Bone Marrow Concentrate Intradiscal Injection for Chronic Discogenic Low Back Pain: A Double-Blind, Placebo Controlled Trial
Phase: NA
Conditions: Discogenic Pain
Sponsor: APM Spine and Sports Physicians

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Title:  Bone Marrow Concentrate intradiscal Injection for Chronic 
Discogenic Low Back Pain: A Double Blind Randomized Controlled 
Trial 
 
 
1. Table of Contents:  
 
 
Cover Sheet 
 
 
 
 
 
 
 
Page 1 
 
Introduction 
 
 
 
 
 
 
 
Page 3 
 
Participant Section: Inclusion and Exclusion Criteria 
 
Page 4 
 
Study Design/Method/Procedures    
                        
Page 8 
 
Risk/Benefit Assessment 
 
 
 
 
 
Page 15 
 
Participant Recruitment and Informed Consent 
 
 
Page 18 
 
References 
 
 
 
 
 
 
 
Page 20

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2. Cover Sheet 
 
Title:  Bone Marrow Concentrate intradiscal Injection for Chronic 
Discogenic Low Back Pain: A Double Blind Randomized Controlled Trial 
 
 
Protocol: # BMC-1788-01 
 
 
 
 
09/21/2017 Version 1.0 
 
 
 
 
 
 
 
 
Principle Investigator: David Levi MD  
 Sub-Investigators: Scott Horn DO, Sara Tyszko PA, Josh Levin MD 
APM Spine and Sports Physicians 
1788 Republic Road 
Virginia Beach, VA 23454 

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3. Introduction 
3A. Type of Study: A double blind randomized placebo controlled trial for an autologous bone 
marrow aspirate product, bone marrow aspiration concentrate, not considered by the FDA to be a 
drug.  The preparation of this substance uses a simple concentration procedure of the bone 
marrow by an FDA approved Arthrex Angel flow cytometry bone marrow concentrate system 
through Arthrex corporation (Naples, FL).  The procedure is considered to be minimal 
manipulation of bone marrow tissue for homologous use as per FDA draft guidance covered 
under Code of Federal Regulations 361 [1, 2]. 
 
3B. Purpose/Objective of the Study: To investigate the efficacy and safety of a single bone 
marrow concentrate injection into one or more intervertebral discs for the treatment of 
discogenic low back pain. 
 
3C. Background of the Study:  Low back pain is an extremely common cause of pain and 
disability.  Although several structures within the spine have been identified as pain generators, 
the intervertebral disc is felt to account for 40-50% of chronic low back pain [3]. The most 
common conservative treatment options include activity restriction, medications, physical 
therapy, chiropractic treatment, and steroid injections.  Many patients have an inadequate 
response to these conservative measures and progress to surgical treatment, either lumbar fusion 
or disc replacement.  Lumbar fusion results for discogenic pain vary considerably, and disc 
replacement results do not appear to be significantly superior to fusion.  While minor 
complications are relatively common with fusion surgery, catastrophic complications can occur. 
These complications are relatively rare.  The larger issue with lumbar fusion for discogenic low 
back pain is the risk/benefit ratio.  It is considered to be an extensive surgical procedure 
involving 3-6 months of recovery.  Although there is evidence that it is superior to conservative 
care, the results are relatively modest [4,5]. In addition, it is not uncommon for patients to 
perceive a lack of effect or even worsening of symptoms. 
 
The pathoanatomy of a painful intervertebral disc has been extensively studied [6,7].  The region 
of the disc felt to illicit pain is the outer portion of the disc, the annulus fibrosis.  The annular 
region can develop tears or fissures in the collagen fibers.  These fissures contain an ingrowth of 
vascularized granulation tissue along with extensive nerve endings.  These changes are felt to 
contribute to the development and perpetuation of discogenic low back pain. [6,7].  
 
Prior conservative treatments aimed at annular tear pathology have been attempted with heat or 
radiofrequency energy with disappointing results [8,9].  Others have investigated the use of 
methylene blue as a neurolytic agent within the disc [10,11].   These investigators published two 
quality clinical studies demonstrating the efficacy of intradiscal methylene blue. Unfortunately, 
further investigations have not produced their excellent results [12, 13].   
 
Ultimately, the ideal treatment for pain induced by annular tears would be through direct healing 
of the tears themselves.  Attempts are being directed toward this goal with research in areas such 
as stem cells, platelet-rich plasma, and specific growth factor injections [14-16].   

4 
 
 
Another therapeutic agent which could potentially promote disc regeneration is bone marrow 
concentrate (BMC).  Bone marrow concentrate is obtained through a simple centrifugation of 
autologous bone marrow aspirate.  Bone marrow aspirate / concentrate has been used extensively 
in orthopedic clinical settings to promote tissue healing [17,18].  Growth factors, cytokines and 
pluripotent stem cells within the aspirate are felt to be responsible for the ability of BMC to 
promote tissue healing in collagen based structures [19,20].   
 
BMC has been used studied in animal and human trials in multiple non-spine orthopedic 
conditions [19-23].  Results have been promising.  BMC has been used in spinal surgery to 
augment fusion with positive results [18].  
 
Recently bone marrow concentrate has been used in the treatment of discogenic low back pain.  
The results of a single trial of BMC intradiscal injection for discogenic LBP have been published 
with 12 and 24 month follow-up [24,25].  Pettine et al. performed a prospective trial using 
autologous bone marrow concentrate in a single treatment into the intervertebral discs.  The 
study included 26 patients who had at least moderate to severe low back pain with activity for 6 
months and at least 3 months of non-operative treatment without significant changes in their 
symptoms.   
 
Pain and function were evaluated by visual analogue scale (VAS) and Oswestry disability index 
(ODI) prior to the procedure and at 3, 6, 12 and 24 months post-injection.  Average VAS and 
ODI scores demonstrated significant improvement at all time points.  At the two year mark, 81% 
of the patients avoided surgery.  Of the 21 non-surgical patients, the average decrease in pain 
was 71% at 2 years.  The authors also compared pre-procedural MRI disc degeneration levels 
(Pfirrman grade) to MRI findings at 12 months.  No discs appeared worse and in 8 patients there 
was actual improvement in the degree of disc degeneration of at least 1 Pfirrman grade at the 
level injected. 
 
BMC appears to have an excellent safety profile.  Pettine et al. reported no significant side 
effects from intradiscal BMC [24,25].  In addition, no significant adverse events have been 
attributed to this treatment in multiple animal and human studies published for a variety of 
orthopedic conditions [19-23, 26].   
 
4. Inclusion/ Exclusion Criteria 
 
4A. Inclusion/exclusion criteria 
 
 Inclusion criteria: 
 
 Chronic low back pain greater than 6 months with low back pain component greater than 
leg pain component if present. 
 
