Accepted Manuscript Intradiscal methylene blue treatment for discogenic low back pain David S. Levi, MD Scott Horn, DO Edward Walko, DO. PII:
S1934-1482(14)00176-2
DOI:
10.1016/j.pmrj.2014.04.008
Reference:
PMRJ 1243
To appear in:
PM&R
Received Date: 11 August 2013 Revised Date:
20 February 2014
Accepted Date: 15 April 2014
Please cite this article as: Levi DS, Horn S, Walko E, Intradiscal methylene blue treatment for discogenic low back pain, PM&R (2014), doi: 10.1016/j.pmrj.2014.04.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Intradiscal methylene blue treatment for discogenic low back pain. David S Levi, MD, Scott Horn, DO, Edward Walko, DO.
APM Spine and Sports Physicians
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Virginia Beach, VA
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ABSTRACT:
2 Background: Low back pain is a leading cause of pain and disability. The intervertebral disc has
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been identified as the most common source of chronic low back pain. Although prior treatments
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directed at intervertebral discs have been disappointing, recent studies show promising
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improvement of pain and function after a single intradiscal injection of methylene blue.
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Objective: To assess changes in pain and function in patients with discogenic low back pain,
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diagnosed by discography, after an intradiscal injection of methylene blue.
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10 Study Design: Prospective trial
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Methods: Patients diagnosed with discogenic pain by discography underwent a single treatment
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of intradiscal injection of methylene blue, determined by prior provocation discography.
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Main Outcome measures: Pain and function measurements were completed at baseline, 1, 2, and
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6 months post-treatment. Patients were considered a categorical success based upon a 30%
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improvement in pain on VAS and function on ODI. Patients were considered a categorical
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failure if they achieved less than 30% improvement in pain and function or pursued other
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invasive treatment options during the trial period.
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Results: Sixteen patients underwent the intradiscal methylene blue injection. Eleven patients
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underwent a single level injection. Four patients underwent a two level injection and one patient
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was injected at three levels. For VAS, at 1, 2 and 6 months post-injection, the categorical
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success rates were 25%, 21%, and 25%, respectively. For ODI, at 1, 2 and 6 months post-
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injection, the categorical success rates were 25%, 21%, and 33%, respectively. The overall
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categorical success rates at 1, 2 and 6 months post-injection, were 19%, 21%, and 25%
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respectively.
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Conclusion: This small trial did not demonstrate an overall clinical success of intradiscal
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methylene blue injection for those patients diagnosed with discogenic pain by discography.
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Introduction
33 Low back pain is a common cause of pain and disability1. Although several structures within the
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spine have been identified as pain generators, the intervertebral disc is felt to account for
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approximately 40% of chronic low back pain2,3. The most common conservative treatment
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options include medications, physical therapy, spinal manipulation, and corticosteroid injections.
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Many patients have an inadequate response to these conservative measures and are left with few
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quality treatment options.
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The most severely disabled patients often progress to surgical options. The most common
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surgical treatment for discogenic pain, lumbar fusion, has significant limitations. Although
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catastrophic complications from lumbar fusion surgery are rare, minor complications are
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relatively common. More concerning, however, is the questionable efficacy of lumbar fusion for
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discogenic pain. Although some studies demonstrate superiority over conservative care, the
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results are modest4,5. Other trials show no significant benefit over non-surgical treatment6.
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The pathoanatomy of a painful intervertebral disc has been extensively studied. The region of
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the disc felt to illicit pain is the outer portion of the intervertebral disc, the annulus fibrosis,
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which may develop tears or fissures within the collagen fibers. These fissures contain an
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ingrowth of vascularized granulation tissue along with extensive nerve endings which may illicit
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pain7,8.
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Prior conservative treatments aimed at annular tear pathology have been attempted with heat or
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radiofrequency energy with disappointing results9,10. More recently, however, Peng and
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colleagues have investigated the use of methylene blue as a neurolytic agent within the disc11,12.
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Based on prior work demonstrating the ability of methylene blue to destroy dermal nerve
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endings13,14, the investigators reasoned that this substance could be injected into a painful
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intervertebral disc to denervate the pain-producing nerve endings within an annular tear. Rat tail
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studies were performed which showed denervation of the annular tears without injury to the disc
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itself (unpublished data described in Peng et al.12).
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Peng and colleagues have published two clinical studies evaluating intradiscal methylene blue
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for patients considering lumbar fusion surgery. The first was a prospective trial of 24 patients
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injected with intradiscal methylene blue at the time of discography. This demonstrated excellent
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efficacy with no adverse events11. A subsequent study was a placebo controlled double-blind
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trial with 36 patients receiving intradiscal methylene blue versus placebo at the time of
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discography12. The treatment group’s mean numeric rating score (NRS) improved from 72 at
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baseline to 25 at 6 months. These improvements were maintained at 24 months. This study also
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showed a highly significant improvement in function compared to the placebo group. The
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authors reported that 92% of patients were completely satisfied or satisfied in the treatment
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group compared to only 14% in the placebo group12. This well designed study demonstrated
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efficacy far beyond that of any current treatment for discogenic low back pain, including lumbar
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fusion surgery15. Once again, no adverse events occurred.
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In the past, there have been a number of potential intradiscal treatments for low back pain.
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However, after initial enthusiasm, most have been disappointing9,16. A prospective trial of
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intradiscal methylene blue was undertaken to help further evaluate the efficacy of this treatment.
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Methods:
81 The study was approved by an independent institutional review board.
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The trial was designed as a prospective trial with patients undergoing a single treatment of
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intradiscal injection of methylene blue, determined by prior provocation discography. Pain and
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function measurements were completed at baseline, 1, 2, and 6 months post-treatment.
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Study participants were screened from a pool of consecutive individuals with chronic low back
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pain who had undergone provocation discography. All patients had failed at least 6 months of
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conservative treatment and were considering lumbar fusion surgery. Patients were referred for
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discography internally, from within the investigators’ practice or externally through a local spine
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surgeon. The discograms were performed at a community outpatient interventional physiatry
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practice by two of the investigators (D.L. and S.H.).
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Inclusion Criteria •
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Chronic discogenic low back pain of 50mm or greater on a visual analog scale (VAS) of 0-100cm
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18-65 years of age
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Low back pain of more than 6 months duration with inadequate response to conservative
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treatment
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Low back symptoms greater than leg symptoms
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Concordant pain on provocation discography at 1-4 levels within 6 months of the study
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procedure (in accordance with International Spine Intervention Society guidelines17)
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Exclusion Criteria
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Active moderate to severe lumbar radiculopathy
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Active infection
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Spinal fracture within the previous 6 months
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Severe psychological illness
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Inability to consent to procedure due to cognitive issues
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Prior fusion surgery at the level considered to be positive on discography
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Pregnant or breastfeeding females
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Severe uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine,
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Radiologic evidence of greater than grade 1 spondylolisthesis at a level considered to be
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positive on discography
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Inflammatory arthritis
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Any cancer within the past 5 years except basal cell or squamous cell skin cancer
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Intradural disc herniation
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Glucose-6-phosphate dehydrogenase deficiency
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Coagulopathy preventing spinal injection
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Inability to stop anticoagulants other than aspirin
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Greater than 30 mg morphine equivalent per day of opioid use
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History of alcohol or drug abuse within the past 5 years
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Use of any investigational drug within the past 30 days
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Low back surgery within the past 12 months
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Steroid injection in the spine within the past 30 days
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Known allergy or sensitivity to methylene blue
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Pending litigation involving the subject's back pain
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Actively applying for disability benefits due to their back pain
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Greater than 4 discs considered positive by provocation discography
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Central stenosis at the level to be injected with an AP diameter less than or equal to 6
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millimeters
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Severe anaphylactic/anaphylactoid reaction to any of the medications used in this study
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Ethical or religious objections to staining body tissue with dye
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Disc leakage into the epidural space during discography at a volume of 2.5 milliliters or
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less
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Intradiscal methylene blue injection treatment procedure:
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The procedure was performed by two of the investigators (D.L. and S.H.). Both are board
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certified in physical medicine and rehabilitation, experienced discographers, fellowship trained
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in spine injections, and serve as instructors for spinal injection procedures at the national level.
