Radiofrequency ablation for the treatment of chronic pain after knee arthroplasty: protocol for a randomized, double-blind study

Abstract

Background

To date, there is no standard treatment for chronic pain after knee arthroplasty. Radiofrequency ablation of the sensory nerves in the knee has become a useful therapeutic approach; however, variability in terms of treatment approaches and anatomical targets causes difficulties in standardizing a reproducible and viable technique. The aim of this study is to determine if radiofrequency ablation of the nerves of the vastus medialis (NVM), vastus intermedius (NVI), vastus lateralis (NVL), and infrapatellar branch of the saphenous nerve (IPBSN) improves pain and disability from baseline to 3 months versus placebo in patients with post-knee arthroplasty pain.

Methods

This double-blind, placebo-controlled, randomized trial will be conducted in two hospitals in Catalonia, Spain. Patients will undergo anaesthetic blocks of nerve branches to determine radiofrequency candidacy. After adequate response to the anaesthetic blocks (≤ 50% of baseline pain levels for > 24 h), patients will be subjected to radiofrequency ablations or control simulations. Treatment responses will be evaluated using clinically validated questionnaires (Western Ontario McMaster Universities Osteoarthritis Index [WOMAC], visual numerical scale for pain, DN4 questionnaire for neuropathic pain, Hospital Anxiety and Depression Scale [HADS], Pain Catastrophizing Scale [PCS]). Follow-up outcome scores will be collected up to 12 weeks after radiofrequency ablation.

Discussion

The planned sample size is 86 patients. As of February 19, 2025, a total of 19 patients have been enrolled, and 12 have completed all study procedures.

Trial registration

NCT05920382

Supplementary Information

The online version contains supplementary material available at 10.1186/s13063-026-09585-8.

Administrative information

Title {1}	Radiofrequency ablation for the treatment of chronic pain after knee arthroplasty: protocol for a randomized, double-blind study
Trial registration {2a and 2b}	NCT05920382
Protocol version {3}	Version 1 (01/06/2022)
Funding {4}	This study was funded by CSAPG (Consorci Sanitari Alt Penedès-Garraf)
Author details {5a}	Italo Gabriel Pisani Address: Consorci Sanitari Alt Penedès-Garraf, Espiral street W/N, Vilafranca del Penedès, 08720, Barcelona, Spain Email: igpisani@csapg.cat Josep María Segur Vilalta Address: Instituto Clínic de Especialidades Médicas y Quirúrgicas, Barcelona, Spain Email: JSEGUR@clinic.cat Jorge Orduña Valls Address: Hospital Quirónsalud Valencia, Av. de Blasco Ibáñez, 14, Valencia, Spain Email: drordunadolor@gmail.com Alejandro Rodriguez-Molinero Address: Consorci Sanitari Alt Penedès-Garraf, Espiral street W/N, Vilafranca del Penedès, 08720, Barcelona, Spain Email: arodriguez@csapg.cat
Name and contact information for the trial sponsor {5b}	Consorci Sanitari Alt Penedès-Garraf, Espirall street W/N, Vilafranca del Penedès, 08720, Barcelona, Spain Tel: 938 180 440 Email: atenciociutadahcap@csapg.cat, visitesvilafranca@csapg.cat
Role of sponsor {5c}	No funding was provided by a study sponsor. The principal investigator is an employee of Consorci Sanitari Alt Penedès-Garraf

Introduction

Background and rationale {6a}

Total knee arthroplasty is an increasingly common treatment for patients with osteoarthritis of the knee, with 74.3 interventions per 100,000 inhabitants conducted in Spain in 2004 and 120.9 interventions per 100,000 inhabitants in 2021 [1]. Despite good outcomes for many patients, approximately 20% of patients who undergo total knee arthroplasty experience chronic pain and reduced quality of life [2]. To date, there are no standard treatments for chronic pain after total knee arthroplasty.

Radiofrequency ablation of the sensory nerves in the knee has become a useful therapeutic approach [3, 4]; however, there is considerable variability in terms of treatment approaches and anatomical targets [5–8]. There is an unmet need to explore the long-term efficacy and safety of radiofrequency ablation after knee arthroplasty as well as to standardize techniques and protocols across different practice settings which will help improve patient outcomes and quality of life [7].

