Does Radiofrequency Ablation of the Articular Nerves of the Knee Prior to Total Knee Replacement Improve Pain Outcomes? A Prospective Randomized Sham-Control Trial With 6 Month Follow Up
Phase: NA
Conditions: Arthroplasty, Replacement, Knee
Sponsor: Northwestern University

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Proposed Research Protocol Form 
 
Title: Does Radiofrequency Ablation of the Articular Nerves of the Knee Prior to Total 
Knee Replacement Improve Pain Outcomes? A Prospective Randomized Sham-Control 
Trial with 6 month Follow Up 
 
Principal Investigator:  
David R. Walega, MD, MSCI 
Associate Professor 
Chief, Division of Pain Medicine 
Department of Anesthesiology 
Northwestern University Feinberg School of Medicine  
Office (312) 695-2500 
d-walega@northwestern.edu 
 
 
Co-PI: Matthew Beal, MD2, David Manning, MD2, Mark Kendall, MD1, Sabrina Robak, RN1  
 
Affiliation:  
1Department of Anesthesiology, Northwestern University Feinberg School of Medicine 
2Department of Orthopedic Surgery, Northwestern University Feinberg School of Medicine 
 
Version: 1.0 
 
Protocol Version Date: 1/30/2015 
  
1.0 Research Aims/Objective: 
 
1.1   Research Question(s):  
Does Cooled Radiofrequency Ablation (C-RFA) of the articular sensory nerve supply to 
the knee prior to unilateral total knee replacement result in improved post-operative knee 
pain scores and decreased perioperative analgesic use as compared to standard 
perioperative medical therapy? 
 
1.2   Null Hypothesis: 
Cooled Radiofrequency Ablation (C-RFA) prior to unilateral total knee replacement has 
no effect on post-operative knee pain scores or pain medication use as compared to 
standard perioperative medical therapy. 
 
2.0   Research significance: 
 
2.1 Background 
 
More than 300,000 total knee joint replacement surgeries are performed per year in the 
United States and safe, effective management of post-operative pain in these patients, often 
elderly, deconditioned, obese, or with co-morbid diseases like sleep apnea, can be challenging 
and often require a multidisciplinary, multimodal approach1-4.  Opiates have been a mainstay of 

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treatment in the post-operative period, although continuous epidurals, peripheral nerve infusions 
of local anesthetic, intra and periarticular injections have all been used in this patient population 
with varying degrees of success and complications5-7. Inadequately controlled postoperative pain 
is not uncommon8,9 and can cause multiple untoward effects, including a hyperdynamic 
circulatory state, increased oxygen consumption, muscle spasm of the quadriceps muscles, 
increased risk of DVT and increased risk of pulmonary embolism, whereas overmedication with 
opiates can cause hypoventilation syndrome, sedation, pruritus, constipation, or delirium, 
especially in the elderly population. Further, poorly controlled pain inhibits early mobilization 
and hinders post-operative physical therapy8, both of which are critical in the early post-
operative period to prevent joint adhesions, capsular contraction, muscle atrophy, and delays or 
limitations in the ultimate functional outcome following TKR. 
A new paradigm for treating post-operative pain following TKR may be the use of cooled 
radiofrequency ablation (C-RFA) of the articular sensory nerve supply of the knee capsule prior 
to surgery, to desensitize the knee by blocking sensory afferents to the anterior capsule and 
thereby decrease post-operative pain.  The clinical efficacy of radiofrequency neurotomy has 
been proven in chronic spine pain, cervicogenic headache and trigeminal neuralgia with a strong 
safety profile in appropriately selected patients.  C-RFA is similar in mechanism to conventional 
RFA: a thermal lesion is created by applying radiofrequency energy through a percutaneous 
electrode placed at a target neural structure. However, in C-RFA, a constant flow of ambient 
water is circulated through the electrode via a peristaltic pump, maintaining a lowered tissue 
temperature by creating a heat sink. By removing heat from tissues immediately adjacent to the 
electrode tip, a lower but effective lesioning temperature is maintained, resulting in less tissue 
charring adjacent to the electrode, less tissue impedance10,11 and more efficient heating and 
neurolysis of target tissue. The volume of tissue heated and the resultant thermal lesion size is 
substantially larger with C-RFA12,13 as compared to conventional RFA, conferring a significant 
therapeutic advantage14. Larger thermal lesions increase the probability of successful neurolysis 
of pain generators that have significant variability in anatomic location.  
To date, few publications have demonstrated the use of RFA for knee pain from OA. 
Choi et al used conventional RFA of the articular nerves in the knee in elderly patients with 
chronic knee pain from OA in a double blind randomized controlled trial published in 201115. 
RFA at three nerve locations was performed with image guidance and each lesion was performed 
at 70 degrees C for 90 seconds with a 22 gauge cannula.  Needle placements were at the region 
connecting the shaft of the femur to the bilateral epicondyles (superior lateral and superior 
medial genicular nerves) and the shaft of the tibia meeting the medial epicondyle (inferior 
genicular nerve)16-18. Patients who underwent RFA reported at least a 50% decrease in pain 
scores at one and three months following the procedure, whereas the sham control group had no 
demonstrable change in pain at these time points15. Oxford knee disability scores and patient 
satisfaction scores were also significantly improved in the RFA group but unchanged in the 
control group.  No adverse events were reported in the 38 patients enrolled in the study15. In a 

