Effect of the Temperature Used in Thermal Radiofrequency Ablation on Outcomes of Lumbar Facets Medial Branches Denervation Procedures: A Randomized Double-Blinded Trial
Phase: NA
Conditions: Low Back Pain
Sponsor: The Cleveland Clinic

 
 
 
 
 
 
Page 1 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
Effect of the Temperature used in Thermal Radiofrequency Ablation on Outcomes of 
Lumbar Facets Medial Branches Denervation Procedures: 
A Randomized Double‐Blinded Trial 
 
Nagy Mekhail, MD, PhD; Shrif Costandi, MD; Youssef Saweris, MD. 
 
Protocol Version 3 
Revision Date: 10/15/2019 

 
 
 
 
 
 
Page 2 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
Amendments to Protocol to-date: 
 Amendment 1 Dated 24MAR2014:  
“The protocol is being updated so that at the 12 month follow-up subjects who do not 
want to come to clinic can complete the questionnaire by mail or phone,” has been added 
to the protocol. 
 
 Amendment 2 Dated 14MAY2014:  
“Change the last item in the exclusion criteria from: k. History of previous RFA at the 
same level(s) in the previous 12 months. To k. History of previous RFA at the same 
level(s) in the previous 6 months,” has been changed on the current version of the 
protocol. 
 
 Amendment 3 Dated 12NOV2014:  
“The investigator would like to add a window of +/- 1 week to the 1, 3, 6 and 12 month 
follow ups,” has been disregarded therefore has not been added to the current protocol 
version. 
 
 Amendment 4 Dated 23JAN2018: 
Change inclusion criteria f. to “f. Adequate response to the diagnostic block(s), 1 or 
more, at the same levels of the intended block (defined as ≥70% pain relief).” – which 
has been updated on current protocol version. 
 
 Amendment 5 Dated 23JAN2018: 
Adjustment to the above stated amendment dated 24MAR2014 “The protocol is being 
updated so that subjects who do not want to come to clinic can complete the 
questionnaire by mail or phone for any of the follow-up visits”. This has been added to 
the protocol. 
 
 Amendment 6 Dated 23JAN2018: 
Spelling mistakes and references have been corrected.  
 
 Amendment 7 Dated 23JAN2018: 
Page numbers have been added. 
 
 Amendment 8 Dated 23JAN2018: 
Protocol version and revision date have been added. 
 
 Amendment 9 Dated 15OCT2019 
Protocol Version and revision date have been updated.  
 

 
 
 
 
 
 
Page 3 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
 Amendment 10 Dated 15OCT2019 
Change exclusion criteria I to “i. Psychopathology including uncontrolled depression, 
somatization or poor coping skills.”– Which has been updated on current protocol 
version. 
 
 

 
 
 
 
 
 
Page 4 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
Study Aims: 
1. To compare the effects of 2 competing temperatures used for thermal Radiofrequency 
Ablation (RFA) of the lumbar facet medial branches in patients with chronic low back 
pain secondary to lumbar facets arthropathy. 
 
2. This prospective study will assess the relative effects of two temperatures (in degrees 
Celsius) used to ablate the targeted nerves in regards to pain management and possible 
complications. 
 
Research Question: 
Which temperature used to produce RF lesion (80oC or 90oC) is associated with better overall 
improvement in facet‐mediated chronic low back pain? 
 
Specific Hypotheses: 
 Primary 
Lumbar facets medial branches RFA at 90oC provides more overall pain relief (i.e. percent of 
improvement), when compared to ablation at 80oC with no additional adverse events. 
 
 Secondary 
Ablation of the lumbar facets nerve supply at 90oC will provide better improvement in the 
functionality level, general mood and quality of life as measured by VAS (Visual Analog Scale) 
pain score, Pain Disability Index (PDI), McGill Pain and Beck Inventory (BI) questionnaire 
scores than those receiving the ablation at 80oC. Furthermore, it is associated with less opioid 
consumption, no  additional unwanted adverse events and/or complications along  with less need 
to repeat RFA procedure over one year follow-up period. 
 
