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Epidural Corticosteroid Injections for Radiculopathy and Spinal Stenosis: A Systematic Review and Meta-analysisEpidural Corticosteroid Injections for Radiculopathy and Spinal Stenosis

Roger Chou, MD; Robin Hashimoto, PhD; Janna Friedly, MD; Rongwei Fu, PhD; Christina Bougatsos, MPH; Tracy Dana, MLS; Sean D. Sullivan, BScPharm, PhD; and Jeffrey Jarvik, MD, MPH
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 25 August 2015.


From Pacific Northwest Evidence-based Practice Center, and Oregon Health & Science University, Portland, Oregon; Spectrum Research, Tacoma, Washington; and Comparative Effectiveness, Cost and Outcomes Research Center and University of Washington, Seattle, Washington.

Disclaimer: The findings and conclusions in this document are those of the authors, who are responsible for its content, and do not necessarily represent the views of the Agency for Healthcare Research and Quality (AHRQ). No statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.

Grant Support: By the Agency for Healthcare Research and Quality (contract no. HHSA290201200014i).

Disclosures: Dr. Chou reports grants from AHRQ during the conduct of the study and royalties from UpToDate, Inc., outside the submitted work. Dr. Hashimoto reports grants from AHRQ during the conduct of the study. Dr. Fu reports grants from AHRQ during the conduct of the study. Ms. Dana reports grants from AHRQ during the conduct of the study and outside the submitted work. Dr. Sullivan reports funds from AHRQ during the conduct of the study. Dr. Jarvik reports grants from AHRQ and PCORI, being cofounder of and a stockholder in PhysioSonics (an ultrasonography-based technology company), personal fees from the GE Healthcare-CER Advisory Board (stopped in September 2012) and HealthHelp (a radiology benefits management company) outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-0934.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.

Requests for Single Reprints: Roger Chou, MD, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239; e-mail, chour@ohsu.edu.

Current Author Addresses: Drs. Chou and Bougatsos and Ms. Dana: Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239.

Dr. Hashimoto: Spectrum Research, 705 South 9th Street, Suite 203, Tacoma, WA 98405.

Dr. Friedly: University of Washington, 325 9th Avenue, Box 359859, Seattle, WA 98104.

Dr. Fu: Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Mail Code CSB669, Portland, OR 97239.

Dr. Sullivan: University of Washington, 1959 NE Pacific Avenue, H-364, Box 357631, Seattle, WA 98195-7630.

Dr. Jarvik: University of Washington, 325 9th Avenue, Box 359728, Seattle, WA 98104-2499.

Author Contributions: Conception and design: R. Chou.

Analysis and interpretation of the data: R. Chou, R. Hashimoto, R. Fu, C. Bougatsos, T. Dana, S.D. Sullivan.

Drafting of the article: R. Chou, R. Fu, C. Bougatsos, T. Dana.

Critical revision of the article for important intellectual content: R. Chou, R. Hashimoto, S.D. Sullivan, J. Jarvik.

Final approval of the article: R. Chou, R. Fu, C. Bougatsos, T. Dana, S.D. Sullivan, J. Jarvik.

Statistical expertise: R. Chou, R. Fu.

Obtaining of funding: R. Chou, S.D. Sullivan.

Administrative, technical, or logistic support: C. Bougatsos, T. Dana.

Collection and assembly of data: R. Chou, R. Hashimoto, C. Bougatsos, T. Dana, S.D. Sullivan.


Ann Intern Med. 2015;163(5):373-381. doi:10.7326/M15-0934
Text Size: A A A

Background: Use of epidural corticosteroid injections is increasing.

Purpose: To review evidence on the benefits and harms of epidural corticosteroid injections in adults with radicular low back pain or spinal stenosis of any duration.

Data Sources: Ovid MEDLINE (through May 2015), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, prior systematic reviews, and reference lists.

Study Selection: Randomized trials of epidural corticosteroid injections versus placebo interventions, or that compared epidural injection techniques, corticosteroids, or doses.