Objectives {7}

The primary objective is to determine if radiofrequency ablation of the nerves of the vastus medialis (NVM), vastus intermedius (NVI), vastus lateralis (NVL), and infrapatellar branch of the saphenous nerve (IPBSN) improves pain and disability from baseline to 3 months versus placebo in patients with post-knee arthroplasty pain.

Secondary objectives are (1) to determine whether radiofrequency ablation of the sensory nerves improves pain from baseline to 3 months compared with placebo in patients with post-knee arthroplasty pain, (2) to determine whether radiofrequency ablation of the sensory nerves improves pain from baseline to 3 months compared with placebo in patients with neuropathic pain after knee arthroplasty; (3) to measure levels of depression and anxiety in patients undergoing radiofrequency ablation and its influence on response to radiofrequency; (4) to compare patient satisfaction in those who undergo radiofrequency ablation of the sensory nerves of the knee for the treatment of chronic pain after knee arthroplasty; (5) to determine if radiofrequency ablation of the sensory nerves of the knee is safe in terms of the number of adverse events associated with the technique; and (6) to assess whether the results of radiofrequency ablation of sensory nerves of the knee are related to the amount of time patients have been suffering from pain.

Trial design {8}

This is a double-blind, placebo-controlled, randomized trial.

Methods: participants, interventions, and outcomes

Study setting {9}

The study will be conducted in two hospitals in Catalonia, Spain, namely the Sant Camil Residence Hospital and the Regional Hospital of L’Alt Penedès. A pain specialist with more than 10 years of experience will identify and conduct the infiltration of the sensory branches of the femoral nerve.

Eligibility criteria {10}

Patients aged > 40 years will be included if they have experienced at least 6 months of post-knee arthroplasty chronic pain over the last 5 years. Pain should have an intensity of ≥ 5/10 on a visual numerical scale and have been stable for the last 30 days. In patients with multiple joint pain, the knee with the greatest pain intensity will be selected.

Patients will be excluded if they have acute knee pain, a psychiatric illness or dementia that may interfere or hinder study assessments, or a diagnosis of fibromyalgia, chronic fatigue syndrome, or central sensitization syndrome. Patients will also be excluded if they have received a knee infiltration with corticosteroids in the last 30 days, have had changes in oral analgesic medication in the last 30 days, or are included as part of another clinical trial.

Who will take informed consent? {26a}

The principal investigator or their representative will obtain informed consent for all patients using a written consent form, including the full name and signature of each patient.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

Not applicable. Biological specimens will not be collected.

Interventions

Explanation for the choice of comparators {6b}

A sham simulation of the radiofrequency ablation was used as a control group. Sham simulations have been employed successfully in previous trials [9–12]. The study is low risk, and the employment of the sham technique is not likely to expose patients to any additional harms.

Intervention description {11a}

Prior to enrolment, patients will be asked to mark the area of greatest pain on a drawing of a knee, both at rest and when moving, and this drawing will be divided into quadrants (Fig. 1). The nerves corresponding to the terminal sensory branches of the femoral nerve will be located and stimulated based on the patients’ drawing. Patients will receive an ultrasound-guided diagnostic block performed with 2% lidocaine 1 mL in each nerve. The block will be verified by neurostimulation of the sensory branches of the knee that correspond to the quadrant that the patient marked. The patient will then be asked to confirm that the areas with the most sensory stimulation correspond to the area previously marked in the drawing.

Fig. 1.

Quadrants of the knees with the nerves that will be stimulated in each quadrant. IPBSN, infrapatellar branch of the saphenous nerve; NVI, nerve to the vastus intermedius; NVL, nerve to the vastus lateralis; NVM, nerve to the vastus medialis

Diagnostic blocks will be considered positive if patients report ≤ 50% of baseline pain levels for > 24 h. Identification of the sensory branches of the knee will be performed using ultrasound anatomical references and a peripheral nerve locator using Stimuplex needles [13].

Patients with a positive diagnostic block will be enrolled in the study and randomized in a 1:1 ratio to either the radiofrequency group or the control group. The radiofrequency group will receive thermal radiofrequency of the sensory nerves of the knee (90 s, 80 °C, 22-g needle with a 10-mm active tip), while the control group will receive a simulation of the radiofrequency (90 s). Both groups will receive 1 mL/nerve infiltrations of local anaesthetics and corticosteroids (bupivacaine 0.5% + dexamethasone 4 mg).