Significance/Importance: 
Chronic lower back pain (LBP) is a significant health care issue in the United States and the 
world. Chronic LBP contributes to decreased quality of life, decreased functionality and 
increased utilization of health care resources. The causes of chronic LBP tend to be multi‐
factorial. Arthropathy of the lumbar facet joints is thought to be a common etiology (15‐45%) 
(1). Radiofrequency Ablation (RFA) of the  medial  branch  nerve  of  the  facet  joint  is  a  well‐
established  treatment modality  used  to   decrease  facet  joint  pains.  However, a   wide range 

 
 
 
 
 
 
Page 5 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
of temperature is being used (70‐90 degrees Celsius). In addition, the optimal temperature that 
provides the best patient outcomes with the least side effects is not well established in the pain 
management literature. 
 
Summary of Literature: 
Gallagher J, Vadi PLPD, Wedley JR, et al. in 1994 studied the efficacy of the radiofrequency 
facet joint denervation in the treatment of LBP in a prospective controlled double-blinded study 
which has shown that radiofrequency is better than sham denervation in patients with clear‐cut 
relief at 6 months and no significant difference between groups among equivocal responders (2) 
.While Van Kleef et al. in a prospective double-blinded study of thirty one patients had 
concluded that radiofrequency lumbar zygapophysial Joint denervation at 80oC results in a 
significant alleviation of pain and functional disability in a select group of patients with chronic 
LBP, both on a short‐term and long‐term basis(3). On the other hand, Leclaire et al. had 
randomly assigned 70 patients with LBP for >3months duration to receive percutaneous 
radiofrequency articular facet denervation at 80oC under fluoroscopic guidance or the same 
procedure without effective denervation (sham therapy). At 4 weeks, the Roland‐Morris score 
had improved by a mean of 8.4% in the neurotomy group and 2.2% in the placebo group, 
showing a treatment effect of 6.2% (P=0.05). At 4 weeks, no significant treatment effect was 
reflected in the Oswestry score (0.6% change) or the visual analog pain score (4.2% change). At 
12 weeks, neither functional disability, as assessed by the Roland‐Morris scale (2.6% change) 
nor Oswestry scale (1.9% change), nor the pain relief, as assessed by the visual analog scale 
(27.6% change) showed any treatment effect (4). It should be noted that in this study, the 
diagnosis of lumbar facets arthropathy was made by a primary care physician rather than a pain 
management specialist. 
 
In 2005, Von Wijik et al. in RCT, had found that there is no difference at 3 months between 
radiofrequency using temperature of 80oC and sham denervation in combined outcome measures, 
however, radiofrequency patients have better Global perceived effect and back pain relief (5) . In 
another prospective study after positive diagnostic block, Nath et al. have found that active 
treatment group using 85oC temperature has shown statistically significant improvement not only 
in back and leg pain but also back and hip movement as well as the sacroiliac joint test. Pre‐
operative sensory deficit and weak or absent ankle reflex normalized (P<0.01) and (P<0.05), 
respectively. There was significant improvement in quality of life variables, global perception of 
improvement, and generalized pain (6). 
 
In a retrospective study done at our department, 100 patients (50.3%) received RFA at 80oC and 
99 patients (49.8%) received RFA at 90oC. there were no clear cut advantage of either 

 
 
 
 
 
 
Page 6 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
temperature. However, the preliminary analysis did not control for potentially confounding 
baseline demographics and disease related characteristics. Thirty eight (38%), 9 (9%), 37 (37%) 
and 16 (16%) patients undergoing RFA at 80oC reported no improvement, minimal improvement 
(<25%), moderate improvement (25‐75%), and marked improvement (>75%) in symptoms 
respectively. Among patients undergoing RFA at 90oC, these numbers were 19 (19%), 1 (1%), 
44 (45%) and 34 (35%), respectively. The proportional odds logistic regression model for relief 
did not indicate a significant difference in relief scores between the two groups (likelihood ratio 
test p=0.033, using an adjusted significant difference criterion at 0.025). Due to the factors 
discussed and the inherent limitations of the retrospective studies, we plan to prospectively study 
the issue in a double-blinded randomized fashion. 
 
Study Population: 
• Patient Population: 
Subjects with chronic low back pain (LBP) of lumbar facet joints origin fulfill the other below 
inclusion criteria and do not meet any of the exclusion criteria will be recruited from Cleveland 
Clinic Pain management outpatient clinic. 
 