Data Extraction: Dual extraction and quality assessment of individual studies, which were used to determine the overall strength of evidence (SOE).

Data Synthesis: 30 placebo-controlled trials evaluated epidural corticosteroid injections for radiculopathy, and 8 trials were done for spinal stenosis. For radiculopathy, epidural corticosteroids were associated with greater immediate-term reduction in pain (weighted mean difference on a scale of 0 to 100, −7.55 [95% CI, −11.4 to −3.74]; SOE, moderate), function (standardized mean difference after exclusion of an outlier trial, −0.33 [CI, −0.56 to −0.09]; SOE, low), and short-term surgery risk (relative risk, 0.62 [CI, 0.41 to 0.92]; SOE, low). Effects were below predefined minimum clinically important difference thresholds, and there were no longer-term benefits. Limited evidence showed no clear effects of technical factors, patient characteristics, or comparator interventions on estimates. There were no clear effects of epidural corticosteroid injections for spinal stenosis (SOE, low to moderate). Serious harms were rare, but harms reporting was suboptimal (SOE, low).

Limitations: The review was restricted to English-language studies. Some meta-analyses were based on small numbers of trials (particularly for spinal stenosis), and most trials had methodological shortcomings.

Conclusion: Epidural corticosteroid injections for radiculopathy were associated with immediate reductions in pain and function. However, benefits were small and not sustained, and there was no effect on long-term surgery risk. Limited evidence suggested no effectiveness for spinal stenosis.

Figures

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Appendix Figure.

Summary of evidence search and selection.

* Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews.

† Reference lists of relevant articles and systematic reviews, among other sources.

‡ The full report (21) also addresses other types of injections, nonradicular and postsurgical back pain, and effects of epidural injections versus active comparators.

§ Some studies are included for more than 1 question.

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Tables

References

Letters

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Comments

Submit a Comment/Letter
Comment
Posted on September 3, 2015
Laxmaiah Manchikanti, MD, Alan David Kaye MD PhD, Joshua A. Hirsch, MD
University of Louisville, LSU School of Medicine, Harvard Medical School
Conflict of Interest: None Declared
We are concerned that the systematic review by Chou et al (1) will have far reaching consequences on patients who might potentially benefit from epidural corticosteroid injections for radiculopathy and spinal stenosis. This systematic review is similar to an earlier publication by Pinto et al (2). The fundamental flaw of this systematic review and previous one (2) is that the authors have converted all placebo to active-control trials, with unproven hypothesis that all therapeutic effects in the epidural space are secondary to steroids (1). In our opinion, this is a scientifically and clinically incorrect methodology. Noteworthy, the therapeutic effectiveness of local anesthetics on a long-term basis has been illustrated in systematic reviews with an efficacy that was equivalent to steroids except in some circumstances (3). Further, methodologically sound systematic reviews showed efficacy of epidural injections in managing radiculopathy, spinal stenosis, and other ailments (3-5). Chou et al’s conversion of active-control trials to placebo control is analogous to studies comparing whole milk to water or skim milk, with water being placebo and skim milk being an active-control. With extensive literature available in reference to placebos and nocebos and their influence on various trials, this approach is unscientific and unjustifiable.
Further, epidural injections have an excellent risk-benefit ratio compared to opioids and NSAIDs, which are themselves responsible for almost 17,000 deaths a year and numerous hospitalizations. Lumbar surgery alone is responsible for over almost 1,300 deaths a year, while deaths over the past two decades related to epidural injections were 131 -- significantly less than any other modality (4,5).
Other deficiencies include inconsistency with standards developed by the Institute of Medicine (IOM) for systematic reviews, perceived intellectual bias and inappropriate methodological quality assessment of the manuscripts. Further, they (1,2) have misinterpreted outcomes assessment data as absolute difference between 2 active control groups, which is not feasible, because active control trials only demonstrate superiority, non-inferiority, or equivalency rather than efficacy. We posit that the absolute effect size can only be measured by a true placebo control – not an impure placebo or one converted from an active agent to placebo on paper.
The policy implications of Chou et al’s systematic review are such that patients will lose access to epidural injections for radiculopathy and spinal stenosis, and seek alternative treatments including narcotic medications and surgery.