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Intradiscal injection: Depending upon patient preference, IV sedation (with midazolam and
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fentanyl), oral anxiolytics (with alprazolam or diazepam), or no sedation was administered prior
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to the procedure. Patients were placed in a prone position in an outpatient fluoroscopy suite.
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Strict sterile technique was observed. The area was cleansed with betadine and chlorhexadine
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and covered with a sterile drape. The skin and superficial tissues was anesthetized with 2-5 ml
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of lidocaine 1%. A standard posterolateral extra-pedicular discogram technique was used under
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intermittent fluoroscopic imaging for each level previously determined to be positive at prior
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discography (which took place between 2 weeks and 6 months prior to the methylene blue
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injection). Using a single needle technique, a 22-gauge spinal needle with stylet was directed
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into the disc nucleus in accordance with International Spine Intervention Society guidelines17.
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One ml of a solution consisting of 0.7ml of Omnipaque 300 and 0.3mL of gentamicin 40mg/mL
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(total of 12mg gentamicin) was then injected for discitis prophylaxis and to ensure intranuclear
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needle tip position in AP and lateral views. Then, a 1.5 ml solution containing 0.5 ml lidocaine
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4% along with 1 ml of methylene blue 10 mg/ml was injected. Therefore, a total volume of 2.5
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ml was injected into each of the discogram-positive discs during the treatment (figure 1). If any
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leakage into the epidural space was observed during the injection, the procedure for that disc was
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halted. After the solution was injected, the needle was removed. The patient either ambulated
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with assistance or was transported by wheelchair to the recovery room.
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The patient was observed clinically for 45 minutes and vital signs were checked upon initially
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arriving to the recovery room and then every 15 minutes. The patient was discharged to a
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companion with written and verbal instructions to include no driving or operating machinery for
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12 hours.
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Outcome measurements
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Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI) were utilized for pain and
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function measurements at baseline and 1, 2, and 6 months following the methylene blue treat-
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ment. A patient was considered to have a successful outcome if the VAS improved by at least
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30% accompanied by at least a 30% improvement in ODI18. In light of the astounding results in
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the Peng et al. study12, these improvement values were chosen as they likely represent a more
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conservative interpretation of success18. In order to more accurately determine a successful
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treatment outcome from the methylene blue, any patient who underwent or pursued other
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invasive treatments during the 6 month follow up period, such as surgery or spinal injections,
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was also considered a failure.
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182 Results
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Sixteen patients, 9 males and 7 females, underwent the intradiscal methylene blue injection with
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an average age of 44. Eleven patients underwent a single level injection. Four patients
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underwent a 2 level injection and one patient was injected at 3 levels.
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There were no intra-procedural or post-procedural complications. No epidural leakage was
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observed during the injection procedure for any patient. There were no new radicular complaints
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and no cases of discitis.
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Categorical success was measured by a minimal improvement of 30% on VAS and ODI. A
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categorical failure was measured by an improvement of less than 30% on VAS and ODI. A
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patient who pursued another invasive spinal treatment such as injection or surgery was also
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considered a failure. Categorical outcomes were designated at 1, 2, and 6 months (figure 2).
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At the one month follow up, 3 out of 16 patients, 19%, were considered a categorical success.
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Eight-one percent of the patients completed data for this time period. All 3 patients who did not
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complete the VAS and ODI at 1 month were considered to be categorical failures. One pursued
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surgical consultation at 3 weeks, 1 pursued the option of biacuplasty by 3 weeks and shortly after
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underwent surgical consultation, and the third underwent an intradiscal injection with steroid at 3
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that treatment. Therefore, based on VAS and ODI data as well as outcome categorization
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designation for pursuing or undergoing other invasive treatments, 13 out of 16 patients, 81%,
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were considered failures at the 1 month follow up. Of the 2 patients that pursued surgery, 1 was
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performed at five months and the other at 12 months post injection, neither improved clinically
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prior to the surgical fusions.
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weeks after the methylene blue injection as she had prior excellent but short term relief with
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At the 2 month follow up, 3 of 14 patients, 21%, met the criteria for success. Within the second
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month of follow up, two further patients were categorized as failures based on pursuit of other
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treatment. One underwent fusion at 5 weeks post injection and the other pursued intradiscal
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steroid injection. Thus far, 5 of the 16 patients were considered failures for pursuing other
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invasive treatment options by the 8 week follow up point. Of the remaining subjects, 3 failed to
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complete VAS and ODI measures, one of whom underwent an intra-articular hip injection and
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surgical consultation for possible hip pathology as the source of her pain. Although arguable,
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this patient was considered a failure in our analysis for pursuing an invasive surgical treatment as
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it was later found that her hip was not the source of her back pain. VAS and ODI data was
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missing on 2 “active” patients (those not pursuing other invasive treatment options), 1 of whom
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was considered successful at 1 month follow up and one considered a failure at 1 month. These
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2 patients were not included in the 2 month analysis. As 6 patients were considered failures for
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pursuing invasive treatment options and 2 patients were missing data, this left only 8 patients
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completing the ODI and VAS measurements at this follow up period. Only three patients met
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the criteria for success at the two month follow up.
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At the 6 month follow up, 4 of 16 patients, 25%, met success criteria. Two patients, both
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considered failures at 1 and 2 month periods, were lost to follow up. In our analysis, we
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considered both to remain in the failure category. The 2 patients who did not complete the 2
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month data, one a failure and one a success, both completed VAS and ODI data at the 6 month
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follow up and remained in their respective 1 month categories. By this point, 6 patients were
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considered categorical failures based on pursuit of other invasive treatment options. Therefore,
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8 patients remained to complete the pain and functional outcome data. Therefore, at this point,
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only 4 patients, 25%, met the criteria for success at 6 months.
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Discussion
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This small prospective study was undertaken to help determine the efficacy of a single intradiscal
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injection of methylene blue for the treatment of discogenic low back pain. Success or failure
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was measured by pain relief, improvement in disability and the pursuit of other invasive
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treatment options. Overall, very limited benefit was seen with an overall categorical success rate
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of only 19%, 21% and 25% for the 1, 2 and 6 month follow up periods, respectively.
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244 The primary analysis of our results was performed in a categorical manner. The initial intention,
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however, was to perform statistical analysis. For several reasons the categorical method was felt
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to be more appropriate. Beyond the small sample size, we did experience a very high drop-out
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rate. Prior to the participation in the study, the patients were informed of the results of Peng et
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al.’s trials11,12. This included Peng et al.’s finding that those patients who ultimately benefitted
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from methylene blue, obtained relief by 24 hours12. Most patients were not improved initially,
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and ethically, we could not discourage them from pursuing other treatment options. Six out of
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the 16 patients choose to pursue other treatment options within the follow up period. This was
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felt to be the primary reason for the high attrition rate. Most of the patients included in this study
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were strongly considering fusion surgery for their low back symptoms. Two patients pursued
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this option during the first month following the methylene blue injection. Several others pursued
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spinal injections which had given them short term (1-2 months) relief in the past. It was not felt
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appropriate to include follow up data after another intervention (spinal injection or surgery) took
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place as this would inappropriately reflect a response from treatment other than methylene blue.