• Inclusion Criteria: 
a. Age >18 years‐old. 
 
b. Subjects who are able to give informed consent and to understand and comply with study 
requirements. 
 
c. Predominantly axial low back pain ≥3 months in duration with no radicular pain below 
the knee that failed to conservative therapy. 
 
d. Subjects who have chronic back pain attributed to lumbar facet joints arthropathy based 
on clinical evaluation (paraspinal tenderness and/or facet loading test in the absence of 
signs and symptoms suggestive of focal neurological deficits). 
 
e. No history of previous back surgery at the intended treatment levels. 
 
f. Adequate response to the diagnostic block(s), 1 or more, at the same levels of the 
intended block (defined as ≥70% pain relief). 
 
g. Patients who will undergo RFA of 3‐4 lumbar facet medial branches on one side only. 
 

 
 
 
 
 
 
Page 7 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
• Exclusion Criteria: 
a. Subjects who decline to provide written consent or follow‐up. 
 
b. Subjects who have a history of adverse reactions to local anesthetic. 
 
c. Subjects who are pregnant. 
 
d. Subjects with bleeding disorders or active anticoagulation that cannot be stopped for few 
days close to the time of the procedure. 
 
e. Subjects who have an active systemic or local infection. 
 
f. Presence of radicular pain extending below the knee. 
 
g. Patients  who  have  other  specific  etiology  of  low  back  pain  (e.g. significant spinal 
canal stenosis or grade 2 or 3 spondylolisthesis). 
 
h. Secondary gain (i.e., ongoing litigation, worker’s compensation or other financial 
incentives). 
 
i. Psychopathology including uncontrolled depression, somatization or poor coping skills. 
 
j. Physical factors including non‐sedentary lifestyle, e.g.; morbid obesity (BMI >35kg/m2). 
 
k. History of previous RFA at the same level(s) in the previous 6 months. 
 
Subject Withdrawal: 
Subjects may voluntarily withdraw from the study at any time. Reasons for withdrawal will be 
recorded on the appropriate case report form (CRF). Pertinent data from such patients (either 
before or after the withdrawal) will be included in analysis if available, unless the patient 
explicitly states that they do not want their data to be included. 
 
Terminating Subject Participation: 
A subject’s participation in the study may be terminated if continued participation in the study is 
not in the subject’s best interest, in the investigator’s opinion. 
 

 
 
 
 
 
 
Page 8 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
Methods: 
• Study design: 
This will be a prospective, randomized double‐blinded study. 
 
• Randomization: 
After Institutional Review Board (IRB) approval and written consent, eligible patients, 
consenting to participate in the study will be randomly assigned to one of the two study groups 
(80oC or 90oC) based on computer‐generated allocations which will be done immediately before 
use. 
 
• Blinding: 
Patient, physician performing the procedure and physician or research fellow assessing the 
outcomes will be blinded to the group assignment. 
 
• Study Protocol: 
Patients must meet all inclusion and exclusion criteria to be eligible for the study. After 
eligibility is confirmed, the patients will receive complete information about the study both 
verbally and in writing. Informed consent must be obtained from the patients prior to 
randomization and study‐specific procedures. Once all eligibility criteria are fulfilled (including 
informed consent), the patients will be randomized, and treatment allocation will be performed. 
Key baseline patients characteristics, as well as patient’s eligibility criteria, will be collected on 
case report forms. 
 
Randomization will be done through an independent study coordinator or research fellow other 
than the one who is assessing the outcomes. Patients will be randomly assigned to one of the two 
groups as 1:1 ratio. 
 
The nurse who is responsible for operating the radiofrequency generator will be the only one 
informed about the randomization results through the unblinded study coordinator. The physician 
and the patient will both be blinded. 
 

 
 
 
 
 
 
Page 9 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
Intravenous access will be inserted for all patients and mild sedation with midazolam will be 
given according to the patient needs. 
 
With the C‐arm guidance a 20‐gauge radiofrequency needles with 10mm active tips will be used 
to ablate 3‐4 lumbar facet medial branches. 
  
At each level, needles will be adjusted to optimize sensory and motor stimulation. For each nerve 
lesion, correct placement is confirmed using electrostimulation at 50Hz, with concordant 
sensation achieved at 0.5V or less. Before denervation, multifidus stimulation and the absence of 
leg muscles contractions is verified with electrostimulation at 2Hz. 
 
The radiofrequency lesions will then be carried out at 80°C (group 1) or 
90°C (group 2) for 90 seconds twice to produce the desired lesions of the medial branches. 
 