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single case report, conventional RFA of periarticular nerves in a patient with chronic knee pain 
following TKR was described with favorable clinical results and drastically improved pain 
control, but the RFA was performed remote to the time of the TKR for the indication of chronic 
pain, not to treat perioperativ pain in the immediate postoperative and rehabilitative periods19.  
Thus, although RFA has been used in patients with chronic knee pain from OA and in 
one case treating chronic pain many months following knee replacement, C-RFA has not been 
used in the perioperative management of pain in patients undergoing total knee joint replacement 
surgery. 
 
The aim of this study is to determine if patients undergoing unilateral total knee replacement 
obtain any pain relieving benefits from C-RFA of the articular sensory nerve supply prior to 
surgery, as compared to sham controls who receive only local anesthetic injections of these same 
nerves without the benefit of ablation treatment.  
 
2.2    Significance 
 
If C-RFA of the articular sensory nerve supply of the knee is found to decrease post-operative 
opiate consumption, provide meaningful pain relief and enhance post op physical therapy, the 
procedure can be integrated into the TKR perioperative treatment algorithm. Such treatment, if 
successful, will ultimately improve short and long term pain outcomes, patient satisfaction, and 
decreased length of hospital stay in a cost effective manner. 
 
3.0   Investigational Plan/Protocol Specifics 
 
General Design and Procedures.  
This study design is a prospective randomized trial of C-RFA of 3 articular branches of the knee 
joint versus sham CRFA to examine the effects on post-operative opiate requirements during the 
first 48 hours after surgery (primary outcome). We will obtain approval from the Institutional 
Review Board at Northwestern University and will complete an informed consent process before 
initiating any study procedure. 
 
Secondary Outcomes include: 
 
a) Visual Analog Scale for pain: (0 (no pain) to 10 (unbearable pain) scale; at rest, mobilization/  
    weight bearing. 
b) Knee Society Scale (clinician); WOMAC (patient) 
c) Time to Physical therapy milestones: 
a. Active SLR 
b. Time until patient can get out of bed 
c. Time until patient able to ambulate  < 100 feet 
d. Time until patient able to ambulate around room > 100 feet 
e. Time until patient is able to climb stairs (quantify specifics, 
how many steps are considered appropriate?) 
d) Patient Global Perception of Change (GPC) 

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e) Patient Satisfaction (Likert Scale) 
f) Hospital Anxiety and Depression Score (HADS) 
e) SF 12 Questionnaire  
f) McGill Pain Questionnaire 
g) Inpatient length of Stay (LOS; days) and Physical Therapy “clearance for discharge” (days)   
h) Complications of the injection procedure 
i) Medication related adverse effects 
 
A total of 60 patients will be randomized. Participants will complete assessments at these time 
points:  
1) Baseline: immediately before the CRFA intervention,  
2) Immediately prior to surgery (Day of Surgery)  
3) 48 hours after the surgery procedure 
4) 1, 3 and 6 months following TKR surgery.   
 