References
1. Chou R, Hashimoto R, Friedly J, Fu R, Bougatsos C, Dana T, Sullivan SD, Jarvik J. Epidural corticosteroid injections for radiculopathy and spinal stenosis: A systematic review and meta-analysis. Ann Intern Med 2015; [Epub ahead of print].
2. Pinto RZ, Maher CG, Ferreira ML, Hancock M, Oliveira VC, McLachlan AJ, Koes B, Ferreira PH. Epidural corticosteroid injections in the management of sciatica: A systematic review and meta-analysis. Ann Intern Med 2012; 157:865-877.
3. Manchikanti L, Nampiaparampil DE, Manchikanti KN, Falco FJE, Singh V, Benyamin RM, Kaye AD, Sehgal N, Soin A, Simopoulos TT, Bakshi S, Gharibo CG, Gilligan CJ, Hirsch JA. Comparison of the efficacy of saline, local anesthetics, and steroids in epidural and facet joint injections for the management of spinal pain: A systematic review of randomized controlled trials. Surg Neurol Int 2015; 6:S194-S235.
4. Manchikanti L, Benyamin RM, Falco FJ, Kaye AD, Hirsch JA. Do epidural injections provide short- and long-term relief for lumbar disc herniation? A systematic review. Clin Orthop Relat Res 2015; 473:1940-1956.
5. Manchikanti L, Kaye AD, Manchikanti KN, Boswell MV, Pampati V, Hirsch JA. Efficacy of epidural injections in the treatment of lumbar central spinal stenosis: A systematic review. Anesth Pain Med 2015; 5:e23139.
Epidural Corticosteroid Injections for Radiculopathy and Spinal Stenosis
Posted on September 5, 2015
Denis F. Darko, MD, FACP, DLFAPA
CEO, NeuroSci R&D Consultancy, LLC Plymouth MN 55446
Conflict of Interest: None Declared
TO THE EDITOR: Chou and colleagues have tried to address an important area of patient care (1) with all the literature that is available, which unfortunately is not much. This small body of data illustrates more what we do not know than what we do know. The paucity of quality studies in this high profile area of medicine is embarrassing. As the authors describe in the Discussion, much, much more remains to be done.

The authors only briefly mention near the end of the Discussion that, "Research is needed to determine whether injections are more effective when given in the context of a more comprehensive pain management approach." While limited evidence exists for the usefulness of specifically designed physical therapy (PT) programs for both radiculopathy (2, 3) and degenerative lumbar spinal stenosis (2, 4), clinical experience suggests that PT might be effective in improving patient outcomes when put in place as part of an appropriate overall treatment plan.

In practical terms, the immediate-term reduction in pain with epidural corticosteroid injections as was found by the authors might provide a window to begin a productive program of active PT. The combination of epidural corticosteroid use followed by active PT should be studied with longer-term follow-up using the outcome measures of improvements in pain and function and change in risk for requiring surgical intervention.

Denis F. Darko, MD, FACP, DLFAPA
NeuroSci R&D Consultancy, LLC
Plymouth, MN 55446-3745

1. Chou R, Hashimoto R, Friedly J, Fu R, Bougatsis C, Dana T, et al. Epidural Corticosteroid Injections for Radiculopathy and Spinal Stenosis: A Systematic Review and Meta-analysis. Ann Intern Med. 2015; 163:373-381. [PMID: 26302454] doi:10.7326/M15-0934

2. Chou R, Qaseem A, Snow V, Casey D, Cross JT Jr., Shekelle P, et al. Diagnosis and Treatment of Low Back Pain: A Joint Clinical Practice Guideline from the American College of Physicians and the American Pain Society. Ann Intern Med. 2007;147:478-491. [PMID: 17909209]

3. North American Spine Society, Clinical Guidelines for Multidisciplinary Spine Care, Diagnosis and Treatment of Lumbar Disc Herniation with Radiculopathy, 2012: 30.