 Average pain at least 40/100 on Visual analogue Scale (VAS) 
 

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 Inadequate response to conservative care including medication, physical therapy, and/or 
spinal injections. 
 
 Males and females at least 18-55 years old. 
 
o Rationale for age limit of 55: Based upon the study by Depalma et al. [27], at age 
55 and less the predicted probability of a discogenic source of pain is higher than 
any other source.  Beyond 55 years of age, zygapophyseal joints have a higher 
predictive probability.  Therefore, the pre-test probability for a test for discogenic 
pain beyond this age is considerably lower. 
 
 Have provided informed consent. 
 
 If female subjects are of child-bearing potential, they must be using an acceptable form of 
birth control. 
 
 Advanced imaging of MRI or CT demonstrating abnormal disc morphology.  
 
 Presumed lumbar discogenic pain based upon either A or B below: 
 
 
A.  Positive provocative discography in accordance with SIS guidelines [28]. 
 
Or 
  
B. Both B1 and B2  
 
B1.  The patient must have MRI findings suggestive of discogenic low 
back pain including either a high intensity zone region or type 
1 or type 2 end plate Modic changes [29-31].  
   
B2.  Exclusion of other structures as source of pain (see below). 
 
Rationale for not requiring discography for inclusion: 
The rationale involves several factors.   Although injecting the BMC at the time 
of discography seems most reasonable, the volume of contrast used for the  
discography test may reach 3ml, when performed in accordance with SIS 
guidelines [28].  This leaves an inadequate volume capacity to accommodate 
much volume of BMC.  Secondly, in accordance with SIS guidelines [28] 
discography requires a negative control disc.  Discography is invasive and may 
have negative detrimental effects on the disc [32].  Therefore, potential harm may 
exist if discography is performed.  BMC is considered to be a very benign 
substance; it is an autologous tissue unlikely to have any detrimental effects [17, 
18, 22].   
 
Subjecting patients to two distinct intradiscal procedures (discography prior to the 
BMC procedure) is difficulty to justify when the purpose of discography 

6 
 
(including injecting a normal control level) would be for qualification of an 
intradiscal injection of a very likely benign substance. 
 
In summary, (as expressed in a prior study of a regenerative intradiscal treatment 
publication [15]), injecting the BMC at the time of discography would not allow 
enough volume for the BMC and performing a separate discography procedure 
“solely for determining the candidacy and level for the [BMC] injection could not 
be justified” [15]. 
 
 
 
 If clinical suspicion for facet pain is present, subjects must have had a negative 
investigation of zygapophysial (facet) joints as the primary source of pain to include 
diagnostic medial branch blocks or intra-articular facet injections or have failed 
radiofrequency ablation (assumed to have had 2 false positive blocks). 
 
 If clinical suspicion for sacroiliac joint pain is present (Paraspinal pain below L5 or 
dominate buttocks pain), subjects must have had a negative investigation of the 
sacroiliac joint as the primary source of pain to include intra-articular sacroiliac 
injections or diagnostic S1-3 lateral branch blocks and L5 dorsal ramus block. 
 
 
Exclusion criteria: 
 
 Active moderate to severe lumbar radiculopathy 
 
 Negative provocative discography.  (Discography is not required for inclusion but prior 
discogram testing found to be negative excludes the patient from the trial.) 
 
 Very severe decrease in disc height at a planned injection level.  A disc height less than 
1/3 expected normal disc height will be an exclusion.   
 
o Rationale for this disc height exclusion criteria: Requirements for 2/3 of normal 
disc height has become the norm for many intra-discal procedure trials which may 
have originated out of the intradiscal electrothermy annuloplasty trials as a 
requirement for device access [8-10].  The authors do not feel that moderate disc 
height loss should preclude needle access nor adequate chance for clinical 
success. 
 
 
 Active infection 
 
 Moderate to severe anemia, thrombocytopenia, or leukopenia 
 
 Spinal fracture within the past 6 months 
 

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 Severe psychological illness 
 
 Inability to consent to procedure due to cognitive issues 
 
 Prior fusion at the level considered to be the source of pain 
 
 Pregnant or breastfeeding females. 
 
 Severe uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, 
pulmonary, cardiac, or neurological disease or any medical condition which would make 
the subject unsuitable for this study. 
 
 Inflammatory arthritis 
 
 Any cancer within the past 5 years except basal cell or squamous cell skin cancer 
 
 Intradural disc herniation 
 
 Coagulopathy preventing spinal injection 
 
 Inability to stop anticoagulants other than aspirin due to other medical issues 
 
 Exceeds 30 mg morphine equivalent per day of opioid use. 
 
 A history of alcohol or drug abuse within the past 5 years. 
 
 Use of any investigational drug within the past 30 days. 
 
 Low back surgery within the past 6 months. 
 
 Steroid injection in the spine within the past 30 days. 
 
 Any intradiscal injection other than contrast dye or anesthetic within the past 30 days. 
 
 A known allergy or sensitivity to heparin or citrate (used for processing BMC) 
 
 Pending litigation involving the subject’s back pain. 
 
 Central stenosis at the level to be injected with an AP diameter less than or equal to 5 mm 
 
 Severe anaphylactic/anaphylactoid reaction to any of the medications used.  (If a patient 
does have a mild or moderate allergy to any of the medications used in the procedure or 
prior anaphylactic/anaphylactoid reaction to any food or drug, they will be given 
prednisone 50 mg PO 13, 7, and 1 hour prior to the procedure and diphenhydramine 
50mg PO 1 hour prior to the procedure.) 

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 In order to mitigate any economic risk, a patient without adequate medical insurance 
coverage for any subsequent tests or procedures deemed clinically necessary will be 
excluded.  BMC is an autologous blood product with multiple clinical uses.  Intradiscal 
administration should not preclude insurance coverage for any subsequent medical issues 
that might develop pertaining to the intradiscal injection itself or the BMC 
 
 
4B. There is no gender discrimination 
Pregnant women will be excluded as above. 
Women of child bearing capacity will need an acceptable form of birth control. 
 
4C. There is no racial discrimination 
 
4D. Persons considered to be of a vulnerable population will not be included in the study. 
 
4E. Age: 18 years – 55 years old 
 
4F. Number of participants:  60 participants expected to be enrolled.  Duration of patient 
enrollment is 3 years. 
 