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It was for this reason that the patients who chose to pursue other invasive treatment options were
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considered categorical failures. In light of these issues and a paucity of VAS and ODI follow-up
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data, our analysis was performed in a categorical manner. Categorical analysis may also be more
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reflective of actual improvement than group mean data analysis particularly in cases of bimodal
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scores19.
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In the randomized placebo controlled trial of intradiscal methylene blue by Peng et al.12, the
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authors reported a dramatic mean pain improvement in NRS from 72 to 25 at 6 month follow-up.
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The pain reductions were accompanied by a similar improvement in function as measured by
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ODI. Based upon these extraordinary results, we expected a high percentage of our patients to
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have a successful outcome. Unfortunately, only 19%-25% (at different time periods) of our
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patients obtained at least 30% improvement in pain and disability. In addition, Peng et al.
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reported that 47% of their patients had complete or near complete relief of pain at 6 month
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follow up. In our study, only 12% of the patients (2/16) had this level of success. Although
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beyond our follow up period, one of these two patients pursued surgical treatment for his low
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back pain at 8 months post injection.
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Our protocol differed slightly from the two Peng et al. studies11,12. In the current trial, the
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intradiscal methylene blue was injected at a separate time point from discography to decrease the
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likelihood of leakage of methylene blue into the epidural space. Peng and colleagues performed
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the methylene blue injection immediately following discography without any adverse events11,12.
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However, because it is known that medications administered into the epidural space diffuse, to a
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small degree, into the subarachnoid space20, and that intrathecal methylene blue is known to be
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neurotoxic21, we felt that this was a potential safety concern. Therefore, patients were excluded
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from the study who leaked during discography into the epidural space at a volume of 2.5ml (our
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total treatment volume with methylene blue) or less. The volume of 2.5 ml for the methylene
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blue injection treatment was chosen by the authors as the smallest reasonable total volume to
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deliver all of the components of the injectate, contrast medium, antibiotic, anesthetic and the
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methylene blue. While it is possible that the difference in protocols could explain the disparity
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in the success rates between our study and that of Peng et al.’s12, we feel that it is doubtful. Our
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protocol ensured that a controlled dosage, 10 mg of methylene blue (equivalent dosage used in
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Peng et al.’s trials11,12), entered the disc. Additionally, in our study, the methylene blue was not
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diluted by variable amounts of contrast medium, nor did it leak into the epidural space. In
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theory, the higher concentration of methylene blue in our study should have allowed for the
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proposed mechanism of action, denervation of the small nerve fibers within the symptomatic
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annular fissures12, to occur to a greater extent. In the current study, we also chose different
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follow up points than Peng et al.’s randomized controlled trial12. The 1, 2 and 6 month data
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points were chosen in our study as Peng et al. reported that those patients who benefitted from
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methylene blue, obtained relief by 24 hours12. In addition the authors reported that the 6 month
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results were statistically equivalent to 12 and 24 months in their randomized controlled trial12
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and the 3 month results was equal to 12 months in their prospective trial11. We did not attempt to
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extend our study beyond 6 months for this reason.
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A retrospective case series of 8 patients undergoing intradiscal methylene blue was published
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using Peng et al.’s11,12 protocol22. This case series assessed pain and functional outcomes in 8
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patients treated with a one-time administration of methylene blue for discogenic back pain.
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Follow-up information was available between 2 months and greater than one year, depending on
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the patient. Results of the study demonstrated only one clinical success with long term
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improvement of pain and function. Four patients had a time-limited clinical benefit in pain
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and/or function between 2 weeks and 5 months. The authors discontinued methylene blue
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prospective trial.
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A prospective trial of 20 patients was also performed by Kim et al. in 201223. The patients
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received intradiscal methylene blue at each disc identified to be positive during provocation
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discography which occurred one week prior. At 3 months follow up, 11 of the 20 patients (55%)
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reported successful outcomes, as defined by an improvement of at least a 2 point change in VAS.
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The average VAS was reduced by 2.2 points. At the 12 month follow up, pain had recurred in 6
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patients who had initial satisfactory results. Successful outcome was maintained in only 5
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patients (20%) for 1 year23. These results, although slightly better than the current study, differ
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greatly from those of Peng et al.11,12.
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There are several limitations of our study. The small number of patients in our study is certainly
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a significant limitation. The planned enrollment was 30 patients. However, as the patients were
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followed very closely during the current trial, the overall poor response to the intradiscal
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methylene blue was very apparent. For this reason, enrollment was discontinued after 16
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patients.
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The significant amount of incomplete data was also a limitation of this study. Most, however,
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was due to the patients pursuing other treatment options. Patients were not discouraged from
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seeking other treatments if they did not obtain adequate relief from the methylene blue injection
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during the study period based on Peng et al.’s report of a very quick response for those ultimately
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successful12. Many pursued other treatments options relatively quickly, within the first 2
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months. For these individuals VAS and ODI scores were not recorded as the data may not
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accurately reflect outcomes from the methylene blue but rather, from the subsequent treatment.
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Unfortunately, the lack of VAS and ODI data on the “failure” patients prohibits mean
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improvement calculation which would be useful in comparison to the other trials.
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Conclusion
338 Although significant limitations were present, this prospective trial of intradiscal methylene blue
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did not demonstrate an overall clinical success for those patients diagnosed with discogenic pain
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by provocation discography. These findings are in stark contrast to the outstanding results from
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a recently published, level one evidence, trial12. Further research is needed to evaluate the
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efficacy of this treatment.
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345 346 347 348 Captions for figures:
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Fig. 1. Lateral fluoroscopic image of intradiscal methylene blue injection with contrast medium.
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Fig. 2. Patient demographics. Number of discs injected. Visual analog scale (VAS) and
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Oswestry Disability Index (ODI) scores at baseline, 1, 2, and 6 month follow up. Clinical course
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affecting categorical designation. Categorical success, Yes (Y) or No (N) (N=Failure).
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References:
361 1. Skovron ML, Szpalski M, Nordin M, et al. Sociocultural factors and back pain: a population-
363
based study in Belgian adults. Spine 1994;19:129–37.
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364
2. Schwarzer A, Aprill C, Derby R., Fortin J., Kine G, Bogduk N. The prevalence and clinical
366
features of internal disc disruption in patients with chronic low back pain. Spine 1995;20:1878-
367
83.
368
SC
365
3. DePalma MJ, Ketchum JM, Saullo T. What is the source of chronic low back pain and does
370
age play a role? Pain Med. 2011;12(2):224-33.
371
M AN U
369
372
4. Fritzell P, Hagg O, Wessberg P, Nordwall A, The Swedish Lumbar Spine Study Group.
373
Volvo award winner in clinical studies: Lumbar fusion versus nonsurgical treatment for chronic
374
low back pain. A multicenter randomized controlled trial from the Swedish Lumbar Spine Study
375
Group. Spine 2001;23:2521-34.
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376 377
5. Hanley EN, David SM. Lumbar arthrodesis for the treatment of back pain. J Bone Joint Surg
378
(Am) 1999;81:716-30.
EP
379
6. Fairbank J, Frost H, Wilson-MacDonald J, Yu L-M, Barker K, Collins R. Randomised
381
controlled trial to compare surgical stabilisation of the lumbar spine with an intensive
382
rehabilitation programme for patients with chronic low back pain: the MRC spine stabilisation
383
trial. Br Med J 2005;330:1233-9.