4. North American Spine Society, Clinical Guidelines for Multidisciplinary Spine Care, Diagnosis and Treatment of Degenerative Lumbar Spinal Stenosis, 2011: 43.
Heterogeniety and use of guidance
Posted on September 9, 2015
G Allison Glass DSc, Neil Maneck BS, Howard T Katz MD
Gulf States Physical Medicine and Rehabilitation
Conflict of Interest: None Declared
We read with great interest Chou et al’s (1) review of the benefits of epidural corticosteroid injections (ECI) in adults with radiculopathy and concluded that the benefits were small and short lived. We are treated a 53-year-old female with left S1 radiculopathy who has recently received her second ECI and reports significant and lasting relief in pain and improved function as measured both in our office and that of another provider. The injections were performed under guidance by a third provider. As this is counter to the finding of Chou et al (1), we did our own review of the eight sources cited by the authors in their analysis of long-term follow-up of function for individuals with radiculopathy (Appendix Table 2 – Function). Of these 8 studies, 5 found significant improvement in function and pain following injection up to at least one year. Three of the studies found no long term benefit. It was notable that of the two studies showing little or no long term benefit, Arden et al (2) based their conclusion on the WEST study which did not use imaging guidance for the placement of the injection, Bush and Hilliar (3) who did not use imaging guidance and Iversen et al (4) who used anatomic markers and a 10 MHz ultrasound transducer. Four studies were performed using real time fluoroscopic imaging and found positive results with both steroid and local anesthetic injections. One study employed the careful use of anatomical markers, and large volumes (up to 20 ml) and saw long term positive results. There was not consistency with respect to corticosteroid or local anesthetic used from study to study nor with the injection volume employed.

A careful examination of the sources cited by Chou et al (1) leads us to suggest that epidural injections, employing fluoroscopic guidance, do in fact provide statistically significant long term (greater than one year) relief from radicular pain and improvement in function. Whether this effect is due to the injection itself, the local anesthetic or the corticosteroid remains an open question. The effect of the choice of corticosteroid and the injection volume employed also remains a question. Perhaps greatest conclusion that can be deduced from Chou et al (1) is the need for a standardized protocol for ECIs.

References:
1. Chou R, Hashimoto R, Friedly J, Fu R, Bougatses C, Dana T, Sullivan SD, Jarvik J. Epidural Corticosteroid Injections for radiculopathy and spinal stenosis. Ann Intern Med. 2015,;163:171-81.
2. Arden NK, Price C, Reading I., Stubing J, Hazelgrove J., Dunne C, et al; WEST Study Group. A multicentre randomized controlled trail of epidural corticosteroid injections for sciatica: the WEST study. Rheumatology (Oxford). 2005;44:1399-406.
3. Bush K, Hillier S. A controlled study of caudal epidural injections of triamcinologne plus procaine for the management of intractable sciatica. Spine. 1991;16:572-5.
4. Iversen T, Solberg TK, Romner B, Wilsgaard T, Twisk J, Anke Am, et al. Effect of caudal epidural steroid injection in chronic lumbar radiculopathy:multicentre, linded, randomize control trail. Spine. 2001;343:d5278.