Power analysis: 
 
With two treatment patients for each placebo patient, 40 treatment and 20 placebo patients will 
be required to achieve 80% power to detect a difference of 0.35 in the proportion of patients with 
successful improvement between groups with a chi-squared test at a level of significance of 0.05, 
assuming the proportion of patients achieving success in the control group is 0.2 (20%)   This is 
based upon the preliminary data calculated success rate (>50% improvement in Pain) from 
Pettine et al. study [24] was 61%.  (Our calculation differs from Pettine et al. as we included 
surgical patients as failures.)  The 95% CI are 44-75% using an n of 40 in our proposed treatment 
group.  The placebo rate is a very well done spinal explanatory study was 13% [33].  The 
placebo rate from an intradiscal study using intradiscal normal saline was 12.5% and 23.5% 
using hyaluronic acid (the carrier for the treatment).  We therefore used the conservative estimate 
of a placebo response rate of 20% in this study.  
 
5. Study design/methods/procedures 
 
5A. Summary of research design 
 
A total of 60 patients with randomization 2:1 ratio (treatment : control).   Pain and function will 
be assessed using VAS and ODI.  Primary outcome will be percentage of patients in the 
treatment group compared to the control group at 6 months categorized as a clinical success, at 
least 50% relief of pain.  Secondary outcomes will be comparison of success rates (at least 50% 
pain relief) at 3 and 12 months.  Other secondary outcome will be percentage of patients in the 
treatment group vs control group with greater than 30% improvement in ODI at 3, 6, and 12 

9 
 
months.  Global Perceived Effect (GPE) will also serve as a secondary out come at 3, 6, and 12 
months.  Medication log and adjunctive treatments will also be recorded and analyzed.   
 
Randomization process: computer randomization program  
Randomization shall be performed through a computer randomization program.  
https://www.random.org/#numbers  (Randomness and Integrity Services Ltd. Dublin, IR.)  A 
random number shall be generated between 1 and 60.  For all randomly generated number from 1 
to 40, the patient will be assigned to the treatment group.  For all randomly generated random 
number from 41 to 60, the patient shall be assigned to the placebo group. 
 
The patients will be blinded to treatment assignment.  The patient will follow up for assessment 
with an investigator who remains blinded to the treatment assignment.  Only the physician 
performing the procedure will be aware of the group assignment.   
 
Based upon previous recommendations for the assessment of blinding success in clinical trials 
[34] the patients will be queried at 2 weeks whether they believe they have received the active 
treatment, the placebo, or if they do not know to which group they were assigned.  
 
Treatment: a single intradiscal injection of autologous bone marrow concentrate into suspected 
painful discs based upon history, image findings and the exclusion of other anatomic structural 
sources of pain such as z-joints and SIJ. 
 
Placebo: Intramuscular injection of normal saline directly above the transverse process at each 
suspected discogenic pain level.  (The physician performing the procedure will not be blinded, 
but the assessor for follow up evaluation will be blinded). 
 
 
A sham bone marrow aspiration will also be performed involving fluoroscopic guidance and 
anesthetic to the iliac crest.  The patient will hear the noise of the bone marrow drill 
(unattached), while a 21 gauge needle is tapped against the periosteum.  
 
Patients will be screened from a pool of existing patients at a community outpatient spine and 
musculoskeletal practice.  These patients will have had an inadequate response to conservative 
treatments, some of whom will be considering fusion surgery.  Some of these patients will be 
considering provocative discography through the recommendation of a local surgeon. One of the 
options discussed will be bone marrow concentrate intradiscal injection under the context of the 
study.  If the patient has any interest in participating in this study, the general risks, benefits and 
literature will be discussed.  The patient will be informed that their status as a patient in the 
principle investigator’s practice and the physician-patient relationship will not be altered 
regardless of their participation in the study.  They will be given a written summary of the study.   
If they have continued interest, an appointment will be arranged for the verbal and written 
consent process.  Once the consent form process has been completed, the patient will perform the 
VAS as well as the ODI which will serve as the baseline measurement data [35].  A pain 
medication query shall be performed as well. 
 

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All procedures will be performed by two of the investigators (DL and SH). Both are board 
certified in Physical Medicine and Rehabilitation, experienced discographers, fellowship trained 
in spine injections and serve as instructors for spinal injection procedures at the national level 
(Spine Intervention Society).  Both investigators have supplemental training and years of 
experience with bone marrow aspiration procedures. 
 
Bone marrow aspiration and intradiscal BMC injection procedure: 
 
Pre-procedure: 
The patient will be offered a P.O. sedative of diazapam 5 to 10 mg or alprazalam 0.5 to 2 mg to 
be taken 30-60 minutes prior to the procedure.  Alternatively, patients will be offered conscious 
sedation in the form of 2 mg to 6 mg midazolam IV with the possible addition of 50 to 150 mcg 
fentanyl IV.   Alternatively, 50-100 mcg fentanyl may be injected IM for pain control.  
Continuous cardiac, pulse oximetry, and clinical monitoring will be performed throughout the 
procedure.  Oxygen by nasal cannula 2 to 4 L may also be used.  Emergency equipment will be 
immediately available.  The investigators (DL and SH) performing the procedure are ACLS 
certified by the American Heart Association.  Conscious sedation, if utilized, will be performed 
in accordance with state requirements including the assistance of a nurse, physician’s assistant or 
a second physician.  
 
 
Bone marrow aspiration procedure:  The patient will be placed in a prone position in our 
outpatient fluoroscopy suite. Strict sterile technique will be observed.  The lower back will be 
cleansed with a solution of chlorhexadine mixed with alcohol and covered with a sterile drape.   
 
The posterior superior iliac spine will be located by fluoroscopy.  A 25 gauge needle will be 
placed down to the periosteum, which will then be anesthetized with 3ml of lidocaine 2%.  An 
additional 2ml will be used to anesthetize the superficial tissues and skin.  The needle, syringes 
and BMC filter are primed with heparin 500 units/ml.  A total of 9 ml of anticoagulant citrate 
dextrose-formula, (ACD-A) is placed in the syringes to prevent clotting of the aspirate and 
divided equally into the 6, 10ml syringes.  A 15g needle with stylet will be directed manually 
down to the periosteum under intermittent fluoroscopic guidance.   The Arrow Oncontrol 
(Teleflex, Morrisville, NC) drill aspiration system will be used with a 15g aspiration needle.  The 
drill, within the sterile cover, shall then be placed and “locked” onto the aspiration needle.  The 
aspiration needle is then advanced by drill into the cavity of the ilium.  The stylet is then 
removed and the syringe attached.  50 ml of bone marrow aspirate is slowly withdrawn by 
negative pressure from 4-6 sites via 10ml syringes.  The stylet is then replaced into the needle.  
The drill reattached to the needle and the needle is slowly withdrawn.  
 
The aspirate is then placed through a bone marrow filter to remove any calcific fragments.  
Using the Angel processing system, the bone marrow is concentrated by means of flow 
cytometry in a sterile closed system. 
 
Immediately after processing of the aspirate, it is relabeled with patient information then 
withdrawn into sterile syringes, and placed onto the sterile field in preparation for the intradiscal 
injection. 