384
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380
385
7. Peng B, Wu W, Hou S, Li P, Zhang C, Yang Y. The pathogenesis of discogenic low back
386
pain. J Bone Joint Surg Br 2005;87:62-7.
387 388
8. Coppes MH, Marani E, Thomeer RT, Groen GJ. Innervation of "painful" lumbar discs.
389
Spine. 1997;22:2342-9.
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390 391
9. Freeman BJ, Fraser RD, Cain CM, Hall DJ, Chapple DC. A randomized, double-blind,
392
controlled trial: intradiscal electrothermal therapy versus placebo for the treatment of chronic
393
discogenic low back pain. Spine. 2005;30:2369-77.
RI PT
394 395
10. Barendse G, van den Berg S, Kessels A, Weber W, van Kleef M. Randomized controlled
396
trial of percutaneous intradiscal radiofrequency thermocoagulation for chronic discogenic back
397
pain. Spine 2001;26:287-92.
SC
398
11. Peng B, Zhang Y, Hou S, Wu W, Fu X. Intradiscal methylene blue injection for the
400
treatment of chronic discogenic low back pain. Eur Spine J 2007;16:33-8.
M AN U
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401 402
12. Peng B, Pang X, Wu Y, Zhao C, Song X. A randomized placebo-controlled trial of
403
intradiscal methylene blue injection for the treatment of chronic discogenic low back pain. Pain
404
2010;149:124-29.
405
13. Eusebio EB, Graham J, Mody N. Treatment of intractable pruritus ani. Dis Colon Rectum
407
1990;33:770-2.
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14. Farouk R, Lee WR. Intradermal methylene blue injection for the treatment of intractable
410
idiopathic pruritus ani. Br J Surg 1997;84:670.
412 413
15. International Spine intervention national meeting 2011. Faculty discussion.
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16. Khot A, Bowditch M, Powell J, Sharp D. The use of intradiscal steroid therapy for lumbar
415
spinal discogenic pain: a randomized controlled trial. Spine 2004; 29: 833-837
416 417
17. Bogduk N. Practical Guidelines. Spinal Diagnostic and Treatment Protocol. International
418
Spine Intervention Society. 2004;20-46.
419
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18. Ostelo RW, Deyo RA, Stratford P et al. Interpreting change scores for pain and functional
421
status in low back pain: towards international consensus regarding minimal important change.
422
Spine 2008; 33(1):90-4.
423 19. MacVicar J, King W, Landers MH, Bogduk N. The effectiveness of lumbar transforaminal
425
injection of steroids: a comprehensive review with systematic analysis of the published data.
426
Pain Med. 2013;14:14-28.
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20. Frumin MJ, Schwartz H, Burns JJ, et al. Sites of sensory blockade during segmental spinal
429
and segmental peridural anesthesia in man. Anesthesiology 1953;14:576–83.
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21. Sharr MM, Weller RO, Brice JG. Spinal cord necrosis after intrathecal injection of
432
methylene blue. J of Neuro, Neurosurg, and Psych. 1978;41:384-86.
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22. Gupta G, Radhakrishna M, Chankowsky J, Asenjo JF. Methylene blue in the treatment of
435
discogenic low back pain. Pain Physician. 2012;15(4):333-8.
436
23. Kim SH, Ahn SH, Cho YW, Lee DG. Effect of Intradiscal Methylene Blue Injection for the
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Chronic Discogenic Low Back Pain: One Year Prospective Follow-up Study. Ann Rehabil Med.
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2012;36(5):657-64
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Patient
Age
Sex
Discs Injected
Pre-procedure VAS/ODI
1 Month F/U
2 Month F/U
6 Month F/U
1
45
F
1
VAS - 7.3
VAS - 2.4
VAS - 1.0
VAS - 5.4
ODI - 38%
ODI - 22%
ODI - 18%
ODI - 28%
Clinical course affecting categorical success or failure
Categorical Success (Y/N) 1 month - Y 2 month - Y 6 month - N
5
6
7
8
9
10
40
52
43
33
47
40
M
M
F
M
F
F
M
1
3
2
1
1
1
1
2
VAS - 6.4
VAS - 5.6
VAS - 7.5
ODI - 56%
ODI - 56%
ODI - 42%
VAS - 7.7
VAS - 5.7
VAS - 6.1
VAS - 4.5
ODI - 38%
ODI - 30%
ODI - 26%
VAS - 6.2
VAS - 6.5
VAS - 6.1
Incomplete
ODI - 36%
ODI - 38%
ODI - 34%
VAS - 5.3
VAS - 2.2
VAS - 2.5
VAS - 3.7
ODI - 38%
ODI - 16%
ODI - 14%
ODI - 14%
VAS - 8.4
VAS - 8.7
ODI - 48%
ODI - 66%
VAS - 7.8
VAS - 6.8
ODI - 52%
ODI - 50%
VAS - 5.0
VAS - 5.3
ODI - 26%
ODI - 26%
VAS - 8.1
VAS - 0.7
ODI - 30%
ODI - 8%
VAS - 8.5
Incomplete
Incomplete
34
Incomplete
F
1
1
VAS - 6.8
VAS - 5.9
ODI - 48%
ODI - 46%
VAS - 9.2
Incomplete
ODI - 42% 13
42
F
1
VAS - 5.7 ODI - 36%
14
62
M
2
Incomplete
VAS - 7.2 ODI - 50%
Incomplete
Incomplete
Underwent intra-discal steroid injection 10 weeks post MB
Incomplete
Incomplete
Incomplete
Incomplete
Incomplete
6 month - N (intent to treat) 1 month - N 2 month - N 6 month - Y 1 month - N 2 month - N 6 month - N (intent to treat) 1 month - Y 2 month - Y 6 month - Y 1 month - N 2 month - N 6 month - N 1 month - N 2 month - excluded from analysis 6 month - N 1 month - N 2 month - N 6 month - N
VAS - 0.1
1 month - Y
ODI - 2%
2 month - excluded from analysis
Incomplete
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M
Incomplete
Surgery at 6 weeks post MB
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12
50
1 month - N 2 month - N
ODI - 42%
ODI - 56% 11
Incomplete
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51
M
2
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4
31
M
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3
43
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2
Incomplete
Biacculoplasty at 1 month; Surgery at 5 months
6 month - Y 1 month - N 2 month - N 6 month - N
Hip injection 3 weeks post MB.
1 month - N
Pursued hip surgery 1 month post which did not improve low back sx
2 month - N 6 month - N
Incomplete
1 month - N Surgical consult at 1 month post MB; SI joint injection 7 weeks post MB, surgery at 1 year
2 month - N 6 month - N
Incomplete
1 month - N Intradiscal steroid injection at 1 month post MB
2 month - N 6 month - N
VAS - 6.3
VAS - 6.3
VAS - 1.0
VAS - 0.5
1 month - N
ODI - 44%
ODI - 28%
ODI - 20%
ODI - 22%
VAS 0- 9.8
VAS - 8.7
VAS - 9.2
VAS - 9.0
1 month - N
ODI - 58%
ODI - 54%
ODI - 42%
ODI - 38%
2 month - N
VAS - 8.3
VAS - 2.1
VAS - 6.2
VAS - 6.4
1 month - N
ODI - 62%
ODI - 56%
ODI - 58%
ODI - 64%
2 month - N
Surgery pursued at 9 months post MB (beyond f/u time)
2 month - Y 6 month - Y
15
39
M
1
6 month - N 16
57
F
1
6 month - N
S1934-1482(14)00176-2
DOI:
10.1016/j.pmrj.2014.04.008
Reference:
PMRJ 1243
To appear in:
PM&R
Received Date: 11 August 2013 Revised Date:
20 February 2014
Accepted Date: 15 April 2014
Please cite this article as: Levi DS, Horn S, Walko E, Intradiscal methylene blue treatment for discogenic low back pain, PM&R (2014), doi: 10.1016/j.pmrj.2014.04.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title Page:
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Intradiscal methylene blue treatment for discogenic low back pain. David S Levi, MD, Scott Horn, DO, Edward Walko, DO.