Updating PRISMA to avoid conflicting evidence from Systematic Reviews and Meta Analyses
Posted on October 2, 2015
Irbaz Bin Riaz, Robert G Badgett
Department of Medicine University of Arizona, University of Kansas School of Medicine - Wichita
Conflict of Interest: None Declared
The recent meta-analysis by Chou et al (1)showed that epidural corticosteroids injections were not effective for the Spinal Stenosis. Although the results of this systematic review sponsored by Agency for Healthcare Research and Quality (AHRQ) are similar to a previous Cochrane meta-analysis (2), juxtaposition of these reviews highlights two difficulties for readers attempting to synthesize a conclusion from contradictory reviews. Firstly, regarding the inclusion of trials, two rigorous sponsors of meta-analyses, AHRQ and Cochrane, disagreed on the included studies. Of the 5 trials published during a period accessible to both analyses, only two (Cuckler and Koc) were included by both reviews. Secondly, regarding conclusions, the recent AHRQ review might have better served readers if it had reconciled its conclusion with the review by Manchikanti (3). For example, the AHRQ review could have acknowledged the review of Manchikanti and explained that the review did not pool studies and so did not have a basis for the positive conclusion that it offered. Admittedly, the difference in included studies and lack of reconciliation of conclusions did not significantly influence the outcome in this example, it certainly could happen in future reviews of more controversial topics. We propose that the PRISMA statement be amended so that when prior, relevant systematic reviews exist, authors of new reviews should provide a reconciliation of conclusions of the current and prior review, along with a table reconciling the studies included. We believe this will assist readers when they are confronted by conflicting meta-analyses.

References:

1. Chou R, Hashimoto R, Friedly J, Fu R, Bougatsos C, Dana T, et al. Epidural Corticosteroid Injections for Radiculopathy and Spinal StenosisA Systematic Review and Meta-analysisEpidural Corticosteroid Injections for Radiculopathy and Spinal Stenosis. Annals of Internal Medicine. 2015;163(5):373-81.
2. Ammendolia C, Stuber KJ, Rok E, Rampersaud R, Kennedy CA, Pennick V, et al. Nonoperative treatment for lumbar spinal stenosis with neurogenic claudication. The Cochrane database of systematic reviews. 2013;8:Cd010712.
3. Manchikanti L, Kaye AD, Manchikanti K, Boswell M, Pampati V, Hirsch J. Efficacy of epidural injections in the treatment of lumbar central spinal stenosis: a systematic review. Anesthesiology and pain medicine. 2015;5(1):e23139.
Comment
Posted on October 2, 2015
Timothy Maus, Belinda Duszynski
Multisociety Pain Workgroup
Conflict of Interest: None Declared
The publication by Chou and colleagues (1) raises significant concerns among physicians treating patients suffering from radicular pain and associated functional impairment. Fourteen medical societies formulated a consensus response to the Agency for Healthcare Quality and Research’s technology assessment, the basis of the current publication, addressing the flawed methodology and resulting aberrant conclusions. (2)

The authors assert the nihilistic position, without evidence, that back and leg pain are un-attributable to a specific cause and, therefore, include studies with patient selection by symptoms, not diagnosis. Current literature demonstrates that radicular and somatic back pain can be specifically diagnosed with systematic application of diagnostic blocks or provocative procedures, synthesized with clinical examination, advanced imaging and electrophysiology. (3) Their position has led to inclusion of heterogeneous study populations; in 29 studies of “epidural steroid injection” versus placebo, radicular pain alone was specified in 22, a mixture of radicular and back pain in six, and back pain alone in one. Correlative imaging findings were required in only 11 studies, leaving the nature of the compressive lesions and degree of compression unknown. With literature demonstrating these factors influence the natural history and efficacy of epidural steroid injections, it is inappropriate to draw conclusions from these heterogeneous studies.

The review is a corruption of evidence-based medicine -- omitting the best available evidence: high quality outcome studies of homogenous patients with contrast confirmation of injectate delivery to the target. Rather, it includes decades-old trials of unguided epidural injections by several routes. Only 7 of the 29 placebo-controlled trials utilized image guidance. Reliance on flawed RCTs leads the authors to conclude there is no evidence supporting the use of image guidance, placing it in conflict with the FDA Safe Use Initiative, which mandates image guidance.