A member of the research team will administer and collect the questionnaires. It will take about 
5-10 minutes to complete the questionnaires.  The research member will visit the patient at 48 
hours to administer the questionnaire and collect data points. It will take approximately 5-10 
minutes to complete the questionnaire. In addition, a member of the research team will contact 
the patient by phone or at scheduled surgical visits at 1 month, 3 months and 6 months.    
 
A member of the research team will look in POWERCHART for physical therapy milestones. 
Other data points such as medication use, length of stay, time for PT clearance, surgical duration 
will be recorded.  Data collection will be placed on a excel sheet and stored in a pass word 
protected computer in the department of anesthesiology. Paper data sheets will be placed in a 
binder and stored in a locked filing cabinet in a locked office located in the department of 
anesthesiology.  
 
Participants  
Inclusion criteria include:  
 
1) Adults 30 to 80 years old  
 
2) OA of the knee scheduled to undergo their first unilateral knee joint replacement  
 
3) Willingness to undergo fluoroscopy-guided C-RFA or sham treatment.  
 
Exclusion criteria include:  
1) Conditions that preclude C-RFA or sham intervention (e.g. pregnancy, severe  
    cardiac/pulmonary compromise; acute illness/infection; coagulopathy or bleeding  
    disorder; allergic reactions/contraindications to a local anesthetic).  
                  2) Prior TKR on either knee 
                  3) Inability to write, speak or read in English 
                  4) Patient refusal 
 
Recruitment  
Site(s) where study will be performed:   
Department of Anesthesiology, 675 N St Clair, Suite 17-200, Chicago, IL 60611  
Department of Orthopedic Surgery, 259 E Erie, Suite 13-100, Chicago, IL 60611   

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Patients who schedule a primary unilateral TKR with their orthopedic surgeon at NM will be 
asked to participate in the study by authorized research personnel. They will be screened to 
determine candidacy for the study; if they meet eligibility criteria, they will read and sign an 
informed consent form to participate. Each participant will be scheduled to see Dr. Walega in the 
Pain Medicine Center for the intervention procedure. They will be asked to be NPO for this visit 
and arrange a driver to accompany them home. This procedure will be performed 2-4 weeks 
prior to their planned knee surgery. The research assistant will calculate Morphine Equivalents 
(ME) of all analgesic medications including opiates, anti-inflammatories and membrane 
stabilizers. 
 
Each participant will complete the following written outcome measures prior to the intervention: 
It will take approximately 10 minutes to complete the questionnaires.* 
VAS pain score 
WOMAC questionnaire  
SF12 questionnaire  
Hospital Anxiety and Depression Inventory questionnaire  
McGill Questionnaire  
 
Following the intervention procedure the following data points will be recorded: 
VAS pain score 
PGIC Questionnaire  
Patient satisfaction 
 
Randomization and Masking Procedures (Treatment vs Control; T vs C)  
A computer-generated 1:1 block randomization scheme will be used to assign participants to 
receive either a CRFA or a sham procedure (wherein no RF energy is delivered after needle 
placement, and only local anesthetic is delivered).  Randomization will be performed by the 
proceduralist immediately before the injection procedure by opening an opaque envelope to 
reveal the participant number and group assignment printed on an index card. Participants, 
surgeons and all other study personnel, including those who will perform follow-up evaluations, 
will be blinded to group assignment. One board certified, fellowship trained anesthesiologist 
(DRW) with 16 years of injection experience will perform all injections. Dr. Walega will not be 
involved in the collection of any primary or secondary data outcome. 
 
Intervention Procedure Description:  
At the time of the intervention procedure, a 22 or 20-g angiocatheter will be placed in the 
participant’s hand/arm for peripheral intravenous access for conscious sedation during the 
procedure. The patient will be positioned supine on a fluoroscopy table with a positioning device 
under the patient’s knee to create 30-40 degrees knee flexion and hemodynamic monitors will be 
placed including NIBP, pulse oximeter and nasal cannula oxygen at 1-4 L/min. The knee will be 
prepped with chloroprep for 1 minute and draped in a sterile fashion. A grounding pad will be 
placed on the patient’s contralateral thigh and connected to the RF generator which will be 
turned on but will not be in the patient’s view. Regardless of group assignment, midazolam 0.5-1 
mg IV aliquots and/or fentanyl 25-50 mcg IV aliquots will be given as needed to provide 

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appropriate anxiolysis and analgesia for needle placement and manipulation for the duration of 
the procedure. NM policies and procedures for conscious sedation will be followed.  
 