APM Spine and Sports Physicians
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Virginia Beach, VA
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ABSTRACT:
2 Background: Low back pain is a leading cause of pain and disability. The intervertebral disc has
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been identified as the most common source of chronic low back pain. Although prior treatments
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directed at intervertebral discs have been disappointing, recent studies show promising
6
improvement of pain and function after a single intradiscal injection of methylene blue.
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Objective: To assess changes in pain and function in patients with discogenic low back pain,
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diagnosed by discography, after an intradiscal injection of methylene blue.
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10 Study Design: Prospective trial
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Methods: Patients diagnosed with discogenic pain by discography underwent a single treatment
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of intradiscal injection of methylene blue, determined by prior provocation discography.
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Main Outcome measures: Pain and function measurements were completed at baseline, 1, 2, and
17
6 months post-treatment. Patients were considered a categorical success based upon a 30%
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improvement in pain on VAS and function on ODI. Patients were considered a categorical
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failure if they achieved less than 30% improvement in pain and function or pursued other
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invasive treatment options during the trial period.
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Results: Sixteen patients underwent the intradiscal methylene blue injection. Eleven patients
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underwent a single level injection. Four patients underwent a two level injection and one patient
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was injected at three levels. For VAS, at 1, 2 and 6 months post-injection, the categorical
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success rates were 25%, 21%, and 25%, respectively. For ODI, at 1, 2 and 6 months post-
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injection, the categorical success rates were 25%, 21%, and 33%, respectively. The overall
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categorical success rates at 1, 2 and 6 months post-injection, were 19%, 21%, and 25%
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respectively.
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Conclusion: This small trial did not demonstrate an overall clinical success of intradiscal
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methylene blue injection for those patients diagnosed with discogenic pain by discography.
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Introduction
33 Low back pain is a common cause of pain and disability1. Although several structures within the
35
spine have been identified as pain generators, the intervertebral disc is felt to account for
36
approximately 40% of chronic low back pain2,3. The most common conservative treatment
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options include medications, physical therapy, spinal manipulation, and corticosteroid injections.
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Many patients have an inadequate response to these conservative measures and are left with few
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quality treatment options.
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The most severely disabled patients often progress to surgical options. The most common
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surgical treatment for discogenic pain, lumbar fusion, has significant limitations. Although
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catastrophic complications from lumbar fusion surgery are rare, minor complications are
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relatively common. More concerning, however, is the questionable efficacy of lumbar fusion for
45
discogenic pain. Although some studies demonstrate superiority over conservative care, the
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results are modest4,5. Other trials show no significant benefit over non-surgical treatment6.
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The pathoanatomy of a painful intervertebral disc has been extensively studied. The region of
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the disc felt to illicit pain is the outer portion of the intervertebral disc, the annulus fibrosis,
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which may develop tears or fissures within the collagen fibers. These fissures contain an
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ingrowth of vascularized granulation tissue along with extensive nerve endings which may illicit
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pain7,8.
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Prior conservative treatments aimed at annular tear pathology have been attempted with heat or
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radiofrequency energy with disappointing results9,10. More recently, however, Peng and
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colleagues have investigated the use of methylene blue as a neurolytic agent within the disc11,12.
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Based on prior work demonstrating the ability of methylene blue to destroy dermal nerve
58
endings13,14, the investigators reasoned that this substance could be injected into a painful
59
intervertebral disc to denervate the pain-producing nerve endings within an annular tear. Rat tail
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studies were performed which showed denervation of the annular tears without injury to the disc
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itself (unpublished data described in Peng et al.12).
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Peng and colleagues have published two clinical studies evaluating intradiscal methylene blue
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for patients considering lumbar fusion surgery. The first was a prospective trial of 24 patients
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injected with intradiscal methylene blue at the time of discography. This demonstrated excellent
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efficacy with no adverse events11. A subsequent study was a placebo controlled double-blind
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trial with 36 patients receiving intradiscal methylene blue versus placebo at the time of
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discography12. The treatment group’s mean numeric rating score (NRS) improved from 72 at
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baseline to 25 at 6 months. These improvements were maintained at 24 months. This study also
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showed a highly significant improvement in function compared to the placebo group. The
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authors reported that 92% of patients were completely satisfied or satisfied in the treatment
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group compared to only 14% in the placebo group12. This well designed study demonstrated
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efficacy far beyond that of any current treatment for discogenic low back pain, including lumbar
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fusion surgery15. Once again, no adverse events occurred.
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In the past, there have been a number of potential intradiscal treatments for low back pain.
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However, after initial enthusiasm, most have been disappointing9,16. A prospective trial of
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intradiscal methylene blue was undertaken to help further evaluate the efficacy of this treatment.
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Methods:
81 The study was approved by an independent institutional review board.
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The trial was designed as a prospective trial with patients undergoing a single treatment of
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intradiscal injection of methylene blue, determined by prior provocation discography. Pain and
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function measurements were completed at baseline, 1, 2, and 6 months post-treatment.
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Study participants were screened from a pool of consecutive individuals with chronic low back
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pain who had undergone provocation discography. All patients had failed at least 6 months of
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conservative treatment and were considering lumbar fusion surgery. Patients were referred for
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discography internally, from within the investigators’ practice or externally through a local spine
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surgeon. The discograms were performed at a community outpatient interventional physiatry
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practice by two of the investigators (D.L. and S.H.).
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Inclusion Criteria •
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Chronic discogenic low back pain of 50mm or greater on a visual analog scale (VAS) of 0-100cm
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18-65 years of age
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•
Low back pain of more than 6 months duration with inadequate response to conservative
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treatment
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•
Low back symptoms greater than leg symptoms
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Concordant pain on provocation discography at 1-4 levels within 6 months of the study
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procedure (in accordance with International Spine Intervention Society guidelines17)
104 105
Exclusion Criteria
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Active moderate to severe lumbar radiculopathy
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Active infection
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Spinal fracture within the previous 6 months
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Severe psychological illness
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Inability to consent to procedure due to cognitive issues
113
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Prior fusion surgery at the level considered to be positive on discography
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Pregnant or breastfeeding females
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Severe uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic, endocrine,
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pulmonary, cardiac, or neurological disease •
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Radiologic evidence of greater than grade 1 spondylolisthesis at a level considered to be
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positive on discography
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Inflammatory arthritis
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Any cancer within the past 5 years except basal cell or squamous cell skin cancer
121
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Intradural disc herniation
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Glucose-6-phosphate dehydrogenase deficiency
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Coagulopathy preventing spinal injection
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•
Inability to stop anticoagulants other than aspirin
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Greater than 30 mg morphine equivalent per day of opioid use
126
•
History of alcohol or drug abuse within the past 5 years
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Use of any investigational drug within the past 30 days
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Low back surgery within the past 12 months
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Steroid injection in the spine within the past 30 days
130
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Known allergy or sensitivity to methylene blue
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Pending litigation involving the subject's back pain
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Actively applying for disability benefits due to their back pain
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Greater than 4 discs considered positive by provocation discography
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Central stenosis at the level to be injected with an AP diameter less than or equal to 6
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millimeters
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Severe anaphylactic/anaphylactoid reaction to any of the medications used in this study
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Ethical or religious objections to staining body tissue with dye
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Disc leakage into the epidural space during discography at a volume of 2.5 milliliters or
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less
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Intradiscal methylene blue injection treatment procedure:
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The procedure was performed by two of the investigators (D.L. and S.H.). Both are board
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certified in physical medicine and rehabilitation, experienced discographers, fellowship trained
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in spine injections, and serve as instructors for spinal injection procedures at the national level.