All patients will be treated as outpatients and sedated using midazolam (2–3 mg) and intravenous fentanyl (50–100 μg). Patients who are unable to tolerate the sedation procedure will be withdrawn from the study.

Criteria for discontinuing or modifying allocated interventions {11b}

Patients can discontinue intervention-related procedures if they withdraw consent, if their clinical condition changes, or if they are unable to follow intervention-related procedures. Reasons for discontinuation will be recorded in the electronic database by the investigator. Participants who discontinue the intervention will remain in the study and continue protocol assessments when possible.

Strategies to improve adherence to interventions {11c}

Not applicable. Treatment adherence is not relevant to this study protocol.

Relevant concomitant care permitted or prohibited during the trial {11d}

During the study period, analgesic treatment with major opioids cannot be modified.

Provisions for posttrial care {30}

After study completion, patients will be made aware of their intervention group, and those in the sham group who did not experience pain relief will be provided the opportunity to receive radiofrequency ablation treatment. The results from radiofrequency ablation of these patients will not be included in the study.

Outcomes {12}

The primary endpoint will be treatment efficacy, defined as a 50% decrease in baseline pain and disability in at least 50% of patients. All primary and secondary endpoints and the methods used to measure them are shown in Table 1 [14–19].

Table 1.

Study endpoints

Endpoint	Assessment tools
Primary endpoint
Treatment efficacy	A 50% decrease in baseline pain and disability in at least 50% of patients measured using the simplified version of the WOMAC questionnaire [18]
Secondary endpoints
Pain	Visual scale ranging from 0 to 10 (where 0 corresponds to no pain and 10 corresponds to maximum perceived pain) [15]
Neuropathic pain	DN4 questionnaire [19]
Depression and anxiety	HADS questionnaire [17]
Degree of satisfaction with assistance provided	The CSAPG satisfaction survey [14]
Assessment of whether the duration of knee pain after knee arthroplasty affects radiofrequency results
Catastrophizing	PCS validated for fibromyalgia [16]
Adverse events	Classified by severity

HADS Hospital Anxiety and Depression Scale, PCS Pain Catastrophizing Scale, WOMAC Western Ontario McMaster Universities Osteoarthritis Index

All questionnaires will be conducted in Spanish.

Participant timeline {13}

A schedule of procedures by visit is shown in Table 2. Outcome measures will be assessed according to hospital visits at baseline and at post-procedure weeks 1, 4, and 12.

Table 2.

Schedule of procedures by patient visit

Visit	Screening	Baseline 1 day pre-diagnostic block	Visit 1 Diagnostic block	Visit 2 Post-diagnostic block control 15 days after visit 1	Visit 3 RF procedure/control	Visit 4 2 weeks post RF	Visit 5 4 weeks post RF	Visit 6 12 weeks post RF	Final visit
Inclusion criteria	X
Informed consent	X
Sociodemographic data	X
Concomitant medications	X
Analgesic treatment	X					X	X	X
Pain evaluation		X	X	X		X	X	X
WOMAC questionnaire		X					X	X
HADS questionnaire		X
DN4 questionnaire		X
PCS questionnaire		X
Satisfaction questionnaire									X
Drawing of pain quadrants			X
RF technique					X
AE registry			X	X	X	X	X	X

AE adverse event, HDSA Hospital Anxiety and Depression Scale, PCS Pain Catastrophizing Scale, RF radiofrequency, WOMAC Western Ontario McMaster Universities Osteoarthritis Index

Sample size {14}

In this study, if the predicted success rate in the radiofrequency group is between 50 and 60%, then at least 43 subjects will be needed in each group to reject the null hypothesis of equal success rates, with a power of 80%. The probability of type 1 error associated with this test is 5%. A loss rate of 10% was considered in the estimate. The chi-square test will be used to evaluate this hypothesis.

Recruitment {15}

Patients identified by the traumatologist as part of routine clinical care within the hospitals will be referred to the pain unit for screening.

Assignment of interventions: allocation

Sequence generation {16a}

The randomization sequence will be implemented using a table of random numbers and following a model of balanced blocks, whose size and composition will not be revealed to the researchers or the personnel in charge of implementing the sequence.

