-arm trial with parallel 
assignment. Participants will be randomized (1:1) to either the intervention 
(cryoneurolysis) or control (standard care) group. Outcome assessors will be blinded to 
group allocation. 
Participants 
Inclusion criteria: 
• Adults (≥18 years) undergoing primary total knee arthroplasty for osteoarthritis. 
• Cognitively normal individuals able to self-assess pain and function. 
• Willing and able to provide informed consent. 
Exclusion criteria: 

• Cancer-related knee pain. 
• Neurological, psychiatric, or medical conditions interfering with self-assessment. 
• Chronic opioid use. 
Interventions 
Participants randomized to the intervention arm will undergo CT-guided cryoneurolysis of 
the upper medial, upper lateral, and lower medial genicular nerves at least 24 hours before 
surgery. Local anesthesia will be administered. Each nerve will be treated with a cryoprobe 
(up to three per patient), induced to -20°C to -100°C, to achieve axonal degeneration. 
The control group will undergo standard total knee arthroplasty without preoperative 
cryoneurolysis. 
Outcomes 
Primary outcome: 
• Change in pain severity as measured by the Brief Pain Inventory (BPI) from baseline to 1 
month postoperatively. 
Secondary outcomes: 
• Knee Injury and Osteoarthritis Outcome Score (KOOS). 
• Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). 
• Complications graded according to the CIRSE classification system. 
• Quality of life improvement at 3, 6, and 12 months postoperatively. 
Sample Size 
A total of 100 patients will be enrolled and randomized equally between the two study arms 
(50 per group). Sample size is based on feasibility and prior literature estimating a 
moderate effect size for cryoneurolysis in postoperative pain reduction. 
Assignment of Interventions (Randomization and Blinding) 
Randomization will be performed using computer-generated random numbers in a 1:1 
ratio. Outcome assessors and statisticians will be blinded to treatment allocation. 
Data Collection and Management 
Clinical data will be collected at baseline, and at 1, 3, 6, and 12 months postoperatively using 
validated questionnaires (BPI, KOOS, WOMAC). Data will be anonymized, stored securely on 
institutional servers, and accessible only to the research team. 
Statistical Methods 
All statistical analyses will be performed using IBM SPSS Statistics version 25 (licensed to 
the National and Kapodistrian University of Athens). Continuous variables will be expressed 
as mean ± standard deviation or median (IQR), as appropriate. Comparisons between 
groups will be made using t-tests or Mann–Whitney U tests for continuous variables and 

chi-square tests for categorical variables. A p-value <0.05 will be considered statistically 
significant. 
Monitoring and Harms 
Adverse events and complications related to cryoneurolysis or TKA will be monitored 
throughout the study. Complications will be graded according to the CIRSE classification 
system. 
Ethics and Dissemination 
This study has received ethics approval from the Institutional Review Board of the National 
and Kapodistrian University of Athens (Approval ID: A9, 10/09/2025). All participants will 
provide written informed consent. Results will be submitted to peer-reviewed journals 
(target: CVIR) and presented at international conferences. 
References 
1. Mont MA et al. Cryoneurolysis Associated With Improved Pain, Function, and Sleep in 
Patients Following Total Knee Arthroplasty. J Arthroplasty. 2025;40:92–101. 
2. Filippiadis D, Efthymiou E, Tsochatzis A, Kelekis A, Prologo JD. Percutaneous 
cryoanalgesia for pain palliation: current status and future trends. Diagn Interv Imaging. 
2021;102:273–8. 
3. Ashoorion V et al. Predictors of persistent post-surgical pain following total knee 
arthroplasty: a systematic review and meta-analysis. Pain Med. 2023;24:369–81. 
4. Ilfeld BM et al. Ultrasound-guided percutaneous cryoneurolysis for treatment of acute 
pain: could cryoanalgesia replace continuous peripheral nerve blocks? Br J Anaesth. 
2017;119:709–12. 
5. Dasa V et al. Percutaneous freezing of sensory nerves prior to total knee arthroplasty. 
Knee. 2016;23:523–8.