• Data Collection: 
Study data for follow-up visits will be collected by one of 3 ways. The follow-up visit 
questionnaires can be filled in-person, sent out to patients by mail or completed over the phone, 
whichever is more convenient for the patient. 
Collected data will then be inputted and managed using REDCap (Research Electronic Data 
Capture) tools hosted at Cleveland Clinic. REDCap is a secure, web‐based application designed 
to support data capture for research studies, providing:  
1) An intuitive interface for validated data entry. 
2) Audit trails for tracking data manipulation and export procedures. 
3) Automated export procedures for seamless data downloads to common statistical packages.  
4) Procedures for importing data from external sources. 
 
• Patient Demographics: 
 Age 
 Sex 
 Smoking 
 BMI 
 History of back surgeries. 

 
 
 
 
 
 
Page 10 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
 Diabetes mellitus. 
 Response to diagnostic blocks 
 
• Patient Baseline data: 
 Preoperative and baseline pain score will be collected using Visual Analog Scale (VAS) 
 Pain Questionnaires: 
o Pain Disability Index (PDI). 
o McGill Pain Questionnaire. 
o Beck Inventory (BI) 
 Oral pain medications in morphine sulfate equivalent mg/day. 
 
• Technique related data: 
 The temperature of the probe used (80oC or 90oC) 
 Duration of application of the RF probe is 90 seconds twice using 10mm active tip probe. 
 Sensory stimulation 0.5mAmp 
 Needle size 20G 
 The number of ablated nerves. 
 Side/Laterality. 
 
• Outcomes Data:  
Outcomes will be measured at baseline and 1, 3, 6 and 12 months follow-up visits post-
procedure. 
 
 Primary outcomes: 
Overall pain relief (i.e. percent of improvement) at each visit mentioned above. 
 
 Secondary outcomes: 
o Postoperative Pain Scores in the subsequent visits using VAS at each visit 
mentioned above. 
o Pain Questionnaires: 
o Pain Disability Index (PDI). 
o McGill Pain Questionnaire. 
o Beck Inventory (BI) 
o Number of repeats of procedure in the first year after index procedure. 

 
 
 
 
 
 
Page 11 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
o Consumption of oral opioids in mg oral morphine equivalents recorded at the 
baseline before the procedure and then in the follow-ups post-procedure (1, 3, 6 
and 12months). 
‐ This table summarizes the morphine equivalent doses for the most commonly used morphine 
derivatives (7). 
 
Drug Name 
 
Oral dose equivalent to 30mg oral 
morphine sulfate 
 
IV dose equivalent to 30mg  
oral morphine sulfate 
Morphine sulfate 
30 mg ( 1:1 ratio) 
10 mg (1:3) 
Hydromorphone 
7.5 mg (1:4 ratio) 
1.5 mg (1:20) 
Meperidine 
300 mg(10:1 ratio) 
100 mg (3.33:1) 
Methadone 
12mg(1:2.5 ratio) 
10 mg (1:3) 
Oxycodone 
15 mg(1:2 ratio) 
N/A 
Hydrocodone 
30 mg(1:1 ratio) 
N/A 
Codeine 
200 mg(6.66:1 ratio) 
120 mg (4:1) 
 
‐ The following formula will be used for Fentanyl transdermal patch: 
o 25 µg/h is equivalent to 87.5 mg morphine/24h 
o 50 µg/h is equivalent to 175 mg morphine/24h 
o 75 µg/h is equivalent to 262.5 mg morphine/24h 
o 100 µg/h is equivalent to 350 mg morphine/24h 
 
• Adverse Events: 
 Persistent paresthesia (yes/no) 
 Nerve injury (yes/no) 
 Infection (yes/no) 
 Bleeding (yes/no) 
 
• Data Analysis: 
Standard descriptive statistics will be used to compare the randomized groups on baseline 
variables. Any obviously imbalanced co-variables (say, with a standardized difference greater 
than 0.20 in absolute value) will be adjusted for in both primary and secondary analyses. Our 
primary analysis will be intent‐to‐treat. 