For active CRFA, three targets for ablation* will be identified with an AP view of the knee:   
1.) Superior lateral genicular nerve 
2.) Superior medial genicular nerve 
3) Inferior medial genicular nerve 
*=locations are based on anatomic studies and Choi et al publication 
 
The skin and deep subcutaneous tissues overlying these target sites will each will be anesthetized 
using 5-10 mL of 1% lidocaine. An 18 G C-RFA cannulas (Cooled Radiofrequency Kit, Halyard 
Health), (75 or 100mm) will be placed through the skin to be optimally positioned via an anterior 
approach at the anatomic location of each of the 3 targets using AP and lateral fluoroscopic 
imaging. The disposable RF electrode that is supplied with RF kit will be placed into the cannula 
and attached to the RF generator; sensory and motor testing will be performed to confirm safe 
and appropriate placement. Following this confirmation, 2 cc of 2% lidocaine will be injected at 
each of these three sites. After 2 minutes, the targets will be lesioned at 60 degrees Celsius for 2 
minutes 30 seconds.  Following this, all needles will be removed and Band-Aids placed on the 
needle placement sites. Participants will be transferred to a recovery area and monitored in a 
reclining position for at least 30 minutes to allow sedation to wear off.   
 
For sham control, the three targets for ablation will be identified in a similar manner. The skin 
overlying the target sites identified with image guidance will each be anesthetized using 5-10 mL 
of 1% lidocaine. A 3.5 or 5 inch 22 gauge Whitacre needle will be placed through the skin to be 
optimally positioned at the anatomic location of each of the 3 targets using AP and lateral 
fluoroscopic imaging. Following this placement confirmation, 2 cc of 2% lidocaine will be 
injected at each of these sites. Non-disposable radiofrequency electrodes will be placed through 
these needles and attached to a RF generator.  The same auditory and visual experience of RF 
lesioning will be mimicked in the sham group as presented in the treatment group (see above). 
After 2 minutes and 30 seconds, the electrodes and needles will be removed and Band-Aids 
placed on the needle placement sites. Participants will be transferred to a recovery area and 
monitored in a reclining position for at least 30 minutes to allow sedation to wear off.   
 
Economic Burden to Subjects:  None 
 
Subject Reimbursement: Participants will receive $100 after completing the 3 month follow up 
and another $50 after completing the 6 month follow up. Participants will be required to provide 
their name, telephone number, and mailing address. The telephone number will be used to 
contact the participants at study intervals and to verify correct mailing address prior to sending 
payment. Participants will be told there is a 4 to 6 week processing time. They will be asked to 
sign an accountability log to document payment. 
 
Statistical Analyses:  
Baseline characteristics (e.g., sociodemographic variables, primary and secondary outcomes) 
will be compared between treatment groups using t-tests or chi-square tests for categorical 
variables. We will conduct intent-to-treat (ITT) analyses for all primary and secondary outcomes 

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using a series of generalized mixed-effects regressions. All statistical tests will be two-sided with 
significance set at p≤.05.  SAS statistical software version 9.2 (SAS Institute Inc., Cary, NC, 
USA) will be used for statistical analyses.  
 
In preliminary analysis, the distributional aspects of the variables under consideration will be 
examined through descriptive statistics. These statistics will include measures of location (mean, 
median, quartiles) and measures of dispersion (range, standard deviation, variance) for 
continuous variables and frequencies of the levels of categorical variables. These measures will 
also assist with a data cleaning/screening procedure to eliminate any possible copying, handling, 
recording or measurement errors. In addition to the features described above, the dependence of 
outcome measures will need to be properly accounted for in the data analysis as measures will be 
made at multiple times for the same participant. Consequently, these observations tend to be 
correlated and require statistical techniques that can properly account for the correlation in order 
to draw valid inference. Our general approach for analyzing these multiple types of data in this 
trial will be the Generalized Linear Mixed-Effect Models (GLMM).  
 