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Placebo Bone Marrow Aspiration:  The patient shall be draped in a manner that injection is not 
visible even if the patient looks behind to observe.  The above set up will be identical as the 
actual bone marrow aspiration.  The area will be anesthetized in a similar manner.  The needle 
shall not be attached to the drill but the drill trigger shall be squeezed so the patient hears the 
noise of the drill.  Simultaneously, a 21g needle will be tapped against the periosteum.  To 
simulate the pressure of aspirating the bone marrow, 3 ml of normal saline shall be injected just 
superficial to the periosteum.  
 
 
 
Determination of disc levels to be injected: 
 
Levels to be injected will be determined by A or B below. 
 
A: Disc level(s) determined to be positive on prior discography performed within the preceding 6 
months using Spine Intervention Society standards [28].    
 
B: As discography is not required in the inclusion criteria, disc levels will be determined by 
clinical and image findings.  MRI findings of high intensity zone, modic changes type 1 or 2, and 
decreased T2 disc signal will be used [29-32] in conjunction with the general location of pain 
and tenderness on exam (upper, middle or lower lumbar location).   
 
Treatment:  
 
Intradiscal injection: The patient will be placed in a prone position in an outpatient fluoroscopy 
suite. Strict sterile technique will be observed.  The lower back will be cleansed with 
chlorhexidine mixed with alcohol and covered with a sterile drape.  A standard posterolateral 
extrapedicular discogram technique will be used under intermittent fluoroscopic imaging for 
each level previously determined to be a presumptive pain generator either clinically or through 
prior discography.  The skin and superficial tissues will be anesthetized with 2-5 ml of lidocaine 
1%.  The needle tip of a 22-gauge or 25-gauge needle with stylet, single or double needle 
technique, will be directed toward the disc into Kambin’s triangle. Depending upon the patient’s 
tolerance of the procedure, one ml lidocaine 2% may be injected just outside the disc annulus.  
The stylet will then be replaced and directed into the disc nucleus.  A volume of 0.6 ml of 
contrast solution consisting of 0.4 ml Omnipaque 240 or 300 contrast agent with 0.2 ml of 
cefazolin 330 mg/ml (for a total of 66 mg at a final concentration of 18 mg/ml based upon 3.5 ml 
total volume) (or in cefazolin allergic patients 0.4 ml of 40 mg/ml gentamicin) will be injected to 
confirm intranuclear location and for discitis prophylaxis.   
Then, 2-3 ml of previously prepared autologous BMC will be injected into the disc.  Thus, a total 
volume of 2.6-3.6 ml will be injected into each of the presumed pain generating discs during the 
treatment.  There may be instances when the disc cannot accommodate the full volume of BMC 
due to high pressure (based on manual pressure estimation) or leakage into the epidural space.  It 
may be necessary for the clinician to inject less than the 2ml of BMC.  At least 1ml of BMC will 

12 
 
need to be injected into a disc to be considered a completed treatment.  If the patient is 
experiencing a great deal of discomfort during the BMC injection, the physician may add 0.2 to 
0.5 ml of ropivicaine 0.2%-1%.   After the solution is injected, the needle will be removed.  The 
alcohol and chlorhexadine will be cleansed from the patient’s back and the drape will be 
removed.  The patient will then either ambulate with assistance or be transported via wheelchair 
to the recovery room. 
 
Placebo treatment procedure: 
 
As it was not felt ethical to puncture a disc for a placebo treatment [32], it was elected to use an 
intramuscular injection of 3ml of normal saline on the dorsal surface of the corresponding 
proximal transverse process.  For example, if the L5/S1 disc was the “treatment” disc, the 
corresponding placebo will be an injection of 3ml of normal saline just dorsal to the L5 
transverse process.  This will be performed for each disc level to be “treated”. 
 
The patient will be placed in a prone position in an outpatient fluoroscopy suite. Strict sterile 
technique will be observed.  The lower back will be cleansed with chlorhexidine mixed with 
alcohol and covered with a sterile drape.  The patient shall be draped in a manner that injection is 
not visible even if the patient looks behind to observe.  The skin will be anesthetized with 2ml 
lidocaine 1% at each level to be injected.  A 22 g spinal needle will be advanced to the transverse 
process at the superior level of each disc to be “treated”. One ml of contrast agent, omnipaque 
240, will be injected.  Then, assuming an appropriate intramuscular contrast pattern, 3ml of 
normal saline shall be injected just dorsal to the transverse process.  After the normal saline is 
injected, the needle will be removed. The alcohol and chlorhexadine will be cleansed from the 
patient’s back and the drape will be removed.  The patient will then either ambulate with 
assistance or be transported via wheelchair to the recovery room. 
 
Rationale for non-intradiscal placebo:  In light of theoretical risk of needle injury to the disc [32], 
it was not felt to be appropriate to have the placebo involve a direct disc injection of normal 
saline.  A normal saline injection into the epidural space using an infraneural (retro-discal) 
transforaminal needle position as a potential placebo was also considered but felt also  to be in 
appropriate due to the risk of unintentional needle position.  The risk of disc puncture with this  
technique is 5% as well the risk of  intrathecal injection is 3% [36].  In addition, a normal saline 
injection into the epidural space might have some dilutional therapeutic benefit as inflammatory 
cytokine have been documented in the epidural space [37] and therefore, normal saline may have 
a dilutional therapeutic benefit. 
 
 
 
The patient will be observed clinically for 30 minutes with vital signs obtained upon initially 
arriving to the recovery room and then every 15 minutes.  The patient will be discharged to a 
companion with written and verbal instructions to include no driving or operating machinery for 
12 hours.  They will be instructed to call for any concerning symptoms such as redness, swelling, 
fever, or increase in pain.  They will also be instructed to call for any bowel or bladder problems, 
worsening of low back symptoms beyond day 2, post-treatment severe low back pain at any 
time, new onset fever, or new or worsening of any lower extremity symptoms.  They will be 

13 
 
given clear written and verbal instructions on how to contact our providers with 24 hour 
availability. They will be offered a prescription for post-procedure pain medication, unless they 
currently have such medication, such as hydrocodone/ acetaminophen 5/325 mg or oxycodone/ 
acetaminophen 5/325 mg to take 1-2 tabs q 4-6hrs prn post-procedure pain, #10-20.  They will be 
instructed not to engage in any strenuous activity for two weeks after the treatment. 
 
Anticipated procedure time 60-90 minutes.  
 
The patient will be contacted by telephone during post-treatment week one to monitor for any 
concerning symptoms or adverse events.  The patient will be seen in our office for routine 
follow-up at post-treatment week 2, 4, and 8 weeks to assess for any adverse events and to 
monitor progress. At baseline 3,6,and 12 months the patients will complete the VAS, ODI and 
Global Perceived effect (GPE not performed at baseline) [35,38].  Patients will be seen more 
frequently if clinically indicated.  
 