Concealment mechanism {16b}

The randomization sequence will be implemented in sealed envelopes, which will be available in the surgical area for assignment of patients directly before radiofrequency ablation.

Implementation {16c}

Independent personnel will implement the randomization sequence.

Assignment of interventions: blinding

Who will be blinded {17a}

Researchers and data analysts will be blinded to study allocation.

Procedure for unblinding if needed {17b}

If the researcher considers it essential to know which technique was used, due to the patient’s clinical situation, they will access the required data and record the incidence. Data from unblinded patients will not be included in subsequent analyses.

Data collection and management

Plans for assessment and collection of outcomes {18a}

Questionnaires used to assess outcomes are shown in Table 2. Researchers will receive training on study procedures and instruments within 2 weeks of study initiation. Researchers will attend a re-training session if advised by the study monitor and/or if they do not recruit patients for a long period of time after the initial training session.

Plans to promote participant retention and complete follow-up {18b}

Periodic reminders were sent to patients throughout the trial via phone calls and messages to confirm appointments. Other strategies to promote participant retention include flexibility in scheduling visits, personalized follow-up through the Pain Unit, and the possibility of direct contact with the study team to address any questions or concerns. Additionally, in the final phase of the study, patients in the placebo group will be offered the option to receive the real radiofrequency ablation treatment if they do not experience the expected pain relief.

Data management {19}

An electronic case report form (eCRF) will be completed for each patient per standard requirements. The sponsor will instruct researchers on how to record data correctly within the eCRF. Each study monitoring procedure will be completed by the researcher who will identify themselves using their unique code and password every time they access the eCRF. All eCRFs will be reviewed, and any missing or unclear entries will be requested throughout the study.

Confidentiality {27}

Patients will be identified by a case number in all reports and communications related to the study. Details of patients’ identity will be stored in confidential files, only used for location and tracking purposes. This file will be treated strictly in accordance with professional confidentiality standards and will be archived under appropriate security measures and restricted access in the terms provided for in Regulation (EU) 2016/679 of the European Parliament and of the Council of April 27, 2016, on Data Protection (GDPR), as well as in Organic Law 03/2018 of December 5. At any time, participants may fully exercise their rights of access, modification, opposition, and cancellation of data, as well as limit the processing of data that is incorrect and request a copy or that it be transferred to a third party (portability). The researcher and the sponsor are obliged to retain the data collected for the study for at least 25 years after its completion.

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

Not applicable. No samples were collected.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

All analyses will be conducted on the intention-to-treat population, including all patients who undergo radiofrequency ablation or control simulation.

Interim analyses {21b}

Not applicable. No interim analyses are planned.

Methods for additional analyses (e.g. subgroup analyses) {20b}

Not applicable. No additional analyses are planned.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

If patients do not provide all relevant information about their health status, either due to forgetfulness or omission, nursing staff will collect the missing data during subsequent visits, both in-person and by phone. Additionally, patients’ medical records will be reviewed to input missing data. In Spain, these records are fully digitalized and integrated with all public health systems.

Study data will be internally reviewed twice a year to ensure quality and compliance with the protocol.

Plans to give access to the full protocol, participant-level data, and statistical code {31c}

The protocol and trial results will be published in a peer-reviewed journal. Study data will be available upon reasonable request from the study sponsor.

Oversight and monitoring

Composition of the coordinating centre and trial steering committee {5d}

This trial does not have a steering committee. The coordinating centre will supervise the operational and administrative management of the study, ensuring compliance with regulatory and methodological standards. The principal investigator designed the protocol and is responsible for the implementation of the study.

Composition of the data monitoring committee and its role and reporting structure {21a}

This study does not have an independent data monitoring committee. The interventions do not involve significant risks to patients, and the trial will be directly supervised by the coordinating centre.

Adverse event reporting and harms {22}

All adverse events (AEs), either observed by the investigator or reported by participants, will be recorded, including a description of the event, the date of onset, an assessment of severity, and the relationship to the intervention. The investigator will also record any actions taken as a result of the AE, whether the study intervention was discontinued, and whether or not the AE resolved. Whenever possible, the overall diagnosis, and not symptoms or signs of the condition, will be recorded.