 
 
 
 
 
 
Page 12 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
 Primary Hypothesis: 
Graphically displayed over follow‐up times (1, 3, 6 and 12 months) using boxplots containing 
the median, quartiles and outliers. At each follow‐up time point (1,3, 6 and 12 months) we will 
assess whether 80°C and 90°C RFA temperatures differ with respect to the percentage of pain 
relief using the Wilcoxon rank‐sum test. The significance criterion will be 0.05/4=0.0125 at each 
time, using a Bonferroni correction to control the type I error at 0.05 for the primary hypothesis.  
In addition to the P‐value, the estimated median percentage of pain relief for each group and 
difference in medians with confidence intervals will be reported. The estimated probability of 
pain relief at 90°C being better than at 80°C with confidence interval will be reported, since the 
Wilcoxon rank sum test has a null hypothesis that this probability is 0.50.   All the confidence 
intervals will be estimated based on bootstrapped standard error with 10,000 bootstrap 
replications (8). 
 
 Interim analyses: 
Interim analyses will be conducted for efficacy and futility at each 25% of the maximum 
enrollment (see Sample Size Considerations) using a group sequential design and gamma 
spending function (using gamma = ‐4 for efficacy and ‐2 for futility).   P‐value boundaries for 
efficacy (futility in parentheses) will be P≤0.0016 (P>0.957), P≤0.0048 (P>0.719), P≤ 0.0147 
(P>0.239), and P≤0.0440 (P>0.0040) at looks 1 through 4, respectively. 
 
 Secondary  hypotheses: We  will  compare  randomized  groups  on  the  following 
variables: 
VAS pain scores/Pain Disability Index (PDI)/McGill Pain questionnaire scores/Beck Inventory 
(BI) scores. 
 
While  the  detailed  description  below  focuses  on  the  VAS  pain  score outcome for brevity, 
the analysis approach will be the same for Pain Disability Index (PDI), McGill Pain 
questionnaire scores, and Beck Inventory (BI) scores. 
 
Graphical analysis will be undertaken to describe the degree of pain reduction observed in 
patients undergoing each treatment.   The association between RFA temperature and pain 
reduction will be performed using a mixed effects model adjusting for time interval and also for 
baseline pain score to increase precision. We will assess the group‐time interaction and assess 
treatment effects at each time if interaction P <0.15. The mixed model will account for potential 
intra‐subject correlation of repeated VAS pain measurements within a patient using a spatial 

 
 
 
 
 
 
Page 13 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
correlation structure. A model‐based Wald test for regression model coefficients will be used to 
evaluate whether or not RFA temperature affects mean pain reduction. 
 
 Opioid Consumption: 
As preliminary retrospective study showed, postoperative opioid consumption is largely binary 
in nature for this patient’s population, as over 60% of our patients did not take any opioids. Thus, 
postoperative opioid consumption within a year of the first RFA will be analyzed as a binary 
outcome, i.e., any versus none (however, dosage information among the subset of patients taking 
any opioids will be described using medians and quartiles for each group). Multivariable logistic 
regression will be used to estimate the adjusted relative risk for postoperative opioid use 
comparing patients undergoing RFA at 90°C to patients undergoing RFA at 80°C. A logistic 
model‐based Wald test for regression coefficients will be used to test the hypothesis of the effect 
of temperature on the postoperative opioids use (i.e., whether or not the relative risk is different 
from a value of 1.0). 
 
 Number of repeat of RFA procedures 
Need for repeated RFA procedure over one year period will be analyzed as a count variable 
using a proportional odds logistic regression model. If the number of repeats greater than 1 is 
very rare, we will use a binary outcome of any RFA procedure comparing two groups of patients. 
 
 Complications: 
Incidence of each individual complication will be reported for each group, with confidence 
intervals.  Possible adverse events (persistent paresthesia, nerve injury, bleeding and infection) 
will be summarized into a single composite binary outcome, i.e., any versus none. The risk of 
experiencing one or more adverse events will be compared between RFA at 90°C and RFA at 
80°C groups using logistic regression. 
 
Type I error will be controlled at 5% for the secondary outcomes using the Bonferroni correction 
for simultaneous hypotheses. SAS 9.3 software (SAS Institute, Cary, NC) and R statistical 
software version 2.7.2 (The R Foundation for Statistical Computing, Vienna, Austria) will be 
used for all analyses and graphics. 
 