Statistical Power  
The power analysis for this study was performed using data from Choi et al and assumptions 
regarding perioperative opiate requirements in patients undergoing TKR without an indwelling 
epidural catheter or peripheral nerve block. A sample size of 28 per group is needed to detect a 
difference in analgesic use of 15 morphine equivalents (ME) per 24 hour cycle, assuming the 
controls use 47 ME per 24 hours cycle with a standard deviation of 19 ME with a power of .81 at 
alpha = 0.05. The sample size calculation was computed using a two-sided Mann-Whitney Test 
(PASS). To correct for lost to follow up and dropout rates, we will recruit 30 patients into each 
treatment group. 
 
Duration of follow-up This trial is designed with 6-month duration of follow up after surgery.  
 
Use of only one exposure to the intervention 
We will not allow repeat injections for either treatment group.  No patients will receive intra-
articular or peri-articular steroids in this study.  
 
Blinding In the current proposal, Dr. Walega is responsible for performing all of the active C-
RFA and sham control procedures. To accommodate proper blinding, identical auditory, visual 
and tactile experiences for both treatment groups will be maintained. We will use deception to 
protect blind. The proceduralist will be blinded to all follow-up data until the study is completed. 
Similarly, the research assistants who perform all follow-up data will be blinded to group 
assignments until the conclusion of the study.  We will also query patients at the 3-month follow-
up to assess their beliefs on what treatment they believe they had and whether they would 
recommend the treatment to a friend. 
 
 
Maintaining Confidentiality The data will be collected and stored in a password-protected 
computer located in the Department of Anesthesiology. Participants will each be assigned an ID 
number, which will be used as the sole identifier on any documents. Subject data will be 
compiled onto a single password protected file, where they will only be identified by their ID 
number.  

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An enrollment log will be the only file where subject names are correlated with ID numbers. 
This will be kept in a separate, secure, password-protected file in compliance with HIPPA and 
hospital policy within the Department of Anesthesiology. 
The randomization assignment will be kept in a binder in a locked cabinet in the pain clinic. A 
copy of the randomization table will kept in a separate, secure, password protected file on a 
computer located in the department of anesthesiology.  
 
 
Risks/Benefits: 
The risks of C-RFA of the articular sensory branches of the knee are minimal. Sensory and 
motor testing of the target structure prior to lesioning reduces the risk of any neurologic injury 
and the motor nerves are not located at the planned lesion sites. Bleeding or infection can occur 
with any needle intervention. 
 
Summary of Recruitment: 
 
 
 
4.0   Data Analysis: 
 
Primary outcome: 
 Between-group difference in analgesic use (MQS III score) at 48 hours.  
 

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Secondary outcomes: Between groups at 48 hours, 1, 3, 6 months in: 
 
1. Visual Analog Scale for pain (at rest, with mobilization or weight bearing)  
2. Knee Society Scale (clinician); WOMAC (patient)   
4. Physical therapy milestones 
 
a. 
Time to active SLR 
      b. 
Time until patient can get out of bed 
c. 
Time until patient able to ambulate < 100 feet 
d. 
Time until patient able to ambulate around room > 100 feet 
e. 
Time until patient is able to climb stairs (quantify specifics, how many steps are 
considered appropriate?) 
5. Patient Global Perception of Change (GPC) 
6.   Patient Satisfaction (Likert scale) 
6. Hospital Anxiety and Depression Score (HADI) 
7.  SF12 
8.   McGill Pain Questionnaire 
9. Inpatient length of Stay (LOS; days) and Physical Therapy “clearance for discharge” 
(days)   
10.   Complications of the injection procedure 
11.   Medication related adverse events (i.e. sedation, nausea, pruritus, delirium) 
 
 
 
4.2   Interpretation of Anticipated Results: 
Statistical analysis 
Means and standard deviations of participant demographic data, as well as mEQ, VAS, and other 
outcome scores will be calculated.  Two tailed paired t tests will be used for parametric data; 
Wilcoxon rank sum tests will be used for non-parametric data in order to compare differences in 
outcome measures between the two treatment groups.