A medication query shall be performed at baseline 3, 6, and 12 months.  In addition, any 
additional treatments obtained during the follow up period shall be recorded.  Other treatments 
during the study period will be discouraged but not forbidden.   
 
 
 Alternatives to bone marrow concentrate treatment: 
 
 These patients have typically had extensive conservative treatment and may be 
considering lumbar fusion surgery (or disc replacement) as a possible treatment option.  
The risks of this type of surgery in the lumbar spine include infection, bleeding, nerve 
injury, paralysis and death.  The most common adverse event or outcome encountered, 
however, is perceived lack of efficacy or worsening of symptoms after this extensive 
surgery and recovery period. 
 
 Although these patients have had inadequate pain relief and functional improvements 
from their prior conservative treatments, they certainly have the alternative of continuing 
with their current treatment regimen, which may be of some benefit.  These treatments 
often include medications, physical therapy, chiropractic care, and spine injections.  The 
risks of spinal injections, although rarely occurring, include infection, bleeding, nerve 
injury, paralysis, and death.  The risks of the various medications used for pain are 
medication dependent and are numerous.  
 
 Other types of intradiscal injections are an option.  Intradiscal methylene blue has shown 
early promise in a quality RCT [11] but investigations to replicate their results have been 
disappointing [12, 13].  Intradiscal steroid may be of benefit for individuals with certain 
end plate changes on MRI [39] but these positive results have been viewed with extreme 
caution based on poor results from prior studies [40].  Other regenerative type treatments 
such as platelet-rich plasma may be also be beneficial [15, 16].  The risks of intradiscal 
injections, although rare, include infection, bleeding, nerve injury, paralysis, and death. 
 

14 
 
 “Alternative” or “complementary” medicine treatments such as acupuncture, 
prolotherapy or homeopathic remedies could also be considered.  Serious risks of 
prolotherapy include paralysis and severe risks of acupuncture include pneumothorax. 
 
 The option of no further treatment may also be a reasonable alternative for some patients. 
 
5B.Analysis of study results: 
The data from the pre and post VAS (0-100 mm) and Oswestry disability index 0-100 will be 
analyzed from baseline to 3, 6, and 12 months [35].  Categorical data will be used.  Primary 
outcome for success will be considered at least 50% improvement in pain by VAS at 6 months 
and secondary outcome at 3 and 12 months.  Additional secondary outcomes will include 3, 6, 
and 12 month minimum of 30% improvement in ODI.  Further secondary outcomes will also 
include a minimum of 30%, and 70% improvement in pain at 3, 6, and 12 months.  All time 
point categorical success rates will be compared to placebo group with 95% CI determined.  
Group data mean pain scores will also be analyzed for each time point using t-tests.  Global 
perceived effect will be analyzed for 3,6,12 months on a 5 point scale using categorical data 
analysis.   
 
Pain medication log at baseline, 3, 6, and 12 months will be analyzed by a simple categorical 
decrease, increase, or unchanged compared to baseline.  Morphine equivalents will not likely be 
helpful as the majority of the subjects will not likely be on opiate medication.  Those patients not 
on medication at baseline shall not be included in the medication analysis. 
 
Adjunctive treatments:  All other therapeutic treatments for LBP during the study period shall be 
recorded at 3, 6 and 12 months.   
 
5C. Monitoring: 
Patients will be contacted by telephone during post-treatment week one to monitor for any 
concerning symptoms or adverse events.  The patient will be seen in follow-up at approximately 
2 weeks and 4 weeks post-treatment to assess for any adverse events.  Patients will also be seen 2 
months, 3, 6, and 12 months post-treatment for evaluation and data collection or more frequently 
if clinically necessary.  Patients will be made aware by verbal and written instructions that they 
have phone access to the study physicians at any time and are instructed to contact the practice 
for any concerning symptoms.  These include redness at the injection site, swelling, fever, bowel 
or bladder problems, worsening of low back symptoms beyond day 2 post-procedure, severe low 
back pain at any time, and new or worsening of any lower extremity symptoms.  Any new or 
worsening lower extremity symptoms such as pain, numbness, or weakness will be evaluated 
clinically, and if needed, further diagnostic tests such as MRI or electrodiagnostic testing will be 
ordered.  Any significant increase in low back pain or fever, without an identified source in the 
7-30 days post intradiscal treatment shall be considered suspicious for discitis.  CBC with 
differential, C-reactive protein, sedimentation rate, as well as MRI shall be performed (CT or 
bone scan if contra-indications to MRI exist).   
 
Any severe adverse event deemed specifically related to the bone marrow concentrate injectate 
shall be reported within 24 hours to the IRB (see adverse events 6C).   
 

15 
 
5D: Storage of data   
 
The research data will be stored in paper files accessible only to the investigators as well as 
research clinical staff under direct supervision of the investigators.  The data will be kept secure 
in a locked cabinet when not in use. 
 
5E. Confidentiality of data 
Data will be kept in a secure location following all HIPAA standards. 
Patients will be assigned a subject number and data will correspond to such number and not any 
identifiable demographic data. 
 
 
6. Risk/Benefit assessment 
 
6 A.  Risks of participation in the study 
Physical risks: 
 
Risks specific to bone marrow aspiration: 
These risks include bleeding, infection and damage to nearby tissues, vessels, nerves or organs.  
Other very unlikely risks include injury to the bone itself including fracture and continued pain 
in the region.  Extremely unlikely risks include:  paralysis, cardiac arrest, brain damage and/or 
death.   Estimated risk of minor complication is less than 1%.  Estimated risk of a catastrophic 
complication is near zero. 
 
Risks specific to placebo bone marrow aspiration: 
These risks include bleeding, infection and damage to nearby tissues, vessels, nerves or organs.  
Estimated risk of minor complication is less than 1%.  Estimated risk of a catastrophic 
complication is near zero. 
 
Risks of intradiscal delivery of the BMC, i.e. the injection procedure itself, are considered 
equivalent to the risk of discography and are as follows: 
 
 Nerve injury, in particular the exiting ventral ramus.  Risk is considered extremely low in 
an awake patient either with no sedation or appropriate conscious sedation [28] 
 
 Discitis with a risk of 0% to 1.3% per disc [41]  
 
 Theoretical risk of bowel injury and nerve root injury are considered an anatomic 
impossibility unless a grossly inappropriate technique is used. Estimated risk is near zero. 
[28] 
 
 Theoretical risk of needle passage through the dura may be estimated at 3% based upon 
data from a retrodiscal transforaminal epidural steroid injection approach [36].  The risk 
of this being clinically significant is less than 1% [28].  
 