The authors’ conclusions are based on invalid statistical analyses, primarily changes in mean pain scores, which are insufficient for drawing conclusions about effectiveness. A National Institutes of Health task force recommended the utilization of categorical outcomes for studying low back pain. (4)

When inappropriate statistics are applied to review heterogeneous populations given heterogeneous treatments, with equal weight given to outdated procedural techniques, results should be viewed with skepticism. A comprehensive examination of the literature, including high quality contemporary outcomes studies of homogenous patient populations, reveals that in carefully selected patients, epidural steroid injections performed to exacting procedural standards provide pain relief and functional improvement in patients suffering from radicular pain. (5)

Sincerely,


American Association of Neurological Surgeons
American Academy of Pain Medicine
American Academy of Physical Medicine and Rehabilitation
American College of Radiology
American Pain Society
American Society of Anesthesiologists
American Society of Neuroradiology
American Society of Regional Anesthesia and Pain Medicine
American Society of Spine Radiology
Congress of Neurological Surgeons
Spine Intervention Society
North American Neuromodulation Society
North American Spine Society
Society of Interventional Radiology



1. Chou R, Hashimoto R, Friedly J, Fu R, Bougatsos C, Dana T, Sullivan SD, Jarvik J. Epidural corticosteroid injections for radiculopathy and spinal stenosis: a systematic review and meta-analysis. Ann Intern Med 2015;163(5):373-381.
2. Multisociety Pain Work Group Letter to Dr. Elise Berliner, AHRQ; July 29, 2015. http://1515docs.org/pdfs/MPW_Letter_to_AHRQ_7-29-2015.pdf
3. DePalma MJ. Diagnostic nihilism toward low back pain: what once was accepted, should no longer be. Pain Med 2015;16(8):1453-4.
4. Deyo RA, Dworkin SF, Amtmann D, Andersson G, Borenstein D, Carragee E, Carrino J, Chou R, Cook K, DeLitto A, Goertz C, Khalsa P, Loeser J, Mackey S, Panagis J, Rainville J, Tosteson T, Turk D, Korff MV, Weiner DK. Report of the NIH Task Force on research standards for chronic low back pain. Pain Med 2014;15(8):1249-67.
5. MacVicar J, King W, Landers MH, Bogduk N. The effectiveness of lumbar transforaminal injection of steroids: a comprehensive review with systematic analysis of the published data. Pain Med 2013;14(1):14-28.

In response
Posted on October 19, 2015
Roger Chou, Robin Hashimoto, Janna Friedly
Oregon Health & Science University (Chou), University of Washington (Friedly), Spectrum Research (Hashimoto)
Conflict of Interest: Grants received by Dr. Chou, Dr. Friedly, and Dr. Hashimoto from the Agency for Healthcare Research and Quality for conducting the review that is the subject of this response.
Manchikanti et al suggest that local anesthetic epidural injections have long-term therapeutic effects and should not be considered a placebo. Our definition of placebo was based on the assumption that epidural injection therapeutic effects are primarily related to the corticosteroid (1). This is consistent with clinical practice and the rational for epidural injections, which are predicated on corticosteroid anti-inflammatory properties. Further, our findings were similar when analyses were stratified according to the type of placebo comparator used (local anesthetic epidural, saline epidural, soft tissue injection, or no injection), arguing against a specific local anesthetic therapeutic effect. In fact, one trial found that pain relief rates were higher with intramuscular saline (13%) or epidural saline (19%) than with epidural local anesthetic (7%) (1).

Maus et al suggest that diagnoses of radiculopathy were too heterogeneous to reach reliable conclusions. To clarify, all of the radiculopathy trials enrolled patients with radicular symptoms, with or without low back pain. Based on meta-regression analyses, requiring imaging correlation or a herniated disc on imaging did not impact estimates.

Maus et al critique our article for including outdated injection techniques, such as trials without imaging guidance. Yet we stratified analyses by the approach used; results for transforaminal injections (all of which were performed with imaging guidance) were similar to the overall findings. It is also incorrect to suggest that analyses were solely based on continuous outcome measures. We also found no differences in categorical measures of pain, function, or composite measures of success at any time point.