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Intradiscal injection: Depending upon patient preference, IV sedation (with midazolam and
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fentanyl), oral anxiolytics (with alprazolam or diazepam), or no sedation was administered prior
150
to the procedure. Patients were placed in a prone position in an outpatient fluoroscopy suite.
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Strict sterile technique was observed. The area was cleansed with betadine and chlorhexadine
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and covered with a sterile drape. The skin and superficial tissues was anesthetized with 2-5 ml
153
of lidocaine 1%. A standard posterolateral extra-pedicular discogram technique was used under
154
intermittent fluoroscopic imaging for each level previously determined to be positive at prior
155
discography (which took place between 2 weeks and 6 months prior to the methylene blue
156
injection). Using a single needle technique, a 22-gauge spinal needle with stylet was directed
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into the disc nucleus in accordance with International Spine Intervention Society guidelines17.
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One ml of a solution consisting of 0.7ml of Omnipaque 300 and 0.3mL of gentamicin 40mg/mL
159
(total of 12mg gentamicin) was then injected for discitis prophylaxis and to ensure intranuclear
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needle tip position in AP and lateral views. Then, a 1.5 ml solution containing 0.5 ml lidocaine
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4% along with 1 ml of methylene blue 10 mg/ml was injected. Therefore, a total volume of 2.5
162
ml was injected into each of the discogram-positive discs during the treatment (figure 1). If any
163
leakage into the epidural space was observed during the injection, the procedure for that disc was
164
halted. After the solution was injected, the needle was removed. The patient either ambulated
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with assistance or was transported by wheelchair to the recovery room.
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The patient was observed clinically for 45 minutes and vital signs were checked upon initially
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arriving to the recovery room and then every 15 minutes. The patient was discharged to a
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companion with written and verbal instructions to include no driving or operating machinery for
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12 hours.
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Outcome measurements
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Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI) were utilized for pain and
174
function measurements at baseline and 1, 2, and 6 months following the methylene blue treat-
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ment. A patient was considered to have a successful outcome if the VAS improved by at least
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30% accompanied by at least a 30% improvement in ODI18. In light of the astounding results in
177
the Peng et al. study12, these improvement values were chosen as they likely represent a more
178
conservative interpretation of success18. In order to more accurately determine a successful
179
treatment outcome from the methylene blue, any patient who underwent or pursued other
180
invasive treatments during the 6 month follow up period, such as surgery or spinal injections,
181
was also considered a failure.
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182 Results
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Sixteen patients, 9 males and 7 females, underwent the intradiscal methylene blue injection with
186
an average age of 44. Eleven patients underwent a single level injection. Four patients
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underwent a 2 level injection and one patient was injected at 3 levels.
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There were no intra-procedural or post-procedural complications. No epidural leakage was
190
observed during the injection procedure for any patient. There were no new radicular complaints
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and no cases of discitis.
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Categorical success was measured by a minimal improvement of 30% on VAS and ODI. A
194
categorical failure was measured by an improvement of less than 30% on VAS and ODI. A
195
patient who pursued another invasive spinal treatment such as injection or surgery was also
196
considered a failure. Categorical outcomes were designated at 1, 2, and 6 months (figure 2).
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At the one month follow up, 3 out of 16 patients, 19%, were considered a categorical success.
199
Eight-one percent of the patients completed data for this time period. All 3 patients who did not
200
complete the VAS and ODI at 1 month were considered to be categorical failures. One pursued
201
surgical consultation at 3 weeks, 1 pursued the option of biacuplasty by 3 weeks and shortly after
202
underwent surgical consultation, and the third underwent an intradiscal injection with steroid at 3
203
1/2
204
that treatment. Therefore, based on VAS and ODI data as well as outcome categorization
205
designation for pursuing or undergoing other invasive treatments, 13 out of 16 patients, 81%,
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were considered failures at the 1 month follow up. Of the 2 patients that pursued surgery, 1 was
207
performed at five months and the other at 12 months post injection, neither improved clinically
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prior to the surgical fusions.
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weeks after the methylene blue injection as she had prior excellent but short term relief with
209
At the 2 month follow up, 3 of 14 patients, 21%, met the criteria for success. Within the second
211
month of follow up, two further patients were categorized as failures based on pursuit of other
212
treatment. One underwent fusion at 5 weeks post injection and the other pursued intradiscal
213
steroid injection. Thus far, 5 of the 16 patients were considered failures for pursuing other
214
invasive treatment options by the 8 week follow up point. Of the remaining subjects, 3 failed to
215
complete VAS and ODI measures, one of whom underwent an intra-articular hip injection and
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surgical consultation for possible hip pathology as the source of her pain. Although arguable,
217
this patient was considered a failure in our analysis for pursuing an invasive surgical treatment as
218
it was later found that her hip was not the source of her back pain. VAS and ODI data was
219
missing on 2 “active” patients (those not pursuing other invasive treatment options), 1 of whom
220
was considered successful at 1 month follow up and one considered a failure at 1 month. These
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2 patients were not included in the 2 month analysis. As 6 patients were considered failures for
222
pursuing invasive treatment options and 2 patients were missing data, this left only 8 patients
223
completing the ODI and VAS measurements at this follow up period. Only three patients met
224
the criteria for success at the two month follow up.
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At the 6 month follow up, 4 of 16 patients, 25%, met success criteria. Two patients, both
227
considered failures at 1 and 2 month periods, were lost to follow up. In our analysis, we
228
considered both to remain in the failure category. The 2 patients who did not complete the 2
229
month data, one a failure and one a success, both completed VAS and ODI data at the 6 month
230
follow up and remained in their respective 1 month categories. By this point, 6 patients were
231
considered categorical failures based on pursuit of other invasive treatment options. Therefore,
232
8 patients remained to complete the pain and functional outcome data. Therefore, at this point,
233
only 4 patients, 25%, met the criteria for success at 6 months.
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Discussion
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This small prospective study was undertaken to help determine the efficacy of a single intradiscal
239
injection of methylene blue for the treatment of discogenic low back pain. Success or failure
240
was measured by pain relief, improvement in disability and the pursuit of other invasive
241
treatment options. Overall, very limited benefit was seen with an overall categorical success rate
242
of only 19%, 21% and 25% for the 1, 2 and 6 month follow up periods, respectively.
243
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244 The primary analysis of our results was performed in a categorical manner. The initial intention,
246
however, was to perform statistical analysis. For several reasons the categorical method was felt
247
to be more appropriate. Beyond the small sample size, we did experience a very high drop-out
248
rate. Prior to the participation in the study, the patients were informed of the results of Peng et
249
al.’s trials11,12. This included Peng et al.’s finding that those patients who ultimately benefitted
250
from methylene blue, obtained relief by 24 hours12. Most patients were not improved initially,
251
and ethically, we could not discourage them from pursuing other treatment options. Six out of
252
the 16 patients choose to pursue other treatment options within the follow up period. This was
253
felt to be the primary reason for the high attrition rate. Most of the patients included in this study
254
were strongly considering fusion surgery for their low back symptoms. Two patients pursued
255
this option during the first month following the methylene blue injection. Several others pursued
256
spinal injections which had given them short term (1-2 months) relief in the past. It was not felt
257
appropriate to include follow up data after another intervention (spinal injection or surgery) took
258
place as this would inappropriately reflect a response from treatment other than methylene blue.