 
 

 
 
 
 
 
 
Page 14 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
 Sample size considerations: 
Sample size estimation is based on the frequency distribution estimated across four categories of 
pain relief used in our preliminary retrospective study. Thus, for these calculations 38%, 9%, 
37%, and 16% of patients undergoing RFA at 80°C are assumed to develop no improvement 
(=0%), minimal improvement (<25%), moderate improvement (25‐75%), and marked 
improvement (>75%) in symptoms, respectively. We further assumed that the data was 
uniformly distributed across each category through simulation, and performed power 
calculations on the simulated data using categories of percent pain relief of 0, 1‐10, 11‐20, 21‐30, 
…, 91 – 100.   In order to have 90% power at the 0.0125 significance level at each time point 
(0.05/4 = 0.0125 at each time point) to detect a clinically significant shift in improvement of 
absolute 15% between RFA at 90°C and RFA at 80°C, a maximum of N=216 total patients 
would be required.  Below we list the proportion of patients in each percent pain relief category 
as assumed for the sample size calculations described above.  Although a 20% increase is in 
general what would be considered a clinically important improvement in pain relief, we plan for 
15% since there may be a nontrivial fraction of patients who experience no relief in either group.   
Adjusting for 3 interim analyses and a final analysis would require a maximum of N=237.  With 
the above parameters, there will be a cumulative 8%, 37%, 75%, and 100% chance of crossing a 
boundary at the 1st through 4th analyses if the alternative hypothesis is true as stated above. 
Group 
0 
1‐10 11‐20 21‐30 31-40 41‐50 51‐60 61‐70 71‐80 81‐90 91‐100 
Control 
.38 
.041 
.035 
.06 
.07 
.067 
.069 
.087 
.062 
.057 
.072 
Experimental 
0 
0 
.399 
.041 
.03 
.083 
.068 
.064 
.077 
.078 
.16 
 
We plan to re‐estimate sample size after obtaining at least 1 and 3 month continuous pain relief 
outcome for the first 60 patients, using the observed shape of the distribution and the variability 
of the outcome, but still based on an absolute 15 percent upward shift from the 80 degrees group. 
Type I error will be controlled using the methods in Kieser 2000 (9). 
 
We will provide results to the Data and Safety Committee on efficacy and safety assessments, 
including conditional power analyses, but the committee will have final say on whether the study 
would progress to the next interim analysis or be stopped. 
 
 

 
 
 
 
 
 
Page 15 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
References 
 
1.  Schwarzer AC, Aprill CN, Deby R et al. Clinical features of patients with pain stemming 
from the lumbar zygapophysial joints. Is the lumbar facet syndrome a clinical entity? 
Spine 1994; 19: 1132‐1137. 
  
2.  Gallagher J, Vadi PLPD, Wedley JR, et al. Radiofrequency facet joint denervation in the 
treatment of low back pain: a prospective controlled double blind study to assess its 
efficacy. Pain Clinic 1994; 193‐8. 
 
3.  Van Kleef M, Barndse GA, Kessels A, Voets HM, Weber WE, De Lange S. Randomized trial 
of radiofrequency lumbar facet denervation for chronic low back pain. Spine 1999; 24: 
1937‐42 
 
4.  Leclaire R, Fortin L, Lambert R, Bergeron YM, Rossignol M. Radiofrequency facet joint 
denervation in the treatment of low back pain: a placebo‐ controlled clinical trial to assess 
efficacy. Spine 2001; 26: 1411‐6; discussion 17. 
 
5.  Van Wijk RM, Geuts JW, Wynne HJ, et al. Radiofrequency denervation of lumbar facets 
joints in the treatment of chronic low back pain: randomized, double –blind, sham lesion‐
controlled trial. Clin J Pain 2005; 21:335‐44. 
 
6.  Nath s, Nath CA, Pettersson K. Percutaneous lumbar zygapophysial (facet) joint neurotomy 
using radiofrequency current, in the management of chronic low back pain: A 
randomized double blind trial. Spine (Phila PA 1976); 33 (12): 1291‐1297; discussion 
1298, 2008. 
 
7.  Vieweg WV, Lipps WF, Fernandez A. Opioids and methadone equivalents for clinicians. 
Prim Care Companion J Clin Psychiatry 2005; 7: 86‐88. 
 
8.  Efron B and Tibshirani R. An introduction to the bootstrap. Monographs on statistics and 
applied probability. 1993, New York: Chapman & Hall. xvi, 436 p. 

 
 
 
 
 
 
Page 16 of 16 
Protocol Version 3 
Revision Date: 10/15/2019 
 
 
9. Kieser M, Friede T: Re‐calculating the sample size in internal pilot study designs with control 
of the type I error rate. Statistics in Medicine 2000; 19: 901‐911