Riaz et al note that it is helpful to discuss the findings of systematic reviews in the context of prior reviews, which we did. The review cited by Riaz et al (3) did not include the largest trial on epidural corticosteroids for spinal stenosis, relied on qualitative synthesis, and classified trial results as positive based on improvement from baseline, even in the absence of differences versus a control intervention. The review (4) cited by Maus et al did not rate study quality and appeared to weight observational studies equally with or higher than randomized trials.

Manchikanti et al suggest that the report was not conducted in accordance with current standards for conducting systematic reviews. However, our review adheres to current methodological standards (5), including risk of bias assessment, evidence synthesis methods, and disclosure of financial and non-financial conflicts of interest prior to conducting the review.

References

(1) Chou R, Hashimoto R, Friedly J, Fu R, et al. Epidural corticosteroid injections for radiculopathy and spinal stenosis: A systematic review and meta-analysis. Ann Intern Med 2015;163:373-81.
(2) Ghahreman A, Ferch R, Bogduk N. The efficacy of transforaminal injection of steroids for the treatment of lumbar radicular pain. Pain Medicine 2010;11:1149-68.
(3) Manchikanti L, Kaye AD, Manchikanti K, Boswell M, Pampati V, Hirsch J. Efficacy of epidural injections in the treatment of lumbar central spinal stenosis: A systematic review. Anesth Pain Med 2015;5:e23139.
(4) MacVicar J, King W, Landers MH, Bogduk N. The effectiveness of lumbar transforaminal injection of steroids. A comprehensive review with systematic analysis of the published data. Pain Med 2013;14:14-28.
(5) Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(14)-EHC063-EF. Rockville, MD: Agency for Healthcare Research and Quality. January 2014. Chapters available at: www.effectivehealthcare.ahrq.gov.
Comment
Posted on October 23, 2015
Harry W. Daniell, MD, FACP
University of California at Davis
Conflict of Interest: None Declared

In their comprehensive review, Chou et al (1) were unable to identify factors which could be used to predict any benefit resulting from epidural corticosteroid injections (ECI), a benefit presumed to result from corticosteroid anti-inflammatory activity. None of the reviewed investigations discussed potential decreases in this activity by the pro-inflammatory activity induced by suppression of post-ECI systemic cortisone levels, which includes any associated increases in pro-inflammatory cytokines, any therapeutic benefit from ECI likely reflecting the sum of these anti-inflammatory and pro-inflammatory factors.
Cortisol levels are independently suppressed by opioids (2), benzodiazepines (3), and multiple other medications including propofol. Post-ECI cortisol decreases typically last for 2-3 weeks but Kay et al (4) demonstrated them to be enhanced and prolonged following midazolam premedication in 14 patients randomized to receive midazolam or placebo premedication before each of 3 weekly ECIs. Therapeutic benefits in their subjects were not reported.
Kirpalani et al (5) suggested less effective cervical ECI in chronic opioid consumers, with it documented in only 1 of 5 but present in 7 of 10 non-consumers (P=0.06).
After treating 3 chronic sustained-action opioid consumers hospitalized with symptomatic adrenal insufficiency soon after lumbar ECI, and four similar outpatients in a solo practice of general internal medicine, serial cortisol levels were measured after lumbar ECI in 6 additional sustained-action opioid consumers. Each of these 13 patients had received 40-80 mg of triamcinolone by ECI, 4 male and 9 female, ages 20-89 with daily morphine sulfate equivalent (MSE) consumption of 50-250 (median 90). None had known adrenal disease or had received other corticosteroids within the preceding 6 months. Each had received premedication before ECI with midazolam, fentanyl, and propofol. Post-ECI cortisol levels are presented in Figure 1.Seven subjects had reported post-ECI weakness, hypotension, or syncope which had been partially explained by chronic benzodiazepine use in 4 and anti-hypertensive medications in 4 others.
Cortisol levels remained subnormal for more than 4 weeks post-ECI in 9 of 11 patients, with none of the 13 developing convincing benefits from ECI.
Our observations support strong inhibition of cortisol formation by their combined medications, without associated clinical benefit from ECI, suggesting potential value in studies designed to examine the possibility of more predictable post-ECI benefit during limitation of post-ECI cortisol levels by minimizing the chronic and premedication use of drugs known to suppress cortisol formation, while also suggesting possible added therapeutic benefit by post-ECI cortisol replacement.