16 
 
 The risk of clinically significant bleeding during discography in a non-anticoagulated 
patient is exceedingly rare and is estimated at less than 1%. 
 
 Severe allergic reactions to the contrast dye, local anesthetic, or antimicrobial skin prep 
are rare and are estimated at less than 1%. 
 
 Vaso-vagal reactions in a non-sedated patient are estimated at 3-4%.  In an awake but 
sedated patient, the risk is estimated at 0-10% [42]. 
 
 Risks of the use of needles include local muscle pain [28]. 
 
 The risk of needle puncture to a disc includes acceleration of disc degeneration and 
increased risk of disc herniation over a 10 year period.  Risk is considered minimal but 
statistically significant over control [32]. 
 
 The risk of accelerated disc degeneration secondary to contrast medium placed into the 
disc.  Possible injury to intervertebral disc cells has been demonstrated experimentally 
[43].  Clinical implications are questionable.  Risk is considered very minimal and is 
estimated at less than 1%. 
 
 General risks of disc injections include the exceedingly rare risk of paralysis or death.  
Estimated near zero. 
 
 General risks of conscious sedation (if utilized) include respiratory depression, cardiac 
arrhythmia or arrest, stroke, or death.  Estimated risk is far less than 1%. 
 
 Risk of venipuncture for IV sedation for the BMC injection procedure (if utilized):  The 
risks of IV access include infection, bleeding, and nerve injury.  The risks of the sedation 
medication itself include low blood pressure, low oxygen level, depression of the 
respiratory drive, cardiovascular compromise, stroke, severe allergic reaction, and death. 
 
 
Risks of bone marrow concentrate within the disc: 
 
 The injectate is an autologous aspiration of bone marrow minimally altered through a 
centrifuge process.  No reported side effects beyond local soreness have been reported in 
other tissues or the spine.  Bone marrow concentrate does contain stem cells.  The 
theoretical risk of the development of a neoplasm does exist however unlikely.  These are 
non-cultured stem cells and therefore, should hold the same risk for tumor development 
as those naturally occurring.  A registry surveillance study which included follow-up 
MRI’s did not reveal any evidence tumor development [22].  However, we do not assume 
the risk of  injury to the disc tissue is zero.  Risk is unable to be quantified but assumed 
much less than 1%. 
 
 Risk of BMC in the epidural space.  With disc injections, leakage may occur into the 
epidural space.  Whole blood is commonly injected into the epidural space for the 

17 
 
purpose of treatment of spinal headache.  Although we would not anticipate a tissue 
response different from whole blood, we do not assume risk of injury to the neural 
structures and dural tissue is zero.  Although there is not extensive data on the effect of 
BMC on nervous tissue, bone marrow has been used extensively during spinal fusion 
procedures without any reports of complications attributed to the bone marrow itself 
[17,18].  Risk is unable to be quantified but assumed much less than 1%. 
 
 The risk of anticoagulant acid citrate dextrose (ACD) used in the processing of the BMC: 
ACD is an FDA approved anticoagulant most often used to prevent clotting of blood 
samples.  It is commonly used in blood transfusions as well as hemodialysis in heparin 
intolerant patients.  The amount of ACD remaining available within the BMC to be 
injected is very small.  Risks are as follows: hypocalcemia, bleeding, severe allergy.  Risk 
is unable to be quantified but assumed to be much less than 1%. 
 
The risk of heparin used to prime the needle, syringes and BMC filtering and processing 
containers of the BMC: heparin is an FDA approved anticoagulant most often used to prevent 
clotting.  It is commonly used clinically at much higher dosages.   
 
Risks of placebo treatment procedure: an intramuscular injection of normal saline. 
 
 Risk of infection for an intramuscular patient estimated at much less than 1%. 
 Risks of the use of needles for an intramuscular injection of contrast and then normal 
saline include local minor skin puncture and muscle pain [28]. 
 Severe allergic reactions to the contrast dye, local anesthetic, or antimicrobial skin prep 
are rare and are estimated at less than 1%. 
 Risk of venipuncture for IV sedation for the injection procedure (if utilized):  The risks of 
IV access include infection, bleeding, and nerve injury.  The risks of the sedation 
medication itself include low blood pressure, low oxygen level, depression of the 
respiratory drive, cardiovascular compromise, stroke, severe allergic reaction, and death. 
Vaso-vagal reactions in a non-sedated patient are estimated at 3-4%.  In an awake but sedated 
patient, the risk is estimated at 0-10% [42]. 
 
The psychological risk does involve the emotional and physical discomfort of undergoing a bone 
marrow aspiration and an intradiscal procedure or placebo procedure. 
 
Social and legal risks are considered minimal.   
 
Economic risk: Considered minimal.  There will be no cost to the patient except for routine 
follow-ups including co-pays and deductibles from commercial insurance. 
 
6 B. Prevention of risks: 
The risks of the delivery of the BMC into the disc will be reduced by following strict sterile 
technique as well as procedural technique as described in SIS guidelines [28].  Prophylactic 
antibiotic will be placed into the disc to minimize the risk of discitis.    
 

18 
 
The discomfort of the procedure shall be minimized with by oral or IV sedation unless the 
patient prefers no sedation.  Intravenous or IM fentanyl may be given for intra-procedural pain 
control.  Local anesthetic, 2-5ml lidocaine 1%, shall be infiltrated in the skin and superficial 
tissues.  Local anesthetic, 1ml 2% may be placed outside the disc to minimize the discomfort of 
the disc injection.  Ropivicaine 0.2- 1% may be placed within the disc as well.  
 
The patients will be monitored for adverse events as previously described. 
 
6C. Adverse events: 
 
Adverse events include: 
   
 Infection including discitis 
 Bleeding, in particular, an epidural hematoma 
 New and/or increased pain, numbness, dysesthesia, or weakness in one or both lower 
extremities 
 Increased low back pain beyond normal flares typical for the patient 
 Allergic reaction 
 Fever 
 Redness at injection site 
 Bowel or bladder dysfunction 
 Paralysis 
 Death 
 
 
 
 
Any minor adverse event will be reported to the IRB within 10 days.  Any serious adverse event 
will be reported to the IRB within 24 hours of being brought to an investigator’s attention.   
 
Our medical staff will be available at all times for any adverse event.  If subsequent diagnostic 
tests or procedures are necessary they will be in accordance with current standard of care.  All 
patients will have medical insurance coverage for any subsequent tests or procedures.  BMC is 
an autologous tissue product with multiple medical uses.  Intradiscal administration should not 
preclude insurance coverage for any subsequent medical issues pertaining to its use. 
 
6D. Benefits: 
 
The potential benefits of participating in the study are significant.  The patient has an opportunity 
to significantly reduce or alleviate his or her pain and disability with a relatively minimally 
invasive procedure compared to fusion surgery.  The benefits to the community as a whole could 
be significant as well, potentially decreasing or even eliminating the need for surgical fusion for 
discogenic pain.   
 