259
It was for this reason that the patients who chose to pursue other invasive treatment options were
260
considered categorical failures. In light of these issues and a paucity of VAS and ODI follow-up
261
data, our analysis was performed in a categorical manner. Categorical analysis may also be more
262
reflective of actual improvement than group mean data analysis particularly in cases of bimodal
263
scores19.
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In the randomized placebo controlled trial of intradiscal methylene blue by Peng et al.12, the
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authors reported a dramatic mean pain improvement in NRS from 72 to 25 at 6 month follow-up.
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The pain reductions were accompanied by a similar improvement in function as measured by
268
ODI. Based upon these extraordinary results, we expected a high percentage of our patients to
269
have a successful outcome. Unfortunately, only 19%-25% (at different time periods) of our
270
patients obtained at least 30% improvement in pain and disability. In addition, Peng et al.
271
reported that 47% of their patients had complete or near complete relief of pain at 6 month
272
follow up. In our study, only 12% of the patients (2/16) had this level of success. Although
273
beyond our follow up period, one of these two patients pursued surgical treatment for his low
274
back pain at 8 months post injection.
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Our protocol differed slightly from the two Peng et al. studies11,12. In the current trial, the
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intradiscal methylene blue was injected at a separate time point from discography to decrease the
278
likelihood of leakage of methylene blue into the epidural space. Peng and colleagues performed
279
the methylene blue injection immediately following discography without any adverse events11,12.
280
However, because it is known that medications administered into the epidural space diffuse, to a
281
small degree, into the subarachnoid space20, and that intrathecal methylene blue is known to be
282
neurotoxic21, we felt that this was a potential safety concern. Therefore, patients were excluded
283
from the study who leaked during discography into the epidural space at a volume of 2.5ml (our
284
total treatment volume with methylene blue) or less. The volume of 2.5 ml for the methylene
285
blue injection treatment was chosen by the authors as the smallest reasonable total volume to
286
deliver all of the components of the injectate, contrast medium, antibiotic, anesthetic and the
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methylene blue. While it is possible that the difference in protocols could explain the disparity
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in the success rates between our study and that of Peng et al.’s12, we feel that it is doubtful. Our
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protocol ensured that a controlled dosage, 10 mg of methylene blue (equivalent dosage used in
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Peng et al.’s trials11,12), entered the disc. Additionally, in our study, the methylene blue was not
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diluted by variable amounts of contrast medium, nor did it leak into the epidural space. In
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theory, the higher concentration of methylene blue in our study should have allowed for the
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proposed mechanism of action, denervation of the small nerve fibers within the symptomatic
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annular fissures12, to occur to a greater extent. In the current study, we also chose different
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follow up points than Peng et al.’s randomized controlled trial12. The 1, 2 and 6 month data
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points were chosen in our study as Peng et al. reported that those patients who benefitted from
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methylene blue, obtained relief by 24 hours12. In addition the authors reported that the 6 month
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results were statistically equivalent to 12 and 24 months in their randomized controlled trial12
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and the 3 month results was equal to 12 months in their prospective trial11. We did not attempt to
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extend our study beyond 6 months for this reason.
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A retrospective case series of 8 patients undergoing intradiscal methylene blue was published
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using Peng et al.’s11,12 protocol22. This case series assessed pain and functional outcomes in 8
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patients treated with a one-time administration of methylene blue for discogenic back pain.
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Follow-up information was available between 2 months and greater than one year, depending on
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the patient. Results of the study demonstrated only one clinical success with long term
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improvement of pain and function. Four patients had a time-limited clinical benefit in pain
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and/or function between 2 weeks and 5 months. The authors discontinued methylene blue
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prospective trial.
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A prospective trial of 20 patients was also performed by Kim et al. in 201223. The patients
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received intradiscal methylene blue at each disc identified to be positive during provocation
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discography which occurred one week prior. At 3 months follow up, 11 of the 20 patients (55%)
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reported successful outcomes, as defined by an improvement of at least a 2 point change in VAS.
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The average VAS was reduced by 2.2 points. At the 12 month follow up, pain had recurred in 6
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patients who had initial satisfactory results. Successful outcome was maintained in only 5
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patients (20%) for 1 year23. These results, although slightly better than the current study, differ
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greatly from those of Peng et al.11,12.
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There are several limitations of our study. The small number of patients in our study is certainly
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a significant limitation. The planned enrollment was 30 patients. However, as the patients were
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followed very closely during the current trial, the overall poor response to the intradiscal
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methylene blue was very apparent. For this reason, enrollment was discontinued after 16
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patients.
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The significant amount of incomplete data was also a limitation of this study. Most, however,
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was due to the patients pursuing other treatment options. Patients were not discouraged from
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seeking other treatments if they did not obtain adequate relief from the methylene blue injection
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during the study period based on Peng et al.’s report of a very quick response for those ultimately
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successful12. Many pursued other treatments options relatively quickly, within the first 2
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months. For these individuals VAS and ODI scores were not recorded as the data may not
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accurately reflect outcomes from the methylene blue but rather, from the subsequent treatment.
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Unfortunately, the lack of VAS and ODI data on the “failure” patients prohibits mean
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improvement calculation which would be useful in comparison to the other trials.
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Conclusion
338 Although significant limitations were present, this prospective trial of intradiscal methylene blue
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did not demonstrate an overall clinical success for those patients diagnosed with discogenic pain
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by provocation discography. These findings are in stark contrast to the outstanding results from
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a recently published, level one evidence, trial12. Further research is needed to evaluate the
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efficacy of this treatment.
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345 346 347 348 Captions for figures:
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Fig. 1. Lateral fluoroscopic image of intradiscal methylene blue injection with contrast medium.
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Fig. 2. Patient demographics. Number of discs injected. Visual analog scale (VAS) and
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Oswestry Disability Index (ODI) scores at baseline, 1, 2, and 6 month follow up. Clinical course
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affecting categorical designation. Categorical success, Yes (Y) or No (N) (N=Failure).
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360
References:
361 1. Skovron ML, Szpalski M, Nordin M, et al. Sociocultural factors and back pain: a population-
363
based study in Belgian adults. Spine 1994;19:129–37.
RI PT
362
364
2. Schwarzer A, Aprill C, Derby R., Fortin J., Kine G, Bogduk N. The prevalence and clinical
366
features of internal disc disruption in patients with chronic low back pain. Spine 1995;20:1878-
367
83.
368
SC
365
3. DePalma MJ, Ketchum JM, Saullo T. What is the source of chronic low back pain and does
370
age play a role? Pain Med. 2011;12(2):224-33.
371
M AN U
369
372
4. Fritzell P, Hagg O, Wessberg P, Nordwall A, The Swedish Lumbar Spine Study Group.
373
Volvo award winner in clinical studies: Lumbar fusion versus nonsurgical treatment for chronic
374
low back pain. A multicenter randomized controlled trial from the Swedish Lumbar Spine Study
375
Group. Spine 2001;23:2521-34.
TE D
376 377
5. Hanley EN, David SM. Lumbar arthrodesis for the treatment of back pain. J Bone Joint Surg
378
(Am) 1999;81:716-30.
EP
379
6. Fairbank J, Frost H, Wilson-MacDonald J, Yu L-M, Barker K, Collins R. Randomised
381
controlled trial to compare surgical stabilisation of the lumbar spine with an intensive
382
rehabilitation programme for patients with chronic low back pain: the MRC spine stabilisation
383
trial. Br Med J 2005;330:1233-9.