References:

1.     Chou R, Hashimoto R, Friedly J, et al. Epidural Corticosteroid Injections for Radiculopathy and Spinal Stenosis. Ann Intern Med. 2015;163:373-381.

2.     Brennan MJ. The effect of opioid therapy on endocrine function. Am J Med. 2013;126(3 suppl 1):S12-8.

3.     Arvat E, Giordano R, Grottoli S, Ghigo E. Benzodiazepines and anterior pituitary function. J Endocrinol Invest. 2002;25:735-747.

4.     Kay J, Findling JW, Raff H. Epidural triamcinolone suppresses the pituitary-adrenal axis in human subjects. Anesth Analg. 1994;79:501-505.

5.     Kirpalani D, Mitra R. Is chronic opioid use a negative predictive factor for response to cervical epidural steroid injections? J Back Musculoskelet Rehabil. 2011;24:123-127.

Challenges of studying epidural injections
Posted on November 24, 2015
Siefferman J, Kiritsy M
New York University School of Medicine
Conflict of Interest: None Declared
Studying epidural injections for “low back pain” (LBP) presents many technical challenges. LBP may involve multiple anatomical and physiological etiologies, has acute and chronic phases, and the epidural itself may be performed in a variety of ways, with different approaches and using a variety of medications. Additionally, no true placebo has been identified. The available literature evaluating the efficacy of lumbar epidural injections are highly varied in methodology, with heterogeneous diagnostic inclusion criteria, placebo controls, procedures tested, medications tested, and follow up times.
Similar to Chou and colleagues, and in advance of their publication, we also performed a systematic review of lumbar epidural injections with the specific goal of teasing out which factors effect efficacy: anatomic etiology of pain, injection approach, and type and volume of injectate. Our conclusions differed about the following:
• Epidural steroid is effective for reducing radicular pain associated with a herniated disc. (Multiple level I evidence studies)
• For undifferentiated causes of LBP, epidural injection of any variety is superior to non-epidural interventions. (Multiple level I evidence studies)
• Epidural injection (steroid or saline) is effective for reducing LBP associated with spinal stenosis. (Multiple level I and II evidence studies)
When comparing epidurals with or without steroid, 9 out of 14 studies demonstrated no difference in the degree of pain relief. However, the 4 of the 5 studies that did favor steroid were examining patients with radicular pain from herniated discs, and the fifth was a meta-analysis examining all causes of low back pain [1-5]. Therefore, there is mixed level I evidence favoring the use of epidural steroid for low back pain of any cause, but strong level I evidence supporting its use for radicular pain due to herniated disc.

References
1. Bicket, M.C., et al., Epidural injections for spinal pain: a systematic review and meta-analysis evaluating the "control" injections in randomized controlled trials. Anesthesiology, 2013. 119(4): p. 907-31.
2. Datta, R. and K.K. Upadhyay, A randomized clinical trial of three different steroid agents for treatment of low backache through the caudal route. Medical Journal Armed Forces India. 67(1): p. 25-33.
3. Ghahreman, A., R. Ferch, and N. Bogduk, The efficacy of transforaminal injection of steroids for the treatment of lumbar radicular pain. Pain Med, 2010. 11(8): p. 1149-68.
4. Manchikanti, L., et al., A randomized, controlled, double-blind trial of fluoroscopic caudal epidural injections in the treatment of lumbar disc herniation and radiculitis. Spine (Phila Pa 1976), 2011. 36(23): p. 1897-905.
5. Manchikanti, L., et al., A randomized, double-blind, active-control trial of the effectiveness of lumbar interlaminar epidural injections in disc herniation. Pain Physician, 2014. 17(1): p. E61-74.

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