 
7. Participant recruitment and informed consent 
 

19 
 
7A. Recruiting: Patients will be screened from a pool of existing patients at a community 
outpatient spine and musculoskeletal practice.  Patients referred by outside clinicians may be 
considered.  These patients will have had an inadequate response to conservative treatments, 
many of whom will be considering fusion surgery.  Some of these patients may be considering 
provocative discography through the recommendation of one of the physicians in the principle 
investigator’s practice or from a local surgeon.  One of the options discussed will be Bone 
marrow concentrate intradiscal injection under the context of the study.  If the patient has any 
interest in participating in this study, the general risks, benefits and results from the previously 
published study for intradiscal BMC will be discussed [24,25].  Some of these patients may wish 
to undergo discography.  The results of the discography help determine their candidacy for 
fusion surgery. Patients who have undergone discography at the request of an outside physician, 
typically a community neurosurgeon or orthopedic surgeon, will also be screened with the 
surgeon’s approval.   
 
 
It will be explained to all potential subjects that their participation in the study is strictly 
voluntary.  Their participation will have no effect on their standing as a patient within their 
current practice.  Nor will it have any effect on the physician-patient relationship.  Their 
treatment course will remain unaffected if they choose not to participate in the study.   
 
7B. Consent: 
Consent form as a separate document submitted with this document. 
 
7C. Obtaining and documenting consent 
One of the investigators will perform the consent process.  This will be verbal and written with 
ample time for any and all questions.  The consent form will be signed by the patient and 
witnessed by one of the research assistants and/or one of the investigators.  The document will be 
stored with other research materials in a locked cabinet when not in use. 
 
7D.  Participant comprehension and capacity 
Measure to ensure appropriate understanding: 
Prior to signing the consent form, the patient will be asked to briefly explain the study risks and 
benefits to one of the investigators. 
 
7 E. Cost to participant 
As previously mentioned in economic risk section: 
 
This will be a funded study without cost to the participant other than co-pays and deductibles 
from commercial insurance for routine follow up visits. 
 
Participants will be compensated for their time at the 3, 6, and 12 month visits with 30 dollars at 
each of the 3 visits.  
 
 
References: 
 

20 
 
1.  Food and Drug Administration. Homologous use of human cells, tissues, and cellular and 
tissue-based products: draft guidance for industry and FDA staff. Available at: 
http://www.fda.gov/down loads/biologicsbloodvaccines/guidancecomplianceregulatoryinform 
ation/guidances/tissue/ucm469751.pdf.  
 
2.  Food and Drug Administration. Minimal manipulation of human cells, tissues, and cellular 
and tissue-based products: draft guidance for industry and Food and Drug Administration staff. 
Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/Guidance 
ComplianceRegulatoryInformation/Guidances/CellularandGeneTher apy/UCM427746.pdf 
 
3.  Schwarzer A, Aprill C, Derby R, Fortin J, Kine G, Bogduk N.  The prevalence and clinical 
features of internal disc disruption in patients with chronic low back pain. Spine 1995;20:1878-
83. 
 
4.  Fritzell P, Hagg O, Wessberg P, Nordwall A. The Swedish Lumbar Spine Study Group.  
Volvo award winner in clinical studies:  Lumbar fusion versus nonsurgical treatment for chronic 
low back pain. A multicenter randomized controlled trial from the Swedish Lumbar Spine Study 
Group.  Spine 2001;23:2521-34. 
 
5.  Hanley EN, David SM.  Lumbar arthodesis for the treatment of back pain.  J Bone Joint Surg 
Am 1999;81:716-30. 
 
6.  Peng B, Wu W, Hou S, Li P, Zhang C, Yang Y.  The pathogenesis of discogenic low back 
pain.  J Bone Joint Surg Br 2005;87:62-7. 
 
7.  Coppes MH, Marani E, Thomeer RT, Groen GJ.  Innervation of "painful" lumbar discs.  
Spine 1997;22:2342-9. 
 
8.  Freeman BJ, Fraser RD, Cain CM, Hall DJ, Chapple DC.  A randomized, double-blind, 
controlled trial: intradiscal electrothermal therapy versus placebo for the treatment of chronic 
discogenic low back pain. Spine 2005;30:2369-77. 
 
9.  Barendse G, van den Berg S, Kessels A, Weber W, van Kleef M.  Randomized controlled trial 
of percutaneous intradiscal radiofrequency thermocoagulation for chronic discogenic back pain.  
Spine 2001;26:287-92. 
 
10.  Peng B,  Zhang Y, Hou S, Wu W, Fu X.  Intradiscal methylene blue injection for the 
treatment of chronic discogenic low back pain.  Eur Spine J 2007;16:33-8. 
 
11.  Peng B, Pang X, Wu Y, Zhao C, Song X.  A randomized placebo-controlled trial of 
intradiscal methylene blue injection for the treatment of chronic discogenic low back pain. Pain 
2010;149:124-29. 
 
12.  Bogduk N. Preliminary results from intradiscal methylene blue trial.  Presented at 
International Spine Intervention Society meeting 2011 Chicago, IL. 

21 
 
 
13.  Levi DS, Horn S, Walko E.  Intradiscal Methylene blue treatment for discogenic low back 
pain. PM&R2014;6(11):1030-1037. 
14.  Nguyen RT, Borg-Stein J, Mcinnis K.  Application of platelet-rich plasma in 
musculoskeletal and sports medicine: an evidence based approach. PMR 2011;3:226-50 
 
15. Levi D, Horn S, Tyszko S, Levin J, Hecht-Leavitt C, Walko E. Intradiscal Platelet-Rich 
Plasma Injection for Chronic Discogenic Low Back Pain: Preliminary Results from a Prospective 
Trial. Pain Med. 2016;17(6):1010-22.  
 
16. Tuakli-Wosornu YA, Terry A, Boachie-Adjei K, Harrison JR, Gribbin CK, LaSalle EE, 
Nguyen JT, Solomon JL, Lutz GE. Lumbar Intradiskal Platelet-Rich Plasma (PRP) Injections: A 
Prospective, Double-Blind, Randomized Controlled Study. PMR. 2016 Jan;8(1):1-10. 
 
 
17.  Connolly JF, Guse R, Tiedeman J, Dehne R. Autologous marrow injection as a substitute for 
operative grafting of tibial nonunions. Clin Orthop Relat Res. 1991;266:259–70. 
 
18.  Muschler GF, Nitto H, Matsukura Y, Boehm C, Valdevit A, Kambic H, Davros W, Powell 
K, Easley K. Spine fusion using cell matrix composites enriched in bone marrow-derived 
cells. Clin Orthop Relat Res.2003;407:102–18 
 
 
19.  Holton J, Imam M, Ward J, Snow M. The Basic Science of Bone Marrow Aspirate 
Concentrate in Chondral Injuries. Orthop Rev (Pavia). 2016;8(3):6659. 
 