AEs or complications will be followed until resolution of the event, stabilization of the event, return to baseline condition after event, if baseline condition is available, or death. AEs that have not resolved by the end of the study will be recorded as not recovered.

Investigators must inform the study sponsor and ethics committee of any serious AEs (SAEs) as soon as they become aware of them. The sponsor will report suspected SAEs and unexpected reactions to the EudraVigilance database after a period of no later than 7 days for serious and unexpected fatal or life-threatening AEs or 15 days for nonfatal and non-life-threatening AEs.

Frequency and plans for auditing trial conduct {23}

Supervision of the trial will be carried out in accordance with Good Clinical Practices, through a clinical monitor, who will be hired for this purpose by the sponsoring centre.

The role of the clinical monitor is to observe and evaluate the quality of the clinical study through periodic visits scheduled to evaluate the researchers’ adherence to the protocol and maintenance of records and reports. The monitor is responsible for checking and communicating that compliance with the clinical research plan is maintained and that any deviation from this plan is communicated; that the investigators have and continue to have the necessary personnel and facilities to conduct the clinical research safely and effectively; that the investigators have and continue to have access to an adequate number of eligible subjects; that the informed consent form as defined in the protocol has been obtained from each of the participants or legal representatives at the time of their recruitment and before any study-related procedures; that electronic records are complete, recorded on time, and consistent with the source data; and that the procedures for recording and reporting AEs and adverse reactions to the sponsor are followed.

The clinical monitor will also review the reports for accuracy, completeness, and legibility of the source documents. At the end of the study, the monitor may make a final visit to ensure that all the study data have been duly completed. The monitor will report the resolution of problems, compliance with follow-up activities, compliance with assigned tasks, and corrective actions.

Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}

The protocol may not be amended by the investigators or study personnel without first obtaining review and approval from the sponsor. No clinically significant amendments (e.g. affecting the rights, safety, or welfare of human subjects participating in the research, the scientific soundness of the research plan, the validity of the data or information resulting from the completion of an approved protocol, or a significant inclusion of new categories of participants) may be made prior to approval by the appropriate ethics committee and competent authorities.

Dissemination plans {31a}

All trial results will be published in a peer-reviewed journal.

Discussion

N/A. All issues have been covered in other sections.

Trial status

The study protocol (version 1) was approved on June 1, 2022.

The first patient was recruited on September 25, 2023, and recruitment is expected to be completed by September 1, 2026.

Abbreviations

AE

Adverse event

eCRF

Electronic case report form

HADS

Hospital Anxiety and Depression Scale

IPBSN

Infrapatellar branch of the saphenous nerve

NVI

Nerves of the vastus intermedius

NVL

Nerves of the vastus lateralis

NVM

Nerves of the vastus medialis

PCS

Pain Catastrophizing Scale

WOMAC

Western Ontario McMaster Universities Osteoarthritis Index

Authors’ contributions {31b}

IPZ was the principal investigator who conceived the study, designed the protocol, led the implementation of the study, applied the intervention techniques, and reviewed the first draft of the manuscript. JOV was an advisor on infiltration techniques and provided expertise in chronic pain management. JMS served as a study mentor, offering scientific and methodological supervision. ARM assisted in writing the protocol and contributed as the Head of the Research Department at CSAPG, ensuring methodological accuracy and study design compliance. All authors have reviewed the manuscript for intellectual content and accuracy and have read and approved the final draft. Medical writing support for this protocol was provided by Claire Line, PhD, and was funded by CSAPG (Consorci Sanitari Alt Penedès-Garraf).

Funding {4}

This study was funded by CSAPG (Consorci Sanitari Alt Penedès-Garraf).

Data availability {29}

All authors will have access to the study data.

Declarations

Ethics approval and consent to participate {24}

Written informed consent will be obtained from all participants. The signed informed consent form will be filed in the study folder, and a copy will be given to the patient. The protocol and informed consent forms will be reviewed and approved by the ethics committee (Research Ethics Committee on Medicinal Products of the Hospital Universitari de Bellvitge (CEIM).

Consent for publication {32}

Not applicable. This manuscript does not contain individual participants’ identifiable data.

Competing interests {28}

All authors declare that they have no financial or other competing interests related to this trial.