384
AC C
380
385
7. Peng B, Wu W, Hou S, Li P, Zhang C, Yang Y. The pathogenesis of discogenic low back
386
pain. J Bone Joint Surg Br 2005;87:62-7.
387 388
8. Coppes MH, Marani E, Thomeer RT, Groen GJ. Innervation of "painful" lumbar discs.
389
Spine. 1997;22:2342-9.
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390 391
9. Freeman BJ, Fraser RD, Cain CM, Hall DJ, Chapple DC. A randomized, double-blind,
392
controlled trial: intradiscal electrothermal therapy versus placebo for the treatment of chronic
393
discogenic low back pain. Spine. 2005;30:2369-77.
RI PT
394 395
10. Barendse G, van den Berg S, Kessels A, Weber W, van Kleef M. Randomized controlled
396
trial of percutaneous intradiscal radiofrequency thermocoagulation for chronic discogenic back
397
pain. Spine 2001;26:287-92.
SC
398
11. Peng B, Zhang Y, Hou S, Wu W, Fu X. Intradiscal methylene blue injection for the
400
treatment of chronic discogenic low back pain. Eur Spine J 2007;16:33-8.
M AN U
399
401 402
12. Peng B, Pang X, Wu Y, Zhao C, Song X. A randomized placebo-controlled trial of
403
intradiscal methylene blue injection for the treatment of chronic discogenic low back pain. Pain
404
2010;149:124-29.
405
13. Eusebio EB, Graham J, Mody N. Treatment of intractable pruritus ani. Dis Colon Rectum
407
1990;33:770-2.
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406
408
14. Farouk R, Lee WR. Intradermal methylene blue injection for the treatment of intractable
410
idiopathic pruritus ani. Br J Surg 1997;84:670.
412 413
15. International Spine intervention national meeting 2011. Faculty discussion.
AC C
411
EP
409
414
16. Khot A, Bowditch M, Powell J, Sharp D. The use of intradiscal steroid therapy for lumbar
415
spinal discogenic pain: a randomized controlled trial. Spine 2004; 29: 833-837
416 417
17. Bogduk N. Practical Guidelines. Spinal Diagnostic and Treatment Protocol. International
418
Spine Intervention Society. 2004;20-46.
419
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420
18. Ostelo RW, Deyo RA, Stratford P et al. Interpreting change scores for pain and functional
421
status in low back pain: towards international consensus regarding minimal important change.
422
Spine 2008; 33(1):90-4.
423 19. MacVicar J, King W, Landers MH, Bogduk N. The effectiveness of lumbar transforaminal
425
injection of steroids: a comprehensive review with systematic analysis of the published data.
426
Pain Med. 2013;14:14-28.
RI PT
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427
20. Frumin MJ, Schwartz H, Burns JJ, et al. Sites of sensory blockade during segmental spinal
429
and segmental peridural anesthesia in man. Anesthesiology 1953;14:576–83.
SC
428
M AN U
430 431
21. Sharr MM, Weller RO, Brice JG. Spinal cord necrosis after intrathecal injection of
432
methylene blue. J of Neuro, Neurosurg, and Psych. 1978;41:384-86.
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22. Gupta G, Radhakrishna M, Chankowsky J, Asenjo JF. Methylene blue in the treatment of
435
discogenic low back pain. Pain Physician. 2012;15(4):333-8.
436
23. Kim SH, Ahn SH, Cho YW, Lee DG. Effect of Intradiscal Methylene Blue Injection for the
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Chronic Discogenic Low Back Pain: One Year Prospective Follow-up Study. Ann Rehabil Med.
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2012;36(5):657-64
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ACCEPTED MANUSCRIPT FIG. 2
Patient
Age
Sex
Discs Injected
Pre-procedure VAS/ODI
1 Month F/U
2 Month F/U
6 Month F/U
1
45
F
1
VAS - 7.3
VAS - 2.4
VAS - 1.0
VAS - 5.4
ODI - 38%
ODI - 22%
ODI - 18%
ODI - 28%
Clinical course affecting categorical success or failure
Categorical Success (Y/N) 1 month - Y 2 month - Y 6 month - N
5
6
7
8
9
10
40
52
43
33
47
40
M
M
F
M
F
F
M
1
3
2
1
1
1
1
2
VAS - 6.4
VAS - 5.6
VAS - 7.5
ODI - 56%
ODI - 56%
ODI - 42%
VAS - 7.7
VAS - 5.7
VAS - 6.1
VAS - 4.5
ODI - 38%
ODI - 30%
ODI - 26%
VAS - 6.2
VAS - 6.5
VAS - 6.1
Incomplete
ODI - 36%
ODI - 38%
ODI - 34%
VAS - 5.3
VAS - 2.2
VAS - 2.5
VAS - 3.7
ODI - 38%
ODI - 16%
ODI - 14%
ODI - 14%
VAS - 8.4
VAS - 8.7
ODI - 48%
ODI - 66%
VAS - 7.8
VAS - 6.8
ODI - 52%
ODI - 50%
VAS - 5.0
VAS - 5.3
ODI - 26%
ODI - 26%
VAS - 8.1
VAS - 0.7
ODI - 30%
ODI - 8%
VAS - 8.5
Incomplete
Incomplete
34
Incomplete
F
1
1
VAS - 6.8
VAS - 5.9
ODI - 48%
ODI - 46%
VAS - 9.2
Incomplete
ODI - 42% 13
42
F
1
VAS - 5.7 ODI - 36%
14
62
M
2
Incomplete
VAS - 7.2 ODI - 50%
Incomplete
Incomplete
Underwent intra-discal steroid injection 10 weeks post MB
Incomplete
Incomplete
Incomplete
Incomplete
Incomplete
6 month - N (intent to treat) 1 month - N 2 month - N 6 month - Y 1 month - N 2 month - N 6 month - N (intent to treat) 1 month - Y 2 month - Y 6 month - Y 1 month - N 2 month - N 6 month - N 1 month - N 2 month - excluded from analysis 6 month - N 1 month - N 2 month - N 6 month - N
VAS - 0.1
1 month - Y
ODI - 2%
2 month - excluded from analysis
Incomplete
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M
Incomplete
Surgery at 6 weeks post MB
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50
1 month - N 2 month - N
ODI - 42%
ODI - 56% 11
Incomplete
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M
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31
M
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Incomplete
Biacculoplasty at 1 month; Surgery at 5 months
6 month - Y 1 month - N 2 month - N 6 month - N
Hip injection 3 weeks post MB.
1 month - N
Pursued hip surgery 1 month post which did not improve low back sx
2 month - N 6 month - N
Incomplete
1 month - N Surgical consult at 1 month post MB; SI joint injection 7 weeks post MB, surgery at 1 year
2 month - N 6 month - N
Incomplete
1 month - N Intradiscal steroid injection at 1 month post MB
2 month - N 6 month - N
VAS - 6.3
VAS - 6.3
VAS - 1.0
VAS - 0.5
1 month - N
ODI - 44%
ODI - 28%
ODI - 20%
ODI - 22%
VAS 0- 9.8
VAS - 8.7
VAS - 9.2
VAS - 9.0
1 month - N
ODI - 58%
ODI - 54%
ODI - 42%
ODI - 38%
2 month - N
VAS - 8.3
VAS - 2.1
VAS - 6.2
VAS - 6.4
1 month - N
ODI - 62%
ODI - 56%
ODI - 58%
ODI - 64%
2 month - N
Surgery pursued at 9 months post MB (beyond f/u time)
2 month - Y 6 month - Y
15
39
M
1
6 month - N 16
57
F
1
6 month - N