20.  Chahla J, Dean CS, Moatshe G, Pascual-Garrido C, Serra Cruz R, LaPrade RF.  
Concentrated Bone Marrow Aspirate for the Treatment of Chondral Injuries and Osteoarthritis of 
the Knee: A Systematic Review of Outcomes. Orthop J Sports Med. 2016 Jan; 
4(1):2325967115625481 e-collection. 
 
21. Shapiro SA, Kazmerchak SE, Heckman MG, Zubair AC, O'Connor MI. A Prospective, 
Single-Blind, Placebo-Controlled Trial of Bone Marrow Aspirate Concentrate for Knee 
Osteoarthritis. Am J Sports Med.2017;45(1):82-90.  
 
22.  Centeno CJ, Al-Sayegh H, Freeman MD3, Smith J, Murrell WD, Bubnov R. A multi-center 
analysis of adverse events among two thousand, three hundred and seventy two adult patients 
undergoing adult autologous stem cell therapy for orthopaedic conditions. Int 
Orthop. 2016;40(8):1755-65.  
 
23.  Centeno C, Pitts J, Al-Sayegh H, Freeman M. Efficacy of autologous bone 
marrow concentrate for knee osteoarthritis with and without adipose graft. Biomed Res 
Int. 2014;2014:37062. 

22 
 
 
24.  Pettine K, Suzuki R, Sand T, Murphy M. Treatment of discogenic back pain with autologous 
bone marrow concentrate injection with minimum two year follow-up. Int 
Orthop. 2016;40(1):135-40. 
 
25.  Pettine KA, Murphy MB, Suzuki RK, Sand TT. Percutaneous injection of autologous bone 
marrow concentrate cells significantly reduces lumbar discogenic pain through 12 months. Stem 
Cells. 2015;33(1):146-56. 
 
26.  Centeno CJ, Al-Sayegh H, Bashir J, Goodyear S, Freeman MD. A prospective multi-site 
registry study of a specific protocol of autologous bone marrow concentrate for the treatment of 
shoulder rotator cuff tears and osteoarthritis. Journal of Pain Research. 2015;8:269-276.  
 
27.  DePalma MJ, Ketchum JM, Saullo T. What is the source of chronic low back pain and does 
age play a role? Pain Med. 2011 Feb;12(2):224-33. 
 
28.  Lumbar Intervertebral Disc Access. In: Bogduk N, ed. Practice Guidelines for Spinal 
Diagnostic and Treatment Procedures, 2nd edition. San Francisco, CA: International Spine 
Intervention Society; 2013:393-434.   
 
29.  Weishaupt D, Zanetti M,  Hodler J,  Min K, Fuchs B,  Pfirrmann C,  Boos N. Painful 
Lumbar Disk Derangement: Relevance of Endplate Abnormalities at MR Imaging. Radiology 
2001; 218: 420-427. 
30.  O'Neill C, Kurgansky M, Kaiser J, Lau W. Accuracy of MRI for diagnosis of discogenic 
pain. Pain Physician 2008;11:311-26. 
31.  Kang CH, Kim YH, Lee SH, Derby R, Kim JH, Chung KB, Sung DJ. Can magnetic 
resonance imaging accurately predict concordant pain provocation during provocative disc 
injection? Skeletal Radiol. 2009 Sep;38(9):877-85. Epub 2009 May 9.  
 
32.  Carragee E, Don A, Hurwitz E, Cuellar J, Carrino J, Herzog R.  Does discography cause 
accelerated progression of degeneration changes in the lumbar disc.  Spine 2009;34:2338-45. 
33.  Ghahreman A, Ferch R, Bogduk N. The Efficacy of Transforaminal Injection of Steroids for 
the Treatment of Lumbar Radicular Pain. Pain Medicine 2010; 11 (8): 1149-68. 
34.  Kolahi J, Bang H, Park J. Towards a proposal for assessment of blinding success in clinical 
trials: up-to-date review. Community Dent Oral Epidemiol. 2009 Dec;37(6):477-84. 
35.  Fairbank JC, Couper J, Davies JB, O’Brien JP.  The Oswestry low back pain disability 
questionnaire.  Physiotherapy 1980;66:271-3. 

23 
 
 
36.  Levi D, Horn S, Corcoran S. The Incidence of Intradiscal, Intrathecal, and Intravascular 
Flow During the Performance of Retrodiscal (Infraneural) Approach for Lumbar 
Transforaminal Epidural Steroid Injections. 
Pain Med. 2016;17(8):1416-22.  
 
37.  Golish SR, Hanna LS, Bowser RP, Montesano PX, Carragee EJ, Scuderi GJ. Outcome of 
lumbar epidural steroid injection is predicted by assay of a complex of fibronectin and aggrecan 
from epidural lavage. Spine. 2011; 15;36(18):1464-9.  
 
38.   Kamper SJ, Ostelo RW, Knol DL, Maher CG, de Vet HC, Hancock MJ. Global Perceived 
Effect scales provided reliable assessments of health transition in people with musculoskeletal 
disorders, but ratings are strongly influenced by current status. J Clin Epidemiol. 2010 
Jul;63(7):760-766. 
 
39.  Cao P, Jiang L, Zhuang C, Yang Y, Zhang Z, Chen W, Zheng T. Intradiscal injection 
therapy for degenerative chronic discogenic low back pain with end plate Modic changes. Spine 
J 2011;11:100-106 
 
40.  Fraser RD. Something is amiss. Spine J 2011;11:107-108 
 
41.  Sharma S, Jones J, Zeballos P, Irwin S, Martin T.  The prevention of discitis during 
discography.  Spine J 2009;9:936-43. 
 
42.  Kennedy, D. J., Levin, J., Rosenquist, R., Singh, V., Smith, C., Stojanovic, M. P. and 
Vorobeychik, Y. Epidural Steroid Injections are Safe and Effective: Multisociety Letter in 
Support of the Safety and Effectiveness of Epidural Steroid Injections. Pain Med, 2015;16:833–
838.  
43.  Gruber HE, Rhyne AL, Hansen KJ, Phillips RC, Hoelscher GL, Ingram JA, Norton HJ, 
Hanley EN. Deleterious effects of discography radiocontrast solution on human annulus cells in 
vitro: changes in cell viability, proliferation, and apoptosis in exposed cells. Spine J. 2012;4:329-
35. 
44.  Depalma MJ, Ketchum JM, Trussell BS, Saullo TR, Slipman CW. Does the location of low 
back pain predict its source? PM&R. 2011 Jan;3(1